FINAL Pathology topics Flashcards

Question

Local invasion in malignancy. Role of stroma. Angiogenesis.

Answer 1

LOCAL INVASION IN MALIGNANCY The translocation on neoplastic cells across tissue barriers. Can be within the same organ of from an organ to the adjacent tissue. *See steps in next topic. ROLL OF STROMA ♥Carrying blood supply, crucial to the growth of the tumor. ♥Determine the consistency of the neoplasm; certain cancers induce a dense, abundant fibrous stroma(desmoplasia) ♥Encapsulation; in benign tumors ANGIOGENESIS Blood vessels are formed in 2 processes: ♥Vasculogenesis – the formation of primitive vascular system from angioblasts during embryonic development. ♥Angiogenesis- new blood vessel development from existing vessels, primarily venules Steps of angiogenesis: 1. Vasodilation and increased permeability induced by NO and VEGF, respectively. 2. Tip cell selection (the single cell which bind the largest amount of VEGF with its receptor) This binding will induce formation of filopodia on these cells, on which more such receptors are found. Also, they secrete proteolytic enzymes which help them break the BM and surrounding matrix. 3. Migration of tip cells toward the angiogenic center (hypoxic cell f.ex.) along with proliferation of endothelial cells “stalk cells” (no gaps left behind) 4. Tubulogenesis; remodeling into capillary tubes (vacuoles fused) 5. Fusion of two stalks 6. Suppression of endothelial proliferation and migration and deposition of the BM 7. Recruitment of peri-endothelial cells (pericytes for small capillaries and fibroblasts for larger vessels) to form the mature vessel #Other GFs involved in angiogenesis: » Angiopoietins 1 & 2, PDGF, TGFβ – participate in the stabilization of the newly formed vessels by recruitment of pericytes and SM cells and deposition of CT. » FGF2 – stimulates the proliferation of endothelial cells, promotes the migration of macrophages and fibroblasts to the damaged area, and stimulates epithelial cells migration to cover epidermal wounds. Growing cancers stimulate angiogenesis. Neovascularization has a dual effect on tumor growth: 1. Perfusion supplies needed nutrients and oxygen 2. Stimulate the growth of adjacent tumor cells by secretion of GFs such as insulin-like growth factors (IGFs) and PDGF from newly formed endothelial cells. These newly-formed vessels are leaky (incompletely formed inter-endothelial junctions, and due to the presence of VEGF), permitting tumor cells and contributing to metastasis.

Answer 2

# The sequence of events that take place in the cell, leading to its replication and division THE CELL CYCLE (proliferation), to form copies of itself. # Phases of cell cycle: » Presynthetic growth phase 1 (G1) – during which the biosynthetic activities of the cell resume at a high rate, mainly production of proteins necessary for DNA replication. » DNA synthesis phase (S) – during which the DNA is replicated, forming two sister chromatids for each chromosome (one for the parental copy, and one for the maternal copy of the chromosome). » Premitotic growth phase 2 (G2) – continuation of protein production needed for division. » Mitosis (M) – a brief phase consists of nuclear division (karyokinesis), organelles distribution and cytoplasm division (cytokinesis). Stages of mitosis: » Prophase – chromatin is condensed into distinct chromosomes and their sister chromatids, bound at the centromere by cohesion protein complex; centrosomes and microtubules appear next to the nucleus. » Metaphase – nuclear membrane disintegrates; formation of kinetochores at the centromere, to which microtubules attach, and the chromosomes are convened along the equatorial plane. » Anaphase – sister chromatids are separated, and pulled apart by the microtubules connected to the kinetochore. » Telophase – formation of nuclear membrane, appearance of nucleoli, chromosomes "relax" and decondense to form chromatin. Non-dividing cells can be found in either cell cycle arrest at G1, or they exit the cycle to enter a phase called G0 => resting phase. The progression of cell cycle through the different stages depends on the ability of the cell to perform an intrinsic quality control => cell cycle checkpoints, thus preventing the replication of damaged DNA, or the mitosis of abnormal cells (arrest cell cycle to allow repair, or induce apoptosis). The regulation and transition between stages of cell cycle are done by proteins called cyclins; these protein complexes bind to CDKs (cyclin-dependent kinases), which promote the mitotic process. # CDKs are inhibited by CDIs (cyclin-dependent kinase inhibitors). The transition between cell cycle stages depends on the amount of CDKs and cyclins of the specific stage (G1/S transition => cyclin D/CDK4). BIOLOGY OF TUMOR CELL GROWTH # Carcinogenesis is the process by which normal cells are transformed into cancer cells. # Tumors arise from clonal growth of cells that have inflicted mutations in 4 classes of genes: » Growth-promoting proto-oncogenes. » Growth-inhibiting tumor suppressor genes. » Genes that regulate apoptosis. » Genes involved in DNA repair. These mutations are caused by carcinogens; Radiation Chemicals Oncogenic viruses etc. Protooncogenes Genes essential for cell growth and differentiation. A gain of function mutation to a protooncogene will transform it into an oncogene and lead to unregulated cell growth. Each of the steps in the picture involve protooncogenes. The key categories of protooncogenes; 1. Growth factors ♥PDGF- brain tumors like astrocytoma PDGF is overexpressed → binds to its receptor in an autocrine fashion → increased cell division 2. Growth factor receptors ♥HER2/NEU epidermal GF R → breast cancer 3. Signal transducers ♥RAS- active when bound to GTP. A mutation in GAP which blocks the hydrolysis of GTP to GDP leading to access signals to reach the nucleus. ♥ABL- its activity is unregulated when the ABL gene is translocated from chromosome 9 to chromosome 22 where is fuses with part of the breakpoint cluster region (BCR), resulting in the production of a hybrid protein with unregulated tyrosine kinase activity. 4. Transcription factors ♥MYC- translocation of this gene t(8,14) leads to its over expression and increased cell proliferation. 5. Cell-cycle regulators (cyclins, CDKs and CKIs) ♥Cyclin D1- translocation of this gene t(11,14) leads to its over expression and increased cell proliferation. Tumor suppressor genes Have a damping effect on the cell cycle and or promote apoptosis. A loss of function mutation to a tumor suppressor gene will lead to unregulated cell growth. *Both copies of the gene must be lost for tumor development. ♥Retinoblastoma gene – RB is in its active state (hypo-phosphorylated) and inhibits E2F transcription factor by binding it, thus preventing the transcription of cyclin E (required for G1/S transition => cyclin E-CDK2 complex). GF signaling leads to cyclin D expression, activation of cyclin D-CDK4/6 complex and the inactivation of RB by phosphorylation => mutations in RB gene render it nonfunctional. ♥P53 gene – arrest cell cycle (P21-CKI) / repair mechanisms (GAD45) / induce apoptosis (puma, noxa) ♥TGFβ pathway – inhibits proliferation by activating growth-inhibiting genes (CDIs), and suppression of growth-promoting genes (MYC, cyclins); compromising its function leads to cancer. * Limitless replicative potential – in normal (somatic) cells, telomerase enzyme is not expressed, and the telomere regions of the chromosomes are shortened until they activate cell cycle checkpoints, leading to the limitation of cell division; in cancerous cells, telomerase prevents the activation of apoptosis by adding DNA sequences to the telomere region, thus preventing activation of checkpoints. *Development of sustained angiogenesis – tumors require blood supply, and trigger the formation of new blood vessels (sprouts) from existing blood vessels in a process of angiogenesis, usually due to hypoxia Hypoxia → activation of hypoxia-induced factor 1α (HIF1α) → transcription of VEGF In normal cells, VHL protein binds to HIF1α and leads to its destruction, while in cancerous cells, HIF1α is not destroyed, leading to transcription of VEGF (vascular endothelial growth factor), and angiogenesis. PROLIFERATIVE POTENTIAL IN NEOPLASIA # Dividing cells – continuously proliferate to replace cells that eventually die. ! Hematopoietic cells in bone marrow, cells of surface epithelia (skin, oral cavity, vagina, GI tract). # Quiescent cells – dividing cells found in G0 state; these cells may enter cell cycle in response to stimulus. ! Parenchymal cells of most solid glandular tissues (liver, kidneys, pancreas). # Non-dividing cells – cannot undergo division in post-natal life (neurons, skeletal and cardiac muscle)

Answer 3

# Refers to parenchymal cells that constitute the neoplasm. DIFFERENTIATION # Differentiation of parenchymal cells is the extent to which they resemble their normal cells of origin, both morphologically and functionally. # The stroma carrying the blood supply is crucial to the growth of tumors, but has no role in differentiation between benign and malignant tumors. # The amount of stromal tissue determines the consistency of the neoplasm => certain cancers induce the formation of a dense, abundant fibrous stroma (desmoplasia), thus the tumor is hard (scirrhous tumor). BENIGN TUMORS - Well differentiated cells that resemble the normal tissue Lipoma => made of mature fat cells filled with lipid vacuoles Chondroma => made of mature chondrocytes that synthesize cartilage matrix - Low mitotic figures (in normal configuration!!) MALIGNANT TUMORS - Wide range of parenchymal differentiation, from well defined cells to completely undifferentiated cells - Resemble primitive undesignated cells The better the differentiation of the cell, the more it retains the functional capabilities of its normal cell of origin. # The more rapidly growing and the more undifferentiated a tumor is, the less likely it is to have specialized functional activity. ANAPLASIA # It is the abnormal lack of differentiation of cells, refers to the reversal in cell differentiation or to the failure of cells to differentiate in the first place. # Anaplasia is the characteristic of malignant tumors, and implies loss of the structural and functional differentiation of normal cells. # Anaplastic cells display pleomorphism PLEOMORPHISM # Variations in the size and shape of cells throughout the tumor. # In anaplastic cells: » Nucleus/cytoplasm ratio approaches 1:1 instead of the normal 1:4 or 1:6. » The nucleus is very large and hyperchromatic (darkly stained); there can be either enormous nucleus or several nuclei. » Chromatin appears rough and clumped. » Numerous and atypical mitotic figures. » Loss of normal cell polarity (the organization and orientation of a certain cell type in comparison with its neighboring cells). » Large nucleoli may appear. # Dysplasia – describes disorderly but non-neoplastic proliferation, and is the loss in the uniformity of individual cells and in their architectural orientation; usually appears in epithelium. Display pleomorphosm ! Carcinoma in situ (CIN-III) => when dysplastic changes involve the entire thickness of the epithelium. GRADING OF CANCER # Attempts to estimate the aggressiveness, or level of malignancy of the tumor, based on: » Cytologic differentiation of tumor cells. » Number of mitoses within the tumor cells. # Grading is in order of increasing anaplasia I (benign) => well-differentiated (low grade) II => moderately differentiated (intermediate grade) III => poorly differentiated (high grade) IV (malignant) => undifferentiated (high grade) # Grading varies with each form of neoplasia: » Gleason system – used to grade adenocarcinoma cells in prostate cancer. » Bloom-Richardson system – for breast cancer. » Fuhrman system – for kidney cancer. LOW GRADE TUMOR - Low mitotic rate - Less aggressive => less mitotic figures, reduced metastaltic capability - Bad prognosis => more difficult to treat (chemotherapy works on dividing cells) - Well differentiated (minimal pleomorphism) - Less favorable => usually non curable HIGH GRADE TUMOR - High mitotic rate => lots of mitotic figures, little differentiation, increased pleomorphism - Very aggressive => spreads very fast - Good prognosis => dividing cells are more easily destroyed, fast treatment results - More favorable => even that it is more violent and dangerous, it is evaluated better and can be cured faster and easier

Answer 4

# Literally means "new growth" – an abnormal mass of tissue, its growth is faster and NEOPLASIA new growth uncoordinated with that of a normal tissue. # Growth persists even after the stimulation ceases, and is independent of regulatory signals; therefore, these cells have some degree of autonomy. # Nevertheless, neoplasias depend on blood supply and some on endocrine support from the host. *Hyperplasia is coordinated, growth does NOT persist after stimulation ceases, and the cells resemble normal cells. It is polyclonal. TUMOR Can be categorized according to: ♥Tissue of origin 1.Parenchyma – made up of transformed cells, or neoplastic cells, from which the tumor originates; determines the biologic behavior of the neoplasm (blood supply) 2.Stroma – supporting, non-neoplastic c. tissue of the host, which is crucial to the growth of the neoplasm since it carries blood vessels (acts as a framework) ♥Clinical course *Both are monoclonal. Malignant neoplasm spread in one of three ways: * Seeding within body cavities (ovary) * Lymphatic spread (carcinoma) * Hematogenous spread (sarcomas, liver & lung are most involved secondary site) *Malignant; Often contains central area of ischemic necrosis because the tumor's blood supply fails to keep up with the rate of growth. NOMENCLATURE ♥Benign- names usually end with the suffix "-oma Mesenchymal origin; "-oma" attached to the name of the cell type from which the tumor arises. fibroma- fibroblasts chondroma- chondroblasts osteoma- osteoblasts Epithelial origin; based on their histogenesis and architecture adenoma- glandular origin, may or may not be glandular in structure OR epithelial origin with glandular structure papilloma- microscopic finger-like projections beyond the surface cyst adenoma- cystic structure polyp- macroscopic finger-like projections into a lumen ♥Malignant – follows that of benign tumors, with certain additions and exceptions: Mesenchymal origin; end with the suffix "-sarcoma” fibrosarcoma chondrosarcoma Leukemia/Lymphoma – malignant neoplasms arising from mesenchymal cells of the blood Epithelial origin; end with the suffix "-carcinoma”, derive from all germ-cell layers (endoderm, mesoderm, ectoderm) adenocarcinoma (cancer of glandular epithelium) squamous cell carcinoma # Mixed tumors – derived from one germ-cell layer that differentiates into more than one cell type => mixed tumor of salivary glands contains epithelial cells as well as stroma and cartilage-like tissue (pleomorphic adenoma), fibroadenoma (female breast, mixed tumor) # Teratoma – special type of mixed tumor, derived from totipotent germ cells, originating from all germ-cell layers; has the capacity to differentiate into any cell type at any location. # Choristoma – congenital anomality in which perfectly functional cells belonging to a certain organ, are found in the wrong place => nodule of well-developed pancreatic tissue is found in the submucosa of the stomach. # Hamartoma – disorganized masses of mature tissue, with characteristic differentiation of the normal surrounding tissue => disorganized hepatic cells, blood vessels and bile ducts are found within the liver.

Answer 5

# Genetic causes – chromosomal syndromes, single gene mutations etc. CONGENITAL ABNORMALITIES Defects affecting the structure and or function of organs, that are present at birth. ♥Malformation Primary errors of morphogenesis that occur due to multifactorial gene defects Can be abnormally formed, partially formed or not formed at all (agenesis). Example: neural tube defects, atresia of the esophagus. ♥Deformation A change in the normal shape or size of normally forming structures, usually due to mechanical effects. Example: the presence of too little amniotic fluid oligohydramnios → restricts the movements of the fetus → micrognathia (a small jaw). ♥Disruption When outer/extrinsic influences cause defects in organs that were previously normally developing. Example: diabetes → increased amount of insulin crossing the placenta → macrosomia (excessive birth weight of the fetus). ♥Dysplasia Abnormal organization of cells in a tissue. Example: osteogenesis imperfecta. *Sequence – single major anomality alters the subsequent development of other structures. Example: posterior urethral valves defect → obstruction of flow of urine into the bladder and hence into the amniotic fluid → oligohydramnios → micrognathia *Associations- abnormalities that occur together more frequently than expected by chance alone. Example: congenital abnormalities of the spine are consistently associated with characteristic types of urinary tract malformation. ETIOLOGY # Environmental influences – viral infections, drugs, irradiation to which the mother is exposed during pregnancy1 . *Most important virus is CMV; can cause vision problems, hearing loss, developmental delay. # Multifactorial inheritance – the combination of environmental influence on the expression of 2 or more genes. PATHOGENESIS # The timing of the prenatal defect – *first 3 weeks, injurious agents can damage enough cells to cause an abortion, or just a few cells from which the embryo can recover. *3 rd -9 th weeks the embryo is extremely susceptible to injuries since organs are being crafted out of germ cells layers. *after the 9th week, fetal period starts. Characterized by growth and maturation of organs, less susceptible to injuries, but more sensitive to growth retardation. # Genes that regulate morphogenesis – these genes are responsible for normal growth and development of the fetus. o Valproic acid is an antiepileptic disrupts expression of HOX genes (control the body plan of an embryo along the head-tail axis); leading to abnormalities o The vitamin A (retinol) derivative all-trans-retinoic acid is essential for normal development and differentiation (cleft lip and cleft palate)

Answer 6

# Chromosomal abnormalities that reflect an atypical number of chromosomes, or a CYTOGENETIC DISORDERS structural abnormality in one or more chromosomes. # These chromosomal abnormalities usually occur when there is an error in cell division following mitosis or meiosis. # Karyotype – a photographic representation of a stained metaphase stage, in which chromosomes are arranged in order of decreasing length. DOWN SYNDROME # Caused by the presence of a 3rd copy of chromosome 21, or part of it. # The presence of an extra chromosome 21 can be caused by: ♥95% Non-disjunction during meiosis. *Non-disjunction of a homologous pair of chromosomes at the 1st meiotic division. *Non-disjunction of sister chromatids during the 2nd meiotic division. The gametes formed this way have either an extra chromosome, or one less chromosome. Fertilization of such gametes by normal gametes will result in 2 types of zygotes: trisomic (3 copies of the chromosome), and monosomic (1 copy of the chromosome). These translocations are much more common than reciprocal translocations and are estimated to occur in approximately 1 in 1,000 live births. They occur only in the acrocentric chromosomes (13, 14, 15, 21, and 22) and involve the loss of the short arms of two of the chromosomes and subsequent fusion of the long arms. An example of a Robertsonian translocation involving chromosomes 14 and 21 Some patients can be mosaic => their cells consist of a mixture of cells, either with 46 or 47 chromosomes. # Clinical features – flat facial profile, mental retardation, cardiac malformations. » Approximately 40% of the patients have congenital heart disease, most commonly defects of the endocardial » Children with trisomy 21 have a 10- to 20-fold increased risk of developing acute leukemia. Both acute lymphoblastic leukemias and acute myeloid leukemias occur » Virtually all patients with trisomy 21 older than age 40 develop neuropathologic changes characteristic of Alzheimer disease » Patients with Down syndrome demonstrate abnormal immune responses that predispose them to serious infections, particularly of the lungs, and to thyroid autoimmunity Reciprocal translocations occur when genetic material is exchanged between any two nonhomologous chromosomes. » Isochromosome – when the centromere divides horizontally rather than vertically, resulting in the loss of one arm. » Deletion – a portion of the chromosome is removed. » Inversion – a portion of the chromosome has broken off, turned upside down and reattached. » Insertion – a portion of DNA was inserted in the chromosome.

Answer 7

# Recessive X-linked inheritance X-LINKED DISORDERS » Transmitted by heterozygous female carriers only to sons, who are hemizygous. » Males will express the disorder, while females will be carriers, and will only express the disorder if they are homozygous to the defected X chromosome. » Affected males will not transmit the disorder to sons, but all daughters will be carriers. » Examples: ♥Duchenne muscular dystrophyMutation in dystrophin gene → no dystrophin protein AT ALL → muscle weakness *Nerves of NMJ are fine, unlike in neuropathies where both the nerve and the muscle are effected. ♥HemophiliaA (factor VIII) / B (factor IX) → impaired hemostasis → bleeding ♥SCIDMutated ɤ chain of receptors of different cytokines → impaired humeral and cellular immunity. *Can be X-linked (T-, B+, NK-) or autosomal recessive ♥Hunter syndromeMucopolysaccharidosis type 2 ♥Lesch-Nyhan syndromeHGPRT efficiency → blocked purine synthesis → hyperuricemia Dominant X-linked inheritance » Rare variant of inheritance. » Transmission of the disease to 50% of the sons and daughters of heterozygous females. » An affected male cannot transmit the disease to sons, but all daughters will be affected. » Examples: Rett syndrome, vitamin D resistant rickets. POLYGENIC INHERITANCE # Refers to inheritance of phenotypic trait, attributed to 2 or more genes, and may be affected by the environment (height, skin color…) # Polygenic inheritance is characterized by: » The risk of expressing a polygenic (multifactorial) disorder depends on the number of mutant genes inherited. » The rate of recurrence of a disorder in first degree relatives is the same as of the affected individual => the risk is always 2%-7% that parents with an affected child will have another affected child. # This form of inheritance is characteristic for diabetes mellitus, hypertension, gout, schizophrenia and bipolar disorders. GOUT Increased consumption of purine rich foods like meat / increased production / increased degradation on cells (chemotherapy) → Purine↑↑↑ → hyperuricemia (high blood uric acid levels) → formation of sharp crystals in places with slow circulation (joints & kidney tubules) → inflammation & tissues destruction → arthritis f.ex. # There are two forms of gout: » Primary – accounts for 90% of the cases, in which the enzymatic defect is unknown (common), or it is due to a metabolic defect causing hyperuricemia, e.g., partial HGPRT deficiency. (Rare). » Secondary –in which the cause of hyperuricemia is known, but gout is NOT the main clinical disorder. e.g. Lesch-Nyhan syndrome – an X-linked disorder in which the enzyme HGPRT is deficient, results in hyperuricemia, severe neurologic disorder and self mutilation; as a result, purine synthesis via the salvage pathway is blocked. # Gout is more common in men, and includes 4 stages: 1) Asymptomatic hyperuricemia. 2) Acute arthritis. 3) Asymptomatic inter-critical period (no attacks during this time). 4) Chronic tophaceous gout.

Answer 8

# A group of autosomal recessive metabolic diseases that result from the defect in LYSOSOMAL STORAGE DISEASES lysosomal function. # When a lysosomal enzyme malfunctions, it will lead to accumulation of the partially degraded insoluble metabolites within the lysosome. # Many disorders have been identified, each resulted from the functional absence of a specific lysosomal enzyme, or proteins involved in their function. TAY-SACHS DISEASE # Deficiency1 in hexoaminidase A enzyme, responsible for breakdown of phospholipids found in neurons, named gangliosides. # When hexoaminidase A is malfunctioning, gangliosides are stored within lysosomes of neurons and glial cells throughout the CNS. # The disease is categorized to several forms according to the onset age: » Infantile – for the first 6 months, infants appear to develop normally; as neurons become swollen due to gangliosides accumulation, a mental and physical deterioration occurs, and the infant becomes blind, deaf, unable to swallow and paralytic => death before the age of 4. » Juvenile – rare, seen in children 2-10 years of age; develop cognitive and motor skill deterioration, motor speech disorder (dysarthria), swallowing difficulties (dysphagia), and lack of coordination (ataxia) => death between 5-15 years old. » Adult (late onset) – first symptoms appear during 30s and 40s; usually not fatal since progress can be stopped, characterized by loss of walking coordination and neurological deterioration, dysphagia, dysarthria, cognitive decline and psychiatric illnesses. NIEMANN-PICK DISEASES # A group of metabolic disorders caused by mutations in SMPD1 gene (types A and B), and NPC1/2 gene (type C). *sphingomyelin phosphodiesterase. # They are considered as lipid storage diseases in which lipids are accumulated in the liver, spleen, lungs, bone marrow and brain. # “zebra” bodies - lamellated myelin figures seen in electron microscopy # Niemann-Pick type A & B – characterized by deficiency of acid sphingomyelinase, and as a result accumulation of sphingomyelin. » Type A – severe deficiency in sphingomyelinase, and the accumulation of sphingomyelin in neurons and phagocytic cells; due to their high content of phagocytic cells, the organs most affected are spleen, liver, bone marrow, lymph nodes and lungs, resulting in massive visceromegaly and severe neurologic deterioration => death by the age of 3. » Type B – suffer from visceromegaly but no neurologic deterioration. # Niemann-Pick type C – caused by defect in lipid transport; affected cells accumulate cholesterol and gangliosides. » marked by ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, and psychomotor regression. GAUCHER DISEASE # Results from mutations in the gene encoding for glucocerebrosidase (a glucosylceramidase activity) found on chromosome 1, resulting in accumulation of glucosylceramide in phagocytic cells => Gaucher cells. # Classification of Gaucher disease: » Type I –(99% of cases) symptoms include enlarged liver and spleen (hepatosplenomegaly), skeletal weakness, bone disease, NO CNS INVOLVEMENT. » Type II – (Acute) begins within 6 months of birth, symptoms include liver and spleen enlargement, extensive brain damage, spasticity, and limb rigidity => death by the age of 2. » Type III – (chronic) characterized by slowly progressive, but milder neurologic symptoms, including enlarged spleen and/or liver, anemia, and respiratory problems. MUCOPOLYSACCHARIDOSES # Characterized by defective degradation of mucopolysaccharides (GAGs) in various tissues. # Mucopolysaccharides are part of ground substance, and are synthesized by fibroblasts. # Accumulation (of Heparan/Dermatan/Keratan Sulfate) results in roughness of facial features, clouding of cornea, joint stiffness, and mental retardation. # MPS is classified from 1 to 7, all of which are autosomal recessive, except type 2 (Hunter syndrome) which is X-linked. GLYCOGEN STORAGE DISEASES # Results from deficiency of any of the enzymes involved in glycogen synthesis or degradation => lead to accumulation of glycogen or abnormal form of glycogen. # Glycogen is most often stored in the cytoplasm, and sometimes within nuclei. # Glycogen storage diseases can be categorized: » Hepatic type – the liver contains enzymes that synthesize glycogen, and also enzymes that break it down; this type of disease is characterized by liver enlargement due to accumulation of glycogen, and by hypoglycemia due to failure of glucose production. ! Von Gierke disease => lack of G-6-phosphatase » Myopathic type – (McArdle syndrome – defected muscle phosphorylase) glycogen is an important energy source in skeletal muscles, so when glycolytic enzymes are defected, glycogen is accumulated, resulting in muscle weakness; characterized by cramps after exercise and failure to produce lactate during exercise. » Pompe disease – caused by deficiency of lysosomal acid maltase and associated with deposition of glycogen in different organs, but cardiomegaly is most prominent. » Brancher disease – deposition of abnormal glycogen

Answer 9

# Occurs when both alleles at a given locus are mutants. AUTOSOMAL RECESSIVE INHERITANCE # Recessive disorders are characterized by: » Parents are usually not affected, siblings may show the disease. » Siblings have 25% chance of being affected. » If the mutant gene occurs at low frequency in the population, it is most likely that the affected patient was born as a result of relatives' marriage. # Most autosomal recessive disorders have the following features: 1) The expression of the defect tends to be more uniform. 2) Complete penetration is common. 3) Onset of the disease is usually at an early age. 4) Although new mutations for recessive disorders occur, they are rarely detected clinically. 5) In many cases, enzyme proteins are affected. CYSTIC FIBROSIS # Widespread disorder of epithelial transport characterized by abnormal transport of Clacross epithelium, leading to thick viscous secretions. # This disorder affects most critically the lungs, but also the GI tract, exocrine glands (like the pancreas) and reproductive system. # Pathogenesis – the primary defect of CF is the abnormal function of an epithelial Clchannel protein encoded by CF transmembrane conductance regulator (CFTR-cystic fibrosis transmembrane conductance regulator) gene, located on chromosome 7; # The most common severe CFTR mutation is a deletion of three nucleotides coding for phenylalanine at amino acid position 508 (ΔF508). This causes misfolding so that the CFTR is unable to translocate into the plasma membrane. # mutations in this gene leave the epithelium relatively impermeable to Cl- ions, and consequently formation of more viscous secretions The impact of this defect is tissue specific: » Sweat glands –hypertonic sweat (increased concentration of salt). » Respiratory and intestinal epithelium – more mucous secretion → defective mucociliary action → accumulation of concentrated secretions that obstruct air passage. » Pancreas – abnormalities are present in 85%-90% of patients. In mild cases => accumulation of mucous in the small ducts with some dilation of the exocrine glands. In advanced cases => the ducts are completely plugged, causing atrophy of the exocrine glands and progressive fibrosis → pancreatic enzymes do not reach duodenum → defective absorption of lipids and proteins → steatorrhea (fatty stool) » Intestine – meconium ileus => thick viscid plugs of mucous obstruct the small intestine of infants. » Pulmonary changes – viscous mucous secretion of the submucosal glands of the respiratory tree; bronchioles are distended and blocked due to this secretion, associated with hyperplasia and hypertrophy of mucous-secreting cells (superimposed infections give rise to chronic bronchitis). » Liver – bile canaliculi are plugged; hepatic steatosis1 is common, and may develop into cirrhosis. » Vas deference – absent, or obstructed by thick secretion.

Answer 10

# Dominance is a relationship between alleles of a gene in which one allele masks AUTOSOMAL DOMINANT INHERITANCE the expression (phenotype) of another allele at the same locus. # Autosomal dominant inheritance affects both males and females, expressed in heterozygote. # Autosomal dominant diseases may include the following features: » Some patients do not have affected parents => new mutations occurred in the egg or sperm; their siblings are not affected. » Some individuals inherit the mutant gene but are phenotypically normal => REDUCED PENETRANCE » Some individuals may inherit the same mutant gene, but they expressed differently => VARIABLE EXPRESSIVITY. » Age of onset is delayed. » 50% reduction in the normal gene product is associated with clinical symptoms. # Reduction of 50% in enzymatic activity can be compensated; therefore the involved genes usually do not encode enzyme proteins. # Two major categories of non-enzymes proteins are affected: 1) Regulatory proteins – involved in regulation of complex metabolic pathways, such as membrane receptors and transport proteins. 2) Structural proteins – such as collagen and cytoskeletal components. # Dominant negative – when a mutated allele impairs the function of the normal allele => when the gene encoding one subunit of a multimeric protein, the product of one mutant allele can interfere with the assembly of a functional normal multimer. MARFAN SYNDROME # Autosomal dominant disorder of c. tissue, affecting fibrillin-1. # Fibrillin-1 is a glycoprotein secreted by fibroblasts and is the major component of microfibrils found in ECM. # Microfibrils serve as scaffoldings for the deposition of elastic fibers. # Fibrillin-1 is encoded by FBN1 gene found on chromosome 15. Mutant FBN1 gene acts as a dominant negative by preventing the assembly of normal microfibrils. In addition to FBN1 mutation, dysregulation of TGFβ production occurs, which results in similar features to Marfan syndrome. # Most cases of Marfan syndrome are familial (75%), the rest are sporadic (arising from mutations in germ cells). Morphology: » Skeletal abnormalities – patients are tall and thin with abnormally long legs, arms and fingers (arachnodactyly), high arch palate, hyper-extensible joints, and spinal and chest deformities. » Ocular changes – bilateral dislocation of the lens (weak suspensory ligaments). » Cardiovascular system – fragmentation of elastic fibers in tunica media of the aorta, leading to aneurysm and death due to aortic rupture; cardiac valves, mainly the mitral, may be extensively distended and result in regurgitation. EHLER-DANLOS SYNDROME Characterized by defects in collagen synthesis or structure; all are single gene disorders, and can be inherited as autosomal recessive, autosomal dominant or X-linked. # Tissues affected are rich in collagen (skin, joints, ligaments etc.). Morphology: » Skin is hyper-extensible, extremely fragile and lacks the normal tensile strength. » Joints are hyper-mobile and prone to dislocations. » Internal organs may rupture (colon, large vessels), cornea may rupture. # Classification of EDSs divides them into 6 groups. # The molecular bases of three of the most common EDS are: 1) Deficiency of lysyl hydroxylase – kyphoscoliosis (type VI) Hydroxylasion of lysyl residues decreases in collagen types I & III, interferes with normal cross-links of collagen molecules; inherited as autosomal recessive disorder. 2) Deficient synthesis of type III collagen – vascular (type IV) Resulting from mutations affecting COL3A1 gene (structural); inherited as an autosomal dominant disorder, characterized by weakness of vessels and intestinal wall 3) Deficient synthesis of type V collagen due to mutations in COL5A1 and COL5A2 is inherited as an autosomal dominant disorder and results in classical EDS..

Answer 11

# Sexual transmission – HIV is found in semen and in vaginal and cervical fluids. AIDS It is caused by the human immunodeficiency virus (HIV) which targets the cells of the immune system (macrophages, DCs and T helper cells) → profound immunosuppression → increased risk of opportunistic infections and tumors that a healthy immune system would have been able to fend off. Transmission This mode of transmission accounts for over 75% of cases, especially male to male transmission. It is aided by other STDs that cause genital ulceration (syphilis, herpes simplex). # Parenteral transmission – intravenous drug abuse. # Mother-to-child transmission MTCT – in the uterus (transplacental), during delivery or via ingestion of contaminated breast milk. Structure: ♥Lipid envelope- originates from the host cell membrane, contains transmembrane glycoproteins; *gp-120- for the 1ry attachment of the virus to the CD4 molecule of the host cell *gp-41- for the fusion with the host cell membrane. ♥Matrix protein- gp-17 ♥Capsid protein- gp-24 ♥Nucleocapsid protein- gp-7 (encloses the nucleic acid) ♥2 copies of (+)SSRNA ♥Viral enzymes (RIP); *Reverse transcriptase *Integrase *Protease The 2 types of HIV 1. HIV type 1 – more common type associated with AIDS in US, Europe and Central Africa. *M (major); more common, and are further divided into subtypes (A-J), which differ in their geographic distribution and their mode of transmission. *O (outlier) 2. HIV type 2 – cause similar disease principally in West Africa and Southern Asia. *Both types are genetically different, but antigenically similar. Pathogenesis →gp120 binds CD4, resulting in a conformational change and exposure of new recognition sites for CCR5 and CXCR4 (cell surface chemokines), which serve as co-receptors. The active site for T helper cells is CXCR4 and CCR5 for other CD4+ cells (macrophages, DCs…). →gp41 undergoes a conformational change that allows it to be inserted into the target cell membrane. →Once internalized, the viral genome undergoes reverse transcription, leading to the formation of complementary DNA (cDNA) that may stay in the cytoplasm or transfer into the nucleus to be integrated into the host genome (in dividing T cells). *After integration, the viral DNA may remain non-transcribed for months or years, and the infection becomes latent; transcription and formation of viral particles will eventually lead to cell death. *Maraviroc- post exposure prophylaxis (within 72 hours) Progression of HIV infection 1. Acute phase The R5 strain will bind to the CCR5 co-receptor of DCs in the epithelial or mucosal tissues. *Initially it only has affinity for this co-receptor, later it acquires affinity for the CXCR4 co-receptor on T helper cells. The DC captures the virus and migrates to the lymph nodes, where it presents it to other CD4+ cells. This leads to a large spike in the virus replication → viremia; increased amounts of viral particles found in blood Viremia is accompanied by a variety of non-specific symptoms (sore throat, fever, rash etc.). 2. Chronic phase → The immune system remains competent at handling most opportunistic infections => CLINICAL LATENCY PERIOD →Destruction of CD4+ T cells steadily progresses, and their number steadily declines. →No symptoms detectable 3. Crisis phase → Low CD4+ T cells count (<500 cells/μL). →Patients develop serious opportunistic infections, secondary neoplasms, and neurologic manifestations. CLINICAL FEATURES # Opportunistic infections – pneumonia, herpes, tuberculosis, influenza. # Neoplasms – Kaposi sarcoma, non-Hodgkin lymphoma, cervical cancer. # CNS involvement – aseptic meningitis, vascular myelopathy, progressive encephalopathy

Answer 12

(check the note, lots of diagrams) BRUTON'S DISEASE – X-LINKED AGAMMAGLOBULINEMIA X-linked disease, characterized by the failure of pre-B cells to differentiate into B cells, resulting in the absence of γ-globulins in the blood mmature B cells have a BCR (a membrane-bund antibody). Pre B cells have “pre B cell receptors” which are composed of two heavy chains only. The BTK gene (Bruton’s tyrosine kinase) plays an important role in the further assembly of this receptor, and it is found on the X chromosome. In XLA there is a mutation in this gene → B cell maturation stopped at pre B cell stage → no B cells leave the bone marrow → far fever/complete lack of circulating plasma cells → far fever/complete lack of circulating antibodies. Because this disease is X-linked recessive it almost exclusively manifested as a disease in men (one X and one Y chromosome). Women with a mutation in this gene in one x chromosome only are carriers only. *Sometimes XLA can develop sporadically rather than being inherited from a parent →6 months- supply on Igs supplied through the placenta runs out Although B cell and antibody mediated immune is compromised, T cell mediated immunity remains intact so that some infection can be cleared Treatment; Life-long intravenous infusion of immunoglobulins from a variety of individuals (passive immunity). Antibiotic in current infections. ISOLATED IgA DEFICIENCY A congenital B cell immunodeficiency in which the terminal differentiation of IgA-secreting B cells to plasma cells is blocked. IgA antibodies provide protection against microbes that multiply in body secretions (tears , saliva , sweat , colostrum and secretions from the GI tract, the genitourinary tract , prostate and respiratory epithelium). Without them, the mucosal antigen exposure increases and the body makes more IgE antibodies against inhalants and foodstuff → hyper allergy *Usually asymptomatic but symptoms are generally diherria and pulmonary infections DIGEORGE SYNDROME / 22q11.2 DELETION SYNDROME A small portion of chromosome 22 is deleted (22q11.2) → developmental abnormalities. This deletion is referred to as a microdeletion because this small portion contains 30 genes (less than 5 million). One of these genes is TBX1, which is involved in the normal development of the 3rd and 4th pharyngeal pouches. (partial/complete) Digeorge syndrome → (mild to moderate/severe) thymic dysfunction → (not fatal/fatal) deficiency in mature T cells. * B cells and serum immunoglobulins are unaffected. The 22q11.2 region encodes genes which can affect other organs and tissues. Symptoms include: » Cardiac abnormalities. » Facial abnormalities (cleft palate, feces-long face/small teeth…) » Mental disorders SEVERE COMBINED IMMUNODEFICIENCY (SCID) A genetic disorder in which both humoral (antibodies, complement proteins…) and cellmediated immunities are impaired, caused by mutations in the gene encoding the common γ-chain of the receptors for different cytokines (IL-2, 4, 7, 9, 15). *IL-7 is very important since it is responsible for stimulating the survival and expansion of immature B cells and T cells precursors. SCID can be: ♥X-linked (T- B+ NK-) ♥Autosomal recessive *Adenosine deaminase (ADA) deficiency is the most common. Mutation in the enzyme → accumulation of adenosine → inhibits DNA synthesis → immune cells are not able to mature (T- B- NK-) *MHC-II gene mutation (T- B+ NK+) → CD4+ T-cell defect *RAG gene mutation (T- B- NK+) → DNA Rearrangement defect Treatment: bone marrow transplantation and gene therapy.

Answer 13

# An autoimmune disease characterized by excessive fibrosis throughout the body, THE SYNDROME A chronic systemic autoimmune disease in which there is a destruction of the exocrine glands: *Lacrimal → dry eyes “keratoconjunctivitis sicca” *Salivary → dry mouth “xerostomia” → increased risk of CARIES! *Sweat → dry skin “xerosis” *Mucous → dry vagina and pain during intercourse “dyspareunia” dry nose and decrease in smell sensation Sjogren’s syndrome is most common in middle aged women Has 2 forms: 1. Primary – known as sicca syndrome, occurs as an isolated disorder where autoantibodies are produced against 2 nuclear antigens => SS-A (Ro) and SS-B (La) (Sjogren’s syndrome antigen A/B, which are ribonucleoproteins) 2. Secondary – associated with another autoimmune disease (RA most commonly). * High risk of develop non-Hodgkin B cell lymphoma (Marginal zone)- unilateral enlargement of the parotid gland. PATHOGENESIS Loss of tolerance in the helper T cells population to ductal epithelial cells of exocrine glands → duct obstruction → atrophy SYSTEMIC SCLEROSIS including the skin, GI tract, lungs, kidneys, heart and skeletal muscle. # Can be classified into 2 groups: » Diffuse scleroderma – initial widespread skin involvement, with rapid progression and early visceral involvement. » Limited scleroderma – mild skin involvement (fingers, face), relatively benign course with late visceral involvement; also called CREST syndrome. Calcinosis => calcification of fingertips Raynaud syndrome => vasospastic disorder causing fingers discoloration Esophageal dysmotility => acid reflux Sclerodactyly => claw hands Telangiectasia => dilation of superficial vessels PATHOGENESIS # Fibroblasts activation with excessive fibrosis. # Helper T cells are activated by an unknown trigger => accumulate in the skin and release cytokines that activate mast cells and macrophages => release fibrogenic cytokines (IL-1, PDGF, TGFβ, FGF). # B cells are also activated => indicated by the presence of hypergammaglobulinemia and ANAs. # 2 types of ANAs are produced: » Anti-DNA topoisomerase I (anti-Scl70) – highly specific for diffuse scleroderma, present in 70% of patients. » Anti-centromere antibodies – highly specific for limited scleroderma (CERST), present in 90% of patients. # Microvascular disease is present early in the course of systemic sclerosis, caused by local T cells reaction, followed by platelets aggregation and release of platelet factors that trigger fibrosis of the adventitia, thus narrowing the microvasculature. MORPHOLOGY # Skin Diffuse sclerotic atrophy with edema (doughy consistency); with progression, replaced by fibrosis of the dermis tightly boubd to subcutaneous structures Increase in compact collagen in the dermis along with thinning of the epidermis. Small vessels show thickening of basement membrane, endothelial cell damage and partial occlusion; arterioles also thicken. GI tract Progressive atrophy, collagenous replacement of the muscular layers (most severe in esophagus) => dysfunction of the esophageal sphincter resulting in gastric reflux Ulceration of the mucosa, excessive collagenization of lamina propria and submucosa Loss of microvilli and villi in small intestine => malabsorption # Musculoskeletal system Synovial hyperplasia and inflammation At later stage => fibrosis # Lungs Fibrosis of small pulmonary vessels => pulmonary hypertension Pulmonary vascular endothelial dusfunction # Kidneys Thickened wall of intertubular arteries => cell proliferation with deposition of glycoproteins and mucopolysaccharides Hypertension not always occur, but when it does, it is associated with fibrinoid necrosis, thrombosis and infarction of arterioles No glomerular change Heart Patchy myocardial fibrosis Thickening of intramyocardial arterioles, caused by microvascular injury Changes in lungs result in right ventricular hypertrophy and failure CLINICAL COURSE # SS affects woman x3 then man (peak btw 50-60) # Distinctive feature of SS is the striking cutaneous involvement # Almost all patient exhibit Raynaud phenomenon

Answer 14

# Histologically, the affected joints show chronic synovitis, characterized by: RHEUMATOID ARTHRITIS A systemic, chronic inflammatory disease affecting primarily the synovial joints. Usually 5 or more joints are affected symmetrically; firstly, the small joints (MCP, MTP) and as it worsens, bigger joints (shoulders, elbows, knees and ankles). Extra articular involvement develops in the skin, heart, blood vessels, muscles and lungs. PATHOGENESIS Interplay of: *environmental factors e.g. infection, smoking → citrullination *genetic factors (susceptibility genes)- * Associated with HLA-DR4, and polymorphism in PTPN22 gene. APCs do not recognize those antigens as self-antigens and carry them to the lymph nodes, where they are presented to TH1 and TH17→ TH cells stimulate B cells to mature into plasma cells and secrete specific antibodies → Antibodies and T helper cells reach synovial joints via the circulation; 1. T-cells (picture) 2. Antibodies bind to citrullinated antigens → formation of immune complexes → chronic inflammation and cell injury → angiogenesis → more immune cells Over time the PANNUS can damage the cartilage (synovial cells secrete proteases), other soft tissues and also erode bone. Eventually, the pannus fills the joint space → fibrosis and calcification result in permanent ankylosis (stiff joint). *Destruction of tendons, ligaments and joint capsules produce the characteristic deformities => radial deviation of the wrist, ulnar deviation of the fingers, bending of fingers… MORPHOLOGY » Synovial cell hyperplasia and proliferation. » Infiltration of inflammatory cells, forming lymphoid follicles in the synivium composed of helper T cells, plasma cells and macrophages. » Increased vascularity due to angiogenesis. » Aggregates of fibrin on synovial surface. » Increased osteoclasts activity. CLINICAL COURSE # Weakness, fever, malaise (a feeling of general discomfort, uneasiness or pain). # Swelling of joints; limiting movements, stiffness especially in the morning.

Answer 15

# Acute necrotizing vasculitis – affects small arteries and arterioles; characterized by SLE A multisystem autoimmune disease that can affect any part of the body, but mostly affects the skin, kidneys, serosal membranes, joints and heart. The diagnosis is established if the patient shows at least 4 symptoms: ➔ Malar rash (butterfly) ➔ Discoid rash ➔ Photosensitivity ➔ Oral ulcers ➔ Serositis (pleuritis, pericarditis…) ➔ Neurological disorders ➔ Renal disorders ➔ Arthritis ➔ Hematologic disorders (anemia, thrombocytopenia, leukopenia…) ➔ ANA PATHOMECHANISM the pathogenesis of SLE involves a combination of environmental factors (UV, smoking, medication, estrogen...) and genetic factors (less effective clearance of nuclear antigens released from apoptotic cells, and failure of T cells and B cells tolerance to those selfantigens). The major defect in SLE is the failure to maintain self-tolerance. Tissue damage occurs in 2 pathways: 1) Deposition of antigen-antibody complexes (type III hypersensitivity). 2) Production of large number of autoantibodies, mainly ANA (type II hypersensitivity). *See topic 21 Spectrum of antibodies: » Anti-nuclear antibodies (ANAs) – produced against nuclear antigens (DNA => Smith antibodies, histones, non-histone proteins, nucleolar antigens). » Anti-phospholipid antibodies – directed against phospholipids of cell membrane, but also disturb coagulation process, since phospholipids are important in the formation of blood clots ("lupus antibodies"). » Antibodies against blood cells – RBCs => hemolytic anemia, platelets => thrombocytopenia, lymphocytes => lymphopenia. MORPHOLOGY necrosis and fibrinous depositions within vessel walls, resulting in fibrous thickening and lumen narrowing. # Joint involvement – swelling and non-specific mononuclear cell infiltration in synovial membranes. # Skin involvement – malar rash (butterfly pattern), worsened by UV light (photosensitivity) due to liquefactive degeneration of basement membrane and edema in dermis-epidermis junction. # CNS involvement – focal neurologic deficits, often related to vascular lesions causing focal cerebral microinfarctions. # Spleen – moderately enlarged with capsular fibrous thickening and follicular hyperplasia. # Serous membranes – pericardium and pleura show inflammatory changes from serous effusions to fibrous exudation. # Heart – manifested in the form of endocarditis, myocarditis and valvular lesions (Libman-Sacks endocarditis which are vegetations formed on the mitral valve). # Kidney involvement – most important clinical feature of SLE, causing renal failure which is the most common; the pathogenesis of all forms of glomerulonephritis in SLE involve deposition of antigen-antibody complexes within the glomeruli: » Class I (5%) – rare, looks normal by light, electron and immunoflorescence microscopy (no histological signs of inflammation). » Class II – mesangial lupus glomerulonephritis (10%-25%) – immune complexes are deposited in the mesangium (increased mesangial matrix). » Class III – focal proliferative glomerulonephritis (20%-35%) – in an otherwise normal glomerulus, 1-2 areas show swelling and proliferation of endothelial and mesangial cells, with neutrophils infiltration and fibrinoid deposits; associated with hemturia and proteinuria. » Class IV – diffuse proliferative glomerulonephritis (35%-60%) – most severe form, most glomeruli show endothelial and mesangial proliferation affecting the entire glomerulus; subendothelial immune complexes deposition; patients suffer from hemturia, proteinuria, hypertension, and renal insufficiency. » Class V – membranous glomerulonephritis (10%-15%) – characterized by widespread thickening of the capillary wall caused by deposition of basement membrane like material, and accumulation of immune complexes; patients have severe proteinuria.

Answer 16

SELF-TOLERANCE Immunological tolerance – the lack of response of the immune system to an antigen. ANTIGEN SPECIFIC! Unlike immunosuppression. Self-tolerance – the immune system of an individual does not develop an immune response toward self-antigens. Failure of self-tolerance results in autoimmunity. During development of B and T lymphocytes, antigen receptors are produced, some of them are a match to the body's own antigens. In order to eliminate self-reactive lymphocytes, 2 groups of mechanisms arise: 1. Central tolerance The elimination of self-reactive B and T cells during their maturation in the 1ry lymphoid organs (bone marrow & thymus). Use AID (antigen-induced death) ♥BM: Non-autoreactive immature B cells can leave the bone marrow and finish the differentiation process. B cells that bind membrane bound antigens will be retained in the bone marrow. They will undergo “receptor editing” until they are unable to bind self-antigens. If they are not able to produce a non-autoreactive BCR, they are eliminated by apoptosis. * Not all self-antigens present in the bone marrow are capable of crosslinking the antigen receptors of autoreactive B cells. Monovalent self-antigens (containing one copy of a given epitope) induce an anergic state in developing immature B cells. Anergic autoreactive B cells can leave the bone marrow, but remain inactive and die within a few days in the circulation. ♥Thymus: Self antigens are processed and presented by APCs (AIRE gene – autoimmune regulator), and any developing T cell that expresses a receptor to those antigens is negatively selected and eliminated by apoptosis. 2. Peripheral tolerance The mechanisms of central tolerance are effective, yet some autoreactive clones still reach the peripheral tissues. Autoreactive T and B cell clones escaping central tolerance mechanisms in the primary lymphoid organs are eliminated or inhibited by the so-called peripheral tolerance mechanisms. ♥B cells First activation signal; Ag-mediated crosslinking of BCR. PAMPS Second activation signal; binding of BCR to Ag presented on MHC-II & CD40-CD40 ligand Third activation signal; cytokines secreted by T helper cell (IL-4, IL-5) If all activation signals are present, B cells will proliferate and mature into plasma cells. If a signal is lacking, the B cell will become anergic. ♥T cells Anergy-functional inactivation Negative / lack of co-stimulation. Suppression (by regulatory T cells) S ecretion of immunosuppressive cytokines (IL-10, TGFβ) Expression of IL-2 R ( CD25), consuming IL-2, and not producing it. Induce expression of CTLA4 on effector T cells. Break down DAMPs (ATP, ADP..) to adenosine; a suppressive mediator Deletion T cells that recognize self-antigens with high affinity in the absence of co-stimulation will undergo apoptosis: Intrinsic mitochondrial pathway / extrinsic death receptor pathway MECHANISMS OF AUTOIMMUNE DISEASE →Gene mutations Autoimmune diseases have a tendency to run in families. Several autoimmune diseases are linked with mutations in the HLA locus (genes that code for MHC proteins) on chromosome 6. The role of MHC genes in autoimmunity is still not clear, especially because they do not distinguish between self and foreign peptide antigens. Several non-HLA genes also confer susceptibility to type I diabetes, including polymorphisms within the gene encoding insulin itself, as well as CTLA4 and PTPN22 (protein tyrosine phosphatase) both are thought to inhibit T cell responses → over responsiveness *Type I diabetes mellites- loss of self-tolerance of T cells → destruction of pancreatic β cells → NO insulin production → blood glucose↑ *Multiple sclerosis- loss of self-tolerance to myelin proteins → demyelination of neurons in the CNS → neurologic deficits *Rheumatoid arthritis- a systemic, chronic inflammatory disease affecting many tissues but principally attacking the joints to produce a nonsuppurative proliferative synovitis that frequently progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis. →Infections Some pathogens that invade cells express proteins which are very similar in structure to self-antigens. When the infected cell will present the pathogenic antigen, the immune system will be triggered, and Plasma cells will start producing antibodies specific to those antigens. BUT these antibodies will also bind to the similar self-antigens, marking healthy cells for attack. *Rheumatic heart disease- streptococcal infections can produce antigens which are similar to self-antigens found in the heart →Privileged sites Certain parts of the body like the cornea are out of reach of most leukocytes because they contain virtually no BVs or lymphatics. Physical damage to these sites will cause self-antigens, which have not yet to be encountered by the immune system, to enter the circulation and be recognized as foreign antigens and destroyed. →Modification of an antigen – in drug induced situations, the drug metabolites initiate conformational change of the antigen. →Epitope spreading – in the thymus, T cells are not exposed to all self-antigens, each antigen has several epitopes, and only the most dominant ones are presented to T cells in the thymus; this, T cells are reactive to the less dominant epitopes are NOT eliminated. →Failure of T cell suppression – insufficient production of IL-10. →Lack of AICD – defect in the interaction of Fas and Fas ligand → SLE

Answer 17

Opportunistic infections – Definition: * An infection by a microorganism that normally does not cause disease but becomes pathogenic when the body's immune system is impaired and unable to fight off infection. * account for the majority of deaths in AIDS and in other diseases with immunosuppression. Major opportunistic infections: Fungal infections: Fungi may cause superficial or deep infections: * Superficial infections involve the skin, hair and nails. They are called dermatophytes. * Deep fungal infections can spread systematically and invade tissues, destroying vital organs in immunocompromised hosts. Fungi are divided into endemic and opportunistic species: * Endemic are invasive species that are limited to particular geographic region. * Opportunistic fungi (e.g. Candida, Aspergilus, Mucor, Cryptococcus) they either colonize individuals or are encountered from environmenta sources. In immunodeficient individuals opportunistic fungi give rise to life threatening invasive infections characterized by tissue necrosis, hemorrhage ect.. patiants with AIDS often are infected by opportunistic fungus Pneomocystis jiroveci (=carinii). Examples: * Pneumocystosis: ❖ caused by P. jiroveci ❖ pneumonia or disseminated disease ❖ OI that causes most often death in AIDS ❖ treatable; prophylaxis possible ❖ transmission: via respiratory tract * Candidiasis (’Thrush’) ❖ caused by C. albicans ❖ oral cavity, trachea, lung, oesophagus * Cryptococcosis ❖ caused by cryptococci (fungi!) ❖ enters via respiratory tract / lung ❖ spreads to lepromeninges -> meningitis ❖ may also affect skin, skeletal system, urinary tract ❖ high mortality ❖ can be treated * Histoplasmosis ❖ caused by H. Capsulatum ❖ by inhalation (birds, bat ‘dropping’) ❖ intracellular parasite in macrophages ❖ epitheloid cell granulomas with necrosis; later fibrosis, calcification; yeasts detectable by silver impregnation ❖ Diff. Dg: TB, sarcoidosis, coccidioidomycosis ❖ in fulminant (imunosuppressed): no granulomas, macrophages filled with fungal yeasts throughout the body. Bacterial infections: * Mycobacteriosis ❖ TB – pulmonary or extrapulmonary. M. tuberculosis block the fusion of of the phagolysosome allowing the bacteria to proliferate unchecked within the macrophage. ❖ ‘atypical’: M. avium intracellulare – often disseminated Usual pathogens * S. aureus, S. pneumoniae, H. influenzae, Salmonella * pneumonia; entiritis; meningitis; disseminated (sepsis) Viral infections: * Viruses are obligate intracellular. * Cytomegalovirus (CMV)- infected cells are enlarged and show a large eosinophilic nuclear inclusion and smaller basophilic cytoplasmic inclusion. ❖ very common, most people had CMV by 40y; stays dormant ❖ via saliva, blood, semen ❖ throat, lung, GI, meningoencephalitis, retinitis * Herpes simplex virus (HSV 1,2)- large nuclear inclusion surrounded by a clear halo. ❖ very common ❖ gingivostomatitis (HSV-1); genital herpes (HSV-2) ❖ keratitis, encephalitis, hepatitis, pneumonia ❖ disseminated to viscera * KSHV/HHV-8 ❖ Kaposi sarcoma * EBV ❖ B-cell lymphomas (e.g. Burkitt lymphoma) * Varicella Zoster Virus (VZV) ❖ cause of chickenpox and shingles ❖ in immunosuppressed: encephalitis, transverse myelitis, necrotising visceral lesions

Answer 18

# A chronic granulomatous disease caused by various strains of Mycobacteria, mainly Mycobacterium TUBERCULOSIS tuberculosis. # Typically attacks the lungs; air-borne, chronic granulomatous disease. # Typically, the centers of tubercular granulomas undergo caseous necrosis. # Two forms of tuberculosis PULMONARY FORM Spreads by inhalation of droplets containing the organism (Mycobacterium tuberculosis) => Tubercle bacillus NON-PULMONARY FORM Most often is caused by ingestion of infected milk (Mycobacterium bovis). Mycobacteria species are obligate aerobes, slowly growing; growth is inhibited by low pH (<6.5) and by long chain fatty acids. # It is important that infection be differentiated from disease. Infection may or may not cause clinically tissue damage. Such people are infected but do not have active disease and therefore cannot transmit to others. # The Mantoux test (DHR)- a positive tuberculin skin test signifies cell mediated hypersensitivitiy to tubercular antigens. It does not differentiate btw infection and disease. False negative may be produce by viral infection, Hodgkin lymphoma ect. # Only a small fraction of those who contract an infection develop active disease. PRIMARY TUBERCULOSIS # Develops in previously unexposed, and therefore unsensitized, persons. # Inhaled bacilli in distal airspaces of the middle portion of the lung, close to the pleura. # As sensitization develops, an area of 1-1.5 cm of gray-white inflammatory dense mass appears => Ghon focus, its center usually undergoes caseous necrosis. The bacilli then drain into regional lymph nodes => Ghon complex – the combination of parenchymal lesion and nodal involvement. Ghon complex undergoes progressive fibrosis, followed by calcification => Ranke complex. Histologicall appearance – granulomatous inflammation, with the presence of giant cells and epitheloid histiocytes. The major consequences of primary TB: » Induces hypersensitivity (DTH). » The foci (locations) of scarring may harbor viable bacilli for years, and serve as a source for reactivation (when host defenses are compromised). » Progressive primary TB – occurs in individuals who are immunocompramised (AIDS), elderly people or malnourished children. SECONDARY TUBERCULOSIS (reactivation tuberculosis) # Arises in a previously sensitized host, by activating Ghon complexes, with spread to a new pulmonary or extra pulmonary site or by exogenous reinfection. Secondary pulmonary tuberculosis is classically localized to the apex of one or both upper lobes. Due to pre-existing hypersensitivity, the bacilli excite a large tissue response that tends to wall off the focus => regional lymph nodes are less involved. Cavitations occur more frequently, resulting in dissemination along the airways. Increased risk of TB exists in all stages of HIV, the manifeatation differ depending on the degree of immunosuppression: » Less severe immunosuppression(CD4+ count>300 cells/mm3 ) present with "usual" secondary TB => apical disease with cavitations. » Advanced immunosuppression (DC4+ count<200 cells/mm3 ) present with symptoms similar to primary TB => middle lobes, lymph nodes involvement. Morphology – » Small focus of solid mass, ~2cm, next to apical pleura. » Sharply defined, firm, gray-white to yellow areas that have a variable amount of central caseous necrosis and peripheral fibrosis. » Histologically, granulomatous inflammation can be seen. Secondary TB (localized, apical) may heal either spontaneously or after therapy, or it may progress along several pathways: » Progressive pulmonary TB – the apical lesion enlarges with expansion of the area of cessation; erosion into a bronchus allows the evacuation of the caseous center, creating an irregular cavity lined by caseous material, and the erosion of blood vessels results in hemoptysis (coughing out blood). » Military pulmonary disease – occurs when organisms drain through the lymph vessels that drain into lymphatic ducts and from there to the venous system => right side of the heart => pulmonary arteries; small, yellow-white solid masses are scattered through the lung parenchyma. With progressive pulmonary TB, the pleural cavity is involved and serous pleural effusions, tuberculous empyema (pus) or fibrous pleuritis may develop. » Systemic miliary TB – when infective foci in the lung spread through pulmonary veins to the left heart and to systemic circulation (liver, BM, spleen ect..) » Isolated-organ TB – usually involves the meninges, kidneys, adrenal glands, bones and fallopian tubes; in vertebrae it is called Pott disease. » Lymphadenitis – most frequent form of extra pulmonary TB, usually occurring in the cervical region. » Intestinal TB – by drinking of contaminated milk; organisms are trapped in the lymphoid tissue of large and small intestine. PATHOGENESIS # The Mycobacteria are ingested by macrophages, but inhibit their normal bactericidal responses by manipulation of endosomal pH => impaired phagolysosome formation. # The bacteria proliferate within the alveolar macrophages, resulting in bacteremia and seeding in multiple sites. Despite the bateremia, most persons at this stage are asymptomatic or have a mild flu like illness. [ in some people with NRAMPI gene- natural resistance ssociated macrophage protein I, the disease may progress from this point without immune response]. # After 3 weeks, cell-mediated immunity develops (tissue hypersensitivity) => bacterial antigens reach the lymph nodes, and presented bound to MHC-II by DCs to CD4+ T-cells. # Under the influence of IL-12 (secreted by macrophages), CD4+ T-cells proliferate into TH1 subset, capable of secreting IFNγ => activating macrophages. # Activated macrophages release mediators such as TNF (recruitment of monocytes which go through activation and differentiate into “epitheloid histiocytes” that characterize the granulomas response), NO (by inducible nitric oxide synthase- antibacterial), and reactive oxygen species. # Immunity to a tubercular infection is primarly mediated by THI cells, which stimulate macrophage to kill bacteria! CLINICAL COURSE # Onset is asymptomatic. # Systemic symptoms related to cytokine release (TNF, IL-1) by activated macrophages, include malaise (nausea), anorexia, weight loss and fever. With progression of the disease => increasing amount of sputum (first mucoid, later purulent); when cavitations appear, the sputum will contain tubercle bacilli. Some degree of hemoptysis. # Pleuritic pain when the infection reaches pleural surface. Extrapulmonary manifestation depend on the organ. # Amyloidosis may develop in persistent cases.

Answer 19

# Occurs when immunologically competent T cells are transplanted into immunologically TRANSPLANT REJECTION All patients have some form of an immunological reaction to a transplanted tissue; except for in the case of identical twins or autograft (Tissue transplanted from one part of the body to another in the same individual). Important term to define first: allograft- the transplant of an organ or tissue from one individual to another of the same species. Rejection of allografts is an immunologic reaction to the MHC molecules present on the cells of the donor’s organ, which are highly polymorphic (no 2 individuals are likely to express the same set of MHC). *Tissue typing- a procedure in which the tissues of a prospective donor and recipient are tested for compatibility prior to transplantation. There are 2 main mechanisms by which the host immune system recognizes and responds to grafts: 1. Direct recognition – APCs in the graft is recognized by T-cells of the recipient, which are stimulated by direct interaction with MHC molecules expressed on the graft. 2. Indirect recognition– the APCs of the host pick up the MHC molecules of the donor, process and present them to T-helper cells of the recipient; in this case, cytotoxic T cells are not involved in killing the graft, but production of antibodies occur The rejection of the graft is made by: T-cell mediated rejection – cytotoxic T cells directly kill cells of the grafted tissue; helper T cells secrete cytokines that trigger DTH reaction, with increased vascular permeability and local accumulation of lymphocytes and macrophages. Antibody-mediated rejection – the antibodies of the host are directed against graft MHC and activate complement as well as recruitment of leukocytes. Categories of graft rejection: ♥Hyperacute rejection – occurs within minutes to a few hours after transplantation due to pre-existing humoral immunity (antibodies); the graft is characterized by acute arteritis, vessel thrombosis and ischemic necrosis. ♥Acute rejection – may occur within days to weeks after transplantation in a nonimmunosuppressed host; it is caused by both cellular and humoral immunity: *Acute cellular rejection – extensive interstitial infiltration of helper and cytotoxic T cells, accompanied by edema and mild hemorrhage, and renal failure. *Acute humoral rejection – characterized by necrotizing vasculitis with endothelial cell necrosis, deposition of antibodies, complement and fibron. ♥Chronic rejection – occurs late after transplantation with increased creatinine in serum (indicates renal dysfunction), dominated by vascular changes, interstitial fibrosis and loss of renal parenchyma. GRAFT VS. HOST REACTION compromised recipients during bone marrow transplantation, or solid organs rich in lymphoid tissue. # The host cannot reject the graft, but the T cells of the donor recognize the tissues of the recipient as foreign and react against them. # There are 2 types of GVHD: Acute – occurs days to weeks after transplantation, causes epithelial cell necrosis in the liver, skin and gut => destruction of small bile ducts (results in jaundice), mucosal ulcerations (results in bloody diarrhea), and generalized rash. Chronic – may follow the acute form or may occur on its own; patients develop skin lesions and manifestations mimicking other autoimmune diseases. *GVHD is a potentially lethal complication that can be minimized by MHC matching or by depletion of donor T cells before transplantation. *Immunosuppression Interfere with protein synthesis or DNA replication thus suppressing the immune system, preventing rejection of the transplanted organ. But a simple infection like the flu will be dangerous. Also, higher chance to get cancer (T cells usually fight off).

Answer 20

TYPE III HYPERSENSITIVITY An accumulation of immune complexes that have not been adequately cleared by innate immune cells deposit in BV walls, causing inflammation and tissue damage. Damaged cell (necrosis f.ex.) → DNA is released → autoreactive B cell binds the Ag → specific T helper cell recognizes the Ag presented by the B cell → release of cytokines → B cell activation → secretion of antibodies → binding of antibodies to Ags → formation of small soluble, less immunogenic complexes → float longer in blood→ complexes are deposited into BMs of blood vessels (+ charged DNA attracted to – charged BM) → activation of the complement system *C3a, C4a, C5a are: *anaphylatoxins → permeability of BV↑ → edema *chemokines → degranulation of neutrophils → vasculitis → damaged cell (+ loop) Here LARGE amounts of complement proteins are used, in contrast to type II hypersensitivity, where SMALL amounts are used. (detection in blood). Examples: ♥Systemic lupus erythematosus SLE ♥Glomerulonephritis- deposition in the BVs of the glomeruli ♥Arthritis (blood filtered to synovial fluid) ♥Serum sickness- Antibodies are produced against antibodies which are produced as a reaction to venom Ags f.ex.). ♥Farmer’s lung- Interaction of IgG with large particles of inhaled allergens; the resulting inflammation compromises gas exchange by the lung. TYPE IV HYPERSENSITIVITY Unlike the other types, it is not antibody-mediated but rather is a type of cell-mediated response by: 1. T helper cells “delayed type hypersensitivity” Called delayed because it takes 48-72 hrs to recruit TH1 cells. ♥The tuberculin test is a classic example – a small amount of protein antigen, extracted from Mycobacterium TB, is injected to the dermis → DCs recognize and transport the tuberculin Ag to the lymph nodes where they present it to naïve T helper cells on MHCII molecules → DC secrete IL-12 → naive T helper cell differentiates into TH1 cell → TH1 cell secretes IFN-γ & TGF-β → inflammation *DTH can also develop in response to contact sensitizing agent, such as nickel or poison ivy (urushiol-causing dermatitis). 2. Cytotoxic T cells “direct cell cytotoxicity” DCs present the Ag on MHC-I molecules → naïve T cell differentiates into cytotoxic T cell → secretion of perforin & granzymes→ destruction of target cell ♥Type I diabetes mellitus – destruction of pancreatic β cells. ♥Rheumatoid arthritis RA – WBCs infiltrate synovial joints and produce antibodies against the constant region of human IgG. *The amount of antigen required to elicit a reaction is much greater than in antibodymediated (type II) hypersensitivity.

Answer 21

# The reactions produced by the normal immune system, which may cause tissue injury. HYPERSENSITIVITY REACTIONS # Hypersensitivity reactions are caused by: ♥autoimmune diseases ♥excessive reaction against microbes ♥immune response against common environmental substances. TYPE II HYPERSENSITIVITY “tissue-specific / cytotoxic hypersensitivity” Antibody-mediated reaction, caused by antibodies produced against antigens found on the patient’s own cell surface (tissue specific). These molecules can be intrinsic to the cell surface, and undergo configuration alterations, or they can be exogenous (drug metabolites like penicillin) Subtypes 1. Target cell depletion/destruction WITHOUT inflammation The antibodies bind the cell surface antigens, and their constant region serves as a ligand for receptors found on macrophages, neutrophils and NK cells; thus, the antibodies "bridge" the interaction of these cells and promote phagocytosis, or they lead to the production on an opsonizing molecule. *Opsonized cells are usually eliminated in spleen – splenectomy may be beneficial Examples: *hemolytic anemia (warm type- Abs destroy RBCs at body temp) *thrombocytopenia *ABO incompatibility *erythroblastosis fetalis 2. Complement / Fc R mediated INFLAMMATION The antibodies bind to cell surface antigens and activate the complement system through the classical pathway – recruit neutrophils and macrophages another example: acute rheumatic fever. 3. Antibody mediated cell DYSFUNCTION The antibodies bind to cell surface antigens, thus block the binding site of their normal ligand and interfere with signal transduction of the cell. Myasthenia gravis => antibodies are directed against AchR of the motor units, this inhibiting neuromuscular transmission, which result in muscle weakness.

Answer 22

# Cannot be accomplished by regeneration alone, but involves replacement of the PROLIFERTAIVE CAPACITIES OF TISSUES The ability of tissues to repair themselves is critically influenced by their intrinsic proliferative capacity. Tissues of the body are divided to 3 groups: * Labile (continuously dividing) tissues – cells are continuously replaced by maturation of stem cells. Include hematopoietic cells in BM and majority of surface epithelia (skin, oral cavity, vagina ,cervix, ducts of exocrine organs, GI and urinary tract) * Stable tissues- minimal replacative activity in normal state, yet can proliferate in response to injury/loss of tissue mass. Can reconstruct parenchyma of liver, kidney and pancreas * Permanent tissues – cells of these tissues are permanently differentiated and nonproliferative, such as neurons and cardiac muscle. REPAIR BY CONNECTIVE TISSUE non-regenerated cells with CT # Stages of repair: » Repair begins within 24 hours of injury by emigration of fibroblasts and their induction, as well as endothelial cell proliferation. » 3-5 days: granulation tissue is apparent » Granulation tissue accumulates CT matrix, resulting in scar formation. # There are 4 components of CT repair: 1) Angiogenesis – formation of new blood vessels; endothelial precursor cells migrate from bone marrow to areas of injury. 2) Migration and proliferation of fibroblasts. 3) Scar formation – deposition of CT – together with vassels and leukocytes is called granulation tissue. 4) Maturation and reorganization of the fibrous tissue. ANGIOGENESIS (topic 41) # Steps of blood vessel formation: » Vasodilation by NO and permeability of existing blood vessels by VEGF (vascular endothelial growth factor). » Migration of endothelial cells to the site of injury. » Proliferation and remodeling of endothelial cells => tube formation. » Recruitment of pericytes and smooth muscle cells to form mature vessel. # Newly formed vessel is leaky during angiogenesis since the interendothelial junctions are not completely formed, and because VEGF increases permeability. # Structural ECM proteins participate in the process by interactions with endothelial cells through integrin receptors. ACTIVATION OF FIBROBLASTS AND DEPOSITION OF CT # Scar formation (deposition of CT) occurs in 2 steps: 1) Migration of fibroblasts into the site of injury and their proliferation there. 2) Deposition of ECM produced by these cells. # The recruitment and stimulation of fibroblasts are driven by growth factors: » PDGF – platelet derived growth factor; promotes proliferation of fibroblasts and smooth muscle cells. » FGF2 – fibroblast growth factor. » TGFβ – transforming growth factor; controls proliferation and differentiation. # Macrophages are important cellular components of granulation tissue that clear the tissue debris, and also secrete mediators that induce fibroblast proliferation and ECM production ECM DEPOSITION # Collagen synthesis by fibroblasts at day 3-5 from the onset of injury. # The same GFs that induce fibroblasts proliferation, mediate collagen synthesis. # Net collagen accumulation depends on increased synthesis along diminished degradation of collagen. # The granulation tissue evolves into a scar composed of inactive, spindle-shaped fibroblasts, dense collagen and ECM components. # As the scar matures, there is progressive vascular regression, which transforms the vascularized granulation tissue into a pale, avascularized scar. TISSUE REMODELING # Transition from granulation tissue into scar tissue involves a shift in composition of the ECM. # Collagen and ECM components are degraded by metalloproteins (MMPs) that are dependent on zinc ions for their activity. # MMPs are produced by many cell types => fibroblasts, macrophages, neutrophils. ! Production is inhibited by TGFβ or by steroids. WOUND HEALING # Involves both epithelial regeneration and the formation of c. tissue scar. # Based on the nature of the wound, healing can occur by 1st or 2nd intention. HEALING BY FIRST INTENTION => clean, uninfected surgical incision # Incision causes only minor disruption of epithelial basement membrane continuity, and death of relatively few epithelial and c. tissue cells => epithelial regeneration predominates over fibrosis => small scar is formed. # Day 1 Incision is filled with fibrin-clotted blood, followed by infiltration of neutrophils. Increased mitotic activity is seen in basal cells at the cut edge of the epidermis. # Day 2 Epithelial cells from both edges begin to migrate and proliferate along the dermis, depositing basement membrane components as they go. The cells meet in the midline, giving a thin, continuous epithelial layer. # Day 3 Neutrophils are replaced by macrophages. The granulation tissue invades the incision space. Collagen fibers are vertically oriented => DO NOT bridge over the incision. Proliferation of epithelial cells continues => thickened epidermal covering. # Day 5 Maximal blood vessel formation (neovascularization). Granulation tissue fills the incisial space. Collagen fibers start to bridge the incision. Epidermis recovers its normal thickness. # Week 2 Continued collagen accumulation and fibroblast proliferation. Diminish of WBC infiltration, edema and vascularity. Increased collagen deposition and regression of vascular channels. # Week 4 The scar comprises cellular c. tissue devoid of inflammatory cells, and covered by normal epidermis. HEALING BY SECOND INTENTION => tissue loss is more extensive (large wound, abscess, ulceration, ischemic necross) # The inflammatory reaction is more intense => necrotic exudate # Abundant development of granulation tissue # Wound contraction by action of myofibroblasts. # Differences between 1st and 2nd intention: 1) At the surface of the wound, a larger clot will be formed, rich in fibrin and fibronectin. 2) Intense inflammation due to greater volume of necrotic debris, exudate and fibrin that must be removed. 3) Larger amount of granulation tissue is formed. 4) 2 nd intention involves wound contraction, due to myofibroblasts WOUND STRENGTH # Sutures give wounds up to 70% of the strength of unwounded skin due to their location. # When sutures are removed, the wound strength is 10% of the strength of unwounded skin, but increases rapidly as wound healing continues. # The recovery of tensile strength results from collagen synthesis exceeding its degradation, and from structural modifications of collagen. # Wound strength reaches up to 70%-80% of the strength of unwounded skin.

Answer 23

# Granulomatous inflammation Although the consequences of acute inflammation are modified by the nature and intensity of the injury, the site and tissue affected, and the ability of the host to mount a response, acute inflammation generally has one of three outcomes: 1. Resolution » When injury is limited with minimal damage, and the tissue is capable of replacing irreversibly injured cells, the outcome is restoration of the tissue to normal structure and function. » Termination of acute inflammation has to occur in order for resolution to take place: *Decay (short half-life) or enzymatic degradation of chemical mediators. *Normalization of vascular permeability. *Cessation of leukocyte emigration with subsequent death (by apoptosis) of extravasated neutrophils. *Leukocytes produce inhibitory mediators => limit inflammation reaction. *Lymphatic drainage and macrophage ingestion clear debris of necrotic cells, edema fluid, inflammatory cells etc. » Leukocyte secrete cytokines that initiate repair process – *blood vessels grow into injured tissue to supply nutrients *fibroblasts lay down collagen to fill defects *residual tissue cells proliferate to restore structural integrity 2. Scarring (fibrosis) » Occurs after substantial tissue destruction. » The tissue is not able to regenerate itself. » Extensive CT deposition occurs in attempt to heal damage or as consequence of chronic inflammation. » Outcome is fibrosis 3. Chronic inflammation Inflammation of prolonged duration (weeks to years) in which continuing inflammation, tissue injury, and healing, often by fibrosis, proceed simultaneously. » Occurs if: ♥Persistent infections by microbes -microbes which are hard to eradicate like mycobacterium tuberculosis ♥Prolonged exposure to toxic agents – non-degradable exogenous agents (silica particles→silicosis), or endogenous (cholesterol crystals→atherosclerosis). ♥Hypersensitivity diseases – caused by excessive and inappropriate activation of the immune system. » May be followed by normal restoration/scarring » Characterized by infiltration of mononuclear cells, consist of macrophages, lymphocytes (both T and B), and plasma cells. » Mediated by cytokines produced by macrophages (TNF, IL-1) and by lymphocytes (mainly T cells => INFγ). » Often includes proliferation of fibroblasts and new blood vessels, with resultant fibrosis and disturbance of architecture. CHRONIC INFLAMMATION A circumscribed tiny lesion (1mm), characterized by aggregations of activated macrophages with scattered lymphocytes. It is a protective defense mechanism of the body which leads to tissue destruction. » Granulomas are formed as a response of: ! Persistant T-cell response to certain microbes (TB/fungi). T-cell derived cytokines are responsible for chronic macrophage activation ! Immune mediated disease (chron) ! Disease of unknown etiology – sarcoidosis, foreign body granulomas Macrophage engulfs a pathogen and transports it to the lymph node where it presents it to a T helper cell → the T helper cell releases the following cytokines: *IL-1 &IL-2: T cell proliferation *TNF-α: fibroblast proliferation (fibrosis) *IFN-ɤ: macrophage activation → macrophage becomes epitheloid cell → epitheloid cells group together to form multinucleated giant cells * multinucleated giant cells= Langerhans cells in TB # Morphology of chronic inflammation: » Epitheloid cells in granulomas => pink granular cytoplasm with indistinct cell boundaries. » Aggregations of epitheloid macrophages are surrounded by a collar of lymphocytes, which secrete cytokines that continuously activate macrophages. » Older granulomas may have a rim of fibroblasts and CT » Multinucleated giant cells (40-50μm) can be found in granulomas, consist of large mass of cytoplasm and many nuclei. ! They are derived from the fusion of over 20 macrophages. » In granulomas that are associated with certain infectious organisms, hypoxia and free radical injuries lead to a central zone of necrosis, with a granular cheesy appearance => CASEOUS NECROSIS » The granulomas associated with Crohn disease, sarcoidosis, and foreign body reactions tend to not have necrotic centers and are said to be “noncaseating.” » Microscopically => amorphous, structureless, granular debris with complete loss of cellular details.

Answer 24

# Outpouring of watery, protein-poor fluid = transudate. SEROUS INFLAMMATION # Fluid derived from: *serum *secretions of mesothelial cells lining serous cavities (peritoneum, pericardium, pleura). * Fluid in a serous cavity is called effusion # Example: skin blister – fluid accumulates beneath or within the epidermis. FIBROUS INFLAMMATION # A consequence of more serious injuries # Greater vascular permeability → larger molecules, such as fibrinogen, cross the endothelial barrier. # Fibrinous exudate => characteristic of inflammation in the lining of body cavities (meninges, pericardium, pleura). # The fibrinous exudate may undergo degradation by fibrinolysis, and cell debris are removed by macrophages → RESOLUTION (restoration of normal tissue structure). # Failure to completely remove fibrin → ORGANIZATION (replacement by ingrowth of fibroblasts and blood vessels) → scar tissue formation # Example: organization of fibrinous pericardial exudate results in fibrous scar tissue that obliterates the pericardial space and restricts myocardial function. PURULENT/SUPPURATIVE INFLAMMATION # Characterized by presence of pus (purulent exudate), containing neutrophils, fibrin, necrotic cells, edema fluid, cell debris and bacteria. # Organisms that are more likely to induce pus formation are called pyogenic (staphylococci). # Abscess – focal collections of pus caused by seeding of pyogenic organisms into the tissue; usually composed of central necrotic region and a peripheral region of preserved neutrophils, surrounded by dilated vessels and fibroblastic proliferation. # With time abscess will be replaced by CT. # Usual outcome: scarring ULCERATIVE INFLAMMATION # Local defect on the surface of an organ, produced by necrosis of cells and shedding of inflammatory necrotic tissue. # Most commonly seen in: » Inflammatory necrosis of mucosa of the mouth, stomach, intestine and urogenital tract. » Tissue necrosis and subcutaneous inflammation of lower extremities in older patients who have circulatory disturbances. # Can be acute or chronic: » Acute – intense PMN infiltration and vascular dilation in the margins of the defect. » Chronic – margins and base of the ulcer develop scarring with accumulation of lymphocytes, macrophages and plasma cells.

Answer 25

# Stimuli for acute inflammation: mnemonic: HIT FT ACUTE INFLAMMATION A protective response intended to: *eliminate the initial cause of cell injury (microbes f.ex) *eliminate necrotic cells and tissues resulting from the original insult Side effect- injury of normal tissues. Acute inflammation is rapid in onset and of short duration, lasting from a few minutes to as long as a few days, and is characterized by fluid and plasma protein exudation and a predominantly neutrophilic leukocyte accumulation. 5 cardinal signs: heat (calor), redness (rubor), swelling (tumor), pain (dolor) and loss of function (functio laesa). 1) Infections by pathogens – bacteria, viruses, fungi, parasites. 2) Trauma – thermal injury (burn), irradiation, toxic chemicals.. 3) Tissue necrosis- like MI (ischemia) 4) Foreign bodies- sutures.. 5) Hypersensitivity reactions Acute inflammation has two major components: 1. Vascular changes ♥Changes in vascular caliber and flow (vasodilation) Short lasting vasoconstriction (few seconds), then arteriolar vasodilation → increased local blood flow → fluid moves to extravascular tissues (transudate) → [RBCs]↑→ viscosity↑ → flow↓→ stasis → margination (accumulation of leukocytes, mainly neutrophils, along the endothelial wall). ♥Increased vascular permeabilit Immediate transient response: Contraction of endothelial cells- by chemical mediators (histamine, bradykinin and leukotrienes) Then, TNF and IL-1 cause further retraction of the endothelium due to changes in the cytoskeleton. Also Integrins!!! They induce signaling cascade → changes in cytoskeleton *Immediate sustained response: Direct endothelial injury- direct injury to endothelial cells is usually seen after severe injuries (e.g., burns, microbes, toxins..). In most cases leakage begins immediately after the injury and persists for several hours or days until the damaged vessels are thrombosed or repaired. Endothelial injury due to leukocytes- may occur as a consequence of leukocyte accumulation along the vessel wall (activated leukocytes release many toxic mediators). Transcytosis-VEGF (vascular endothelial growth factor) induces channel formation (fusion of intracellular vesicles) → increased transport of fluids and proteins through channels Leakage from renewed blood vessels !!All of the mentioned mechanisms will enable fluid rich in cells and proteins (exudate) to exit from the blood vessel into the injured tissue, inducing edema. ♥Increased adhesion of leukocytes Expression of selectins and integrins to promote extravasation. 2. Cellular events Recruitment and activation of leukocytes (mainly neutrophils (PMN), also macrophages..) → emigration from the vascular lumen to the extravascular space and accumulation in the focus of injury. Free floating ↓ Margination and rolling- Macrophages recognize pathogen → secrete IL-1&TNF) → endothelium starts expressing E selectin receptors Histamine, thrombin.. → endothelium starts expressing P selectin receptors E&P selectin receptors bind to L selectins (selectin ligands), which are expresses constitutively on leukocytes. ↓ Firm adhesion- endothelium starts expressing integrin ligands mainly ICAM, VCAM (due to IL-1, TNF) which bind to integrin receptors (LFA-1) on leukocytes. ↓ Extravasation (diapedesis) Mediated by CD31 (PECAM-1), on both leukocytes and endothelium. Leukocytes squeeze between cells at intercellular junctions, through the basement membrane (by secretion of collagenases). ↓ Invasion (chemotaxis) Leukocytes migrate toward the site of inflammation along a chemical gradient of chemokines (bacterial products, cytokines, components of complement sys – C5) Leukocyte activation Once leukocytes have been recruited to the site of infection or tissue necrosis, they must be activated to perform their functions. Stimuli for activation include microbes, products of necrotic cells, and several mediators. Leukocytes use various receptors to sense these, inducing a number of responses: ♥Phagocytosis *Recognition and attachment *Engulfment ♥Intracellular destruction of phagocytosed microbes and dead cellsin phagolysosomes containing reactive oxygen and nitrogen species and lysosomal enzymes. ♥Liberation of substances that destroy extracellular microbes and dead tissues by NETosisa framework of nuclear chromatin with embedded antimicrobial peptides and enzymes which prevents the spread of the microbes by trapping them. ♥Amplification of the inflammatory reaction- by production of mediators like arachidonic acid metabolites and cytokines, recruiting and activating more leukocytes *Leukocytes also cause injury to normal cells. ↓ Termination # Decay (short half-life) or enzymatic degradation of chemical mediators. # Normalization of vascular permeability. # Cessation of leukocyte emigration with subsequent death (by apoptosis) of extravasated neutrophils. # Leukocytes produce inhibitory mediators => limit inflammation reaction. # Lymphatic drainage and macrophage ingestion clear debris of necrotic cells, edema fluid, inflammatory cells etc. *Recognition of microbes, necrotic cells and foreign substances are accomplished by PRRs MEDIATORS OF INFLAMMATION # Vasoactive amines Histamine => permeability , epithelial cells contraction Serotonin => similar to histamine, derived from platelets # Amino acids metabolites COX pathway => thromboxane A2 – vasoconstrictor, platelet aggregator; prostaglandins – vasodilator, platelet inhibitor LOX pathway => leukotrienes # Cytokines Soluble proteins, signaling molecules Macrophages secrete TNF, IL-1 # Kinin system Factor XII links kinin, coagulation, plasminogen, complement # Complement system C3a and C5a => anaphylatoxins – mediate degranulation C3b => opsonization

Answer 26

# Non-progressive stage = compensatory mechanisms CATEGORIES OF SHOCK 1. Cardiogenic shock – due to severe CO↓ (failure of pump in LV). Caused by: ➔ Myocardial infarction ➔ Ventricular arrhythmias ➔ Cardiac tamponade- fluid in the pericardium builds up, resulting in compression of the heart. ➔ Outflow obstruction 2. Hypovolemic shock – results from loss of blood or plasma volume. Caused by: ➔ Hemorrhage ➔ Severe burns ➔ Trauma ➔ Vomit, diarrhea 3. Vasodilative shock- ♥Septic shock – caused by microbial infection, usually G(+) followed by G(-) and fungi. ♥Neurogenic shock – anesthetic accident or spinal injury => loss of vascular tone. ♥Anaphylactic shock – systemic vasodilation and increased vascular permeability caused by type I hypersensitivity reaction (IgE). STAGES OF SHOCK Body can still compensate for the loss of blood and decreased MAP by: *short term changes: SNS↑ → CO=HR↑∙SV → CO↑ → MAP↑ *long term changes: RAS↑, ADH↑, ANP↓(volume↑) # Progressive stage – compensatory mechanisms are no longer adequate. » Anaerobic metabolism → lactic acidosis AND not enough ATP » Confusion, consciousness # Irreversible stage » Tissue and organ damage cannot be repaired => death » NO increased synthesis worsen myocardial contraction » Lysosomal enzyme leakage MORPHOLOGY # Although any organ can be affected, brain, heart, kidneys, adrenals and GI tract are most commonly involved. Tissue changes occur as a result of hypoxic cell injury. Brain => ischemic encephalopathy Liver => fatty change, nutmeg liver (liver dysfunction due to venous congestion) Kidney => tubular ischemic injury – electrolyte imbalance, fibrin thrombi Adrenals => cortical cell lipid depletion – decrease in cortical production, lead to decreased perfusion GI => focal mucosal hemorrhage and necrosis Heart => areas of ischemic coagulative necrosis *Except for neuronal and cardiomyocyte loss, affected tissues can recover completely if the patient survives.

Answer 27

An intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin. The vast majority of emboli derive from a dislodged thrombus—hence the term thromboembolism. Less common types of emboli include fat droplets, bubbles of air or nitrogen, atherosclerotic debris (cholesterol emboli), tumor fragments, bits of bone marrow, and amniotic fluid. Inevitably, emboli lodge in vessels too small to permit further passage, resulting in partial or complete vascular occlusion; depending on the site of origin, emboli can lodge anywhere in the vascular tree. The primary consequence of systemic embolization is ischemic necrosis (infarction) of downstream tissues, while embolization in the pulmonary circulation leads to hypoxia, hypotension, and right-sided heart failure. TYPES OF EMBOLISM ♥ Pulmonary thromboembolism » Originates from DVT, above the knee level. » Passes through the right side of the heart into the pulmonary circulation. » Depending on size, may cause the occlusion of: » Most pulmonary emboli (60% to 80%) are small and clinically silent, but a large embolus that blocks a major pulmonary artery can cause sudden death. ➔ Main pulmonary artery ➔ Impact across the bifurcation of right and left pulmonary arteries => saddle embolus ➔ arterioles » Most pulmonary emboli (60% to 80%) are small and clinically silent, but a large embolus that blocks a major pulmonary artery can cause sudden death. » Consequences of occlusion: 1. Effect on the cardiovascular system: *Left side of the heart will also be affected: 2. Effect on lungs: → respiratory alkalosis *Rarely, an embolus passes through an atrial or ventricular defect and enters the systemic circulation (paradoxical embolism). ♥ Systemic thromboembolism » Emboli in the systemic circulation, most of them arise from intracardial mural thrombi. » Most associated with left ventricular wall infarcts. » The major sites for embolization are lower extremities and CNS, and to lesser extent the kidneys, intestine and spleen. ♥ Fat embolism » Caused by fractures of long bones (contain fatty marrow), or by soft tissue trauma. » Involves *mechanical obstruction Occlude pulmonary and cerebral vasculature – directly and by platelet aggregation *biochemical injury rupture of marrow vasculature → fat enters circulation → FFA released from the fat globules → local toxic injury to endothelium. » Fat embolism syndrome (10%): - Pulmonary insufficiency - Neurologic symptoms - Anemia - Thrombocytopenia => Appear after 1-3 days after injury with sudden onset of tachypnea (rapid breathing), dyspnea (shortness of breathing), tachycardia (rapid HR). ♥ Gas (air) embolism » Gas bubbles in circulation physically obstruct vascular flow. » Air => 100ml are required to produce clinical effects, caused by penetrating chest injury or during obstetric procedures. » Nitrogen (decompression sickness) => occurs when deep sea divers ascend rapidly, thus exposed to sudden change in atmospheric pressure. when air is breathed in high pressure, increased amounts of gas (mainly nitrogen) become soluble and dissolve on blood; if sudden pressure change occurs, insoluble nitrogen bubbles are formed. ♥ Amniotic fluid embolism » An uncommon, grave complication of labor and the immediate postpartum period. » The mortality rate approaches 80%, making it the most common cause of maternal death in the developed world. » Escape of amniotic fluid into maternal circulation. Amniotic fluid contains large amount of TF, and may induce coagulation cascade (causes DIC). » Sudden severe dyspnea (shortness of breath), cyanosis (bluish or purplish discoloration of the skin or mucous membranes due to low oxygen saturation) and hypotensive shock. » Pulmonary edema develops.

Answer 28

# The pathologic form of hemostasis, involves the formation of an intravascular blood THROMBOSIS clot (thrombus) in an uninjured vessel, or thrombotic occlusion of a vessel after relatively minor injury. The three risk factors of thrombosis (Virchow's triad): ➔ Endothelial injury ➔ Stasis/turbulence of blood flow ➔ Blood hypercoagulability # Endothelium – Injured endothelium will not be able to: *Be a physical barrier, separating the blood from the subendothelial collagen (VWF comes in contact with collagen it undergoes a conformational change, enabling it to bind PLTs) and underlying TF (binds and activates factor VII, forming the extrinsic tenase complex). *Release substances that have an antithrombotic effect: NO, PGI2, ecto-ADPase (ADP needed for recruitment) Release substances that have an anticoagulant effect: TFPI, TPA, HLm. *Endothel may be dysfunctional (not only damaged) and create an imbalance between the anticoagulant and procoagulant activities of the endothelium may induce thrombosis => hypertension, bacterial endotoxins, vasculitis. # Turbulence – any alterations in the laminar blood flow that causes endothelial injury/dysfunction, as well as forming countercurrents and local pockets of stasis (the flow stops allowing platelets and leukocytes to come in contact with endothel) => ▪ aneurysm (arterial dilation) ▪ acute myocardial infraction (blood flow decreases or stops to a part of the heart) ▪ bed-care patients ▪ hyper-viscosity syndromes (polycythemia) ▪ sickle cell anemia ▪ ulcerated atherosclerosis ▪ mitral valve stenosis (after RA) results in atrial dilation # Hypercoagulability – when the balance between the pro and anticoagulant proteins is upset. Primary => inherited ▪ Factor V Leiden ▪ Less common, mutations in anticoagulant genes of AT III, proteins C&S. Secondary => acquired ▪ Heparin-induced thrombocytopenia (HIT): autoantibodies that bind complexes of heparin and platelets (platelet factor-4). Platelet binding activates them and agg them. ▪ Antiphospholipid antibody syndrome: manifestations are recurrent thrombosis and miscarriages and thrombocytopenia. Caused by antibodies to phospholipids of cell membrane which induce endothel injury. Some patients may have secondary Antiphospholipid syndrome due to another autoimmune disease (SLE), patients without an underlying autoimmune disease are classified as primary. ▪ Oral contraceptives: contain estrogen, stimulate the liver to produce plasma proteins, including coagulation factors and reduced syn of AT III; upon smoking, the contained compounds may induce endothelial wall injury => collagen exposure => promotion of coagulation cascade. ▪ Age: increased platelet agg and PGI2 MORPHOLOGY OF THROMBI # Thrombi can develop anywhere in the cardiovascular system. # The size and shape of the thrombus depends on the site of origin and the cause: Arterial/cardiac thrombi – begin at the sites of endothelial injury or turbulence. Venous thrombi – occur at sites of stasis. # Thrombi are attached to the vascular surface: Arterial – grows in a retrograde direction from the point of attachment. Venous – extends in the direction of blood flow. The propagation portion of the thrombus tends to be poorly attached to the surface, and therefore prone to fragmentation, generating an embolus. # Lines of Zahn – laminations on the thrombi (gross or microscopical), representing pale platelet & fibrin layers alternating with darker erythrocyte-rich layers => help distinguish antemortem thrombosis from postmortem state (no laminations after death). Also, postmortem blood clots are not attached to the vessel wall. # Types of thrombi: » Mural thrombi – occur in heart chambers or aortic lumen, caused by abnormal myocardial contraction1 or endomyocardial injury2 . Non-occlusive. » Arterial thrombi – occlusive, develop due to endothelial injury. Composed of mainly PLT but also fibrin, erythrocytes and leukocytes. » Venous thrombi (phlebothrombosis) – occlusive, caused by activation of coagulation cascade and platelets (minor role), contain more erythrocytes and are called red/stasis thrombi. » Postmortem clots – gelatinous composition, with a dark red portion (red cells have settles by gravity), and a yellow "chicken fat" portion; usually, they are not attached to the vessel surface. » Vegetations – thrombi on heart valves due to damage caused by bacterial or fungal infections3 . *Venous and postmortem thrombi are sometimes mixed but venous thrombi are firm, focally attached to the vessel wall and contain gray strands of deposited fibrin. FATE OF THE THROMBUS # Propagation – thrombus enlarges due to accumulation of more platelets and fibrin increasing odds of obstruction/embolism. # Embolization – the thrombi are fragmented and transported elsewhere in the vasculature. # Dissolution – thrombi are removed by fibrinolytic activity. In older thrombi, lysis is inefficient. # Organization and recanalization – older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cell and fibroblasts. In time, capillary channels are formed reestablishing the continuity of the lumen. recanalization may occur without organization due to enzymatic digestion due to entrapped WBC. DISSEMINATED INTRAVASCULAR COAGULATION » DIC is the sudden onset of widespread thrombosis within the microcirculation. The thrombi are generally microscopic in size, yet so numerous that they often lead to ischemia, particularly in the brain, lungs, heart, and kidneys and to hemolysis (RBCs are traumatized while passing through vessels narrowed by thrombi). To complicate matters, the widespread microvascular thrombosis consumes PLT & clotting factors (hence the synonym consumption coagulopathy). Thus, other parts of the body start to bleed with even the slightest damage to the BV walls. *DIC is NOT a primary disease but rather a potential complication of numerous conditions associated with widespread activation of thrombin, ranging from obstetric complications (The release of TF or thromboplastic substances into the circulation from the placenta) to advanced malignancy. In G(-) and G(+) sepsis, endo- or exotoxins cause increased synthesis and release of TF from monocytes release IL-1 and TNF, both increase the expression of TF and decrease the expression of thrombomodulin (anticoagulator, activates protein C) => activation of extrinsic coagulation pathway.

Answer 29

# Active process of increased blood flow to different tissues due to arteriolar vasodilation, The terms hyperemia and congestion both indicate a local increased volume of blood in a tissue. HYPEREMIA as occurs in inflammation/exercising skeletal muscle. # Redder than normal due to accumulation of oxygenated blood # Hyperemia occurs when a tissue increases its activity, thus utilizing certain substances and releasing metabolites => pO2 , pCO2 , pH , temperature , utilization of glucose, FAs and other nutrients. # The presence of certain metabolites (CO2, adenosine) will initiate vasodilation in order to increase the blood flow; thus, waste products are cleared from the tissue, and new blood, rich in oxygen and nutrients, supplies the tissue. # Vasodilation can also be caused by ➔ Sympathetic tone ➔ Vasodilators (histamine, bradykinin) ➔ inflammation CONGESTION # Passive process refers to impaired venous flow out of the tissue, usually occurs when the heart is unable to provide sufficient pump action to distribute the blood (=>systemic), or when there is an obstruction of the vein (=>local). # The tissue becomes cyanotic due to accumulation of deoxygenated blood. # Congestion can be acute or chronic. # In chronic congestion hypoxia may lead to parenchymal death and 20 tissue fibrosis. Intravascular pressure may cause edema/vessel rupture – focal hemorrhage HEMORRHAGE # Extravasation of blood from the vessels into the extravascular space. # Caused by: ➔ Trauma (most common cause) ➔ Atherosclerosis ➔ Inflammatory or neoplastic erosion of vessel wall ➔ Chronic congestion Hemorrhage can be external to the tissue or confined within it (hematoma). # Sizes of hemorrhages: Petechia => minute (1-2 mm) hemorrhage into skin, mucous membrane or serosal surface, associated with thrombocytopenia, defective platelet function and loss of vascular wall support – vitamin C deficiency. Purpura => 3-5 mm, can occur with trauma, vasculitis, vascular fragility. Ecchymoses => 1-2 cm subcutaneous hematoma; RBCs are phagocytosed and degraded by macrophages: Hb (red-blue) bilirubin (blue-green) hemosiderin (golden brown). # Large accumulations of blood in a body cavity are named according to the cavity: hemothorax, hemopericardium, hemoperitoneum, hemarthrosis (joints). # Patients with extensive hemorrhage may develop jaundice due to [bilirubin] . # Recurrent external bleedings (ulcers, menstruation) can lead to iron loss and to iron deficiency anemia. # Blood loss of over 20% may cause hemorrhagic shock

Answer 30

# The abnormal accumulation of fluids in the interstitium, characterized by tissue EDEMA swelling. # Extravascular fluids can accumulate in body cavities (hydrothorax, hydropericardiun, hydroperitoneum/ascites). # Ansarca – severe edema, selling of subcutaneous tissue and fluid accumulation in body cavities # Edematous fluid can be either transudate or exudates: » Trabsudate – results from increased hydrostatic or decreased oncotic pressure of plasma; non-inflammatory fluid with low protein content, specific gravity<1.012. » Exudates – results from increased permeability of blood vessels caused by inflammation; viscous, yellowish-white fluid with high protein content and inflammatory leukocytes, specific gravity>1.012. EDEMA FORMATION Increased hydrostatic pressure Systemic edema mostly due to congestive heart failure : CO => renal perfusion => activation of RAS => retention of Na+ , water => heart cannot increase CO (due to failure) => extra fluid will increase hydrostatic pressure in veins => edema. Treated with anti-aldosteron/diuretics Venous obstruction (example: thrombosis) will result in local edema distal to the site of thrombus (Pc => absorption is impaired). Decreased plasma oncotic pressure Albumin is the serum protein most responsible for maintaining intravascular oncotic pressure. Reduced synthesis of albumin/albumin is lost decreases oncotic pressure of the plasma, which leads to net movement of fluid from the plasma into the interstitium. Causes of albumin loss ➔ Nephritic syndrome (glomerular permeability ). ➔ Diffuse liver diseases, such as cirrhosis (synthesis ). ➔ Protein malnutrition. Reduced intravascular volume => same manifestations as congestive heart failure (20 hyperaldosteronism, renal hypoperfusion) Lymphatic obstruction Impaired lymphatic drainage => localized lymphoedema. Can be cause by ➔ Inflammatory or neoplastic obstruction (parasites => fibrosis of lymphatics and lymph nodes). ➔ Surgical removal of lymph nodes (as therapy for breast cancer) => arm edema. Na+ and water retention Primary => associated with renal dysfunction. Water accompany Na+ Increased hydrostatic pressure due to intravascular expansion Decreased oncotic pressure (within the vessels) Secondary => due to congestive heart failure. MORPHOLOGY OF EDEMA Microscopically => appears as a clearing and separation of ECM elements with cell swelling. Edema is most commonly encountered in subcutaneous tissues, lungs and brain. # Subcutaneous edema – in regions with high hydrostatic pressure. » Dependent edema => a gravity-dependent distribution, also a prominent feature of cardiac failure, appears mostly on legs. » Edema due to renal dysfunction is more severe than cardiac edema, and affects body parts equally. » Pitting edema => finger pressure over edematous subcutaneous tissue displaces the fluid and creates a finger-shape depression. # Pulmonary edema – most frequently seen in left ventricular failure, with lungs weigh 2-3 times their normal weight. # Brain edema – may be localized to site of injury (infarct, abscess, neoplasm), or generalized1 (encephalitis, obstruction of venous outflow).

Answer 31

# A condition in which misfolded proteins (usually have a beta pleated sheet AMYLOIDOSIS configuration), which are soluble in their normal configuration, aggregate and form abnormal fibrils. These deposit in the extracellular space predominantly (tends to be localized around BVs), causing tissue damage and functional compromise. *Usually proteins are degraded *IC- (proteasome pathway) *EC- (macrophages) # Amyloid – an insoluble fibrous protein, formed by aggregation of over 20 different misfolded proteins, which has some characteristics of starch (amylase). » Composed of non-branching fibrils, each has β-pleated sheet configuration. » Amorphous eosinophilic appearance in H&E. » Staining with Congo red dye will give apple-green birefringence coloration in polarized light. # They are made of 95% Fibrillar proteins which are bound to the rest 5% of P proteins (PG, GAG (heparin/dermatan sulfate) and serum amyloid P component (SAP)). 3 distinct forms of amyloid proteins: » AL protein (Amyloid Light-chain) ▪ Produced by plasma cells. ▪ Composed of immunoglobulin light chains (defective degradation of light chain) ▪ Associated with some forms of monoclonal B-cell proliferation (multiple myeloma). » AA protein (Amyloid-Associated) ▪ Derived from a serum precursor SAA => serum amyloid-associated. ▪ SAA id synthesized in the liver, and increased during acute phase response (under influence of IL-1, IL-6). ▪ Associated with chronic inflammatory disorders. ▪ Defective proteolysis of SAA leads to its aggregation as AA fibrils. » Aβ amyloid ▪ Derived from TM GP amyloid precursor protein (APP) ▪ Found in cerebral lesions of Alzheimer disease ▪ Deposits in cerebral blood vessels # Other proteins associated with amyloid deposits: » Transthyretin (TTR) – related to familial amyloid polyneuropathies, deposits in the heart of aged people » β2-MG – component of MHC-I, identified as amyloid fibril subunit (Aβ2m) – high cc in patoents with renal disease 1. SYSTEMIC AMYLOIDOSIS When the amyloids are deposited systemically. In this case, the damaged organs CANNOT be removed and therefore must be transplanted! A biopsy can be taken from the abdominal fat pad or from the mucosa of the rectum. # Primary = associated with monoclonal plasma cell proliferation » Plasma cell dyscrasias: overproduction of light chain → leakage to blood → misfolding and aggregation → AL type amyloid → deposition into tissues. » Most common form. » Monoclonal plasma cell prolif (5-15% in patients with multiple myeloma) » Syn of abnormal ampunt of Ig (monoclonal gammaopathy), producing M protein. » Plasma cells may also produce either the λ (lambda) or κ (kappa) light chains => BENCE JONES PROTEINS. » Deposition of AL in kidneys, heart, PNS, GI tract. (?) # Secondary = complication of an underlying chronic inflammatory process » Inflammation → macrophages produce IL-1, IL-6 → SAA (acute phase protein) is secreted by the liver → AA amyloid is derived from it. » Deposition occurs due to association with: ▪ inflammatory condition tuberculosis, bronchiatitis, chronic osteomyelitis ▪ autoimmune state – RA, bowel disease ▪ renal carcinoma, Hodgkin lymphoma # Hemodialysis-associated beta 2 microglobulin is a structural component of MHC-I, which isn’t filtered from the blood during dialysis and is thus deposited in joints. 2. LOCALIZED AMYLOIDOSIS Amyloid deposition is limited to a single organ => produce nodular masses. Affects mainly the lungs, larynx, skin, urinary bladder and tongue. # Senile cerebral Plaques containing αβ amyloid which is derived from β amyloid precursor protein, located on chromosome 21. This explains why individuals with down syndrome have Alzheimer’s at a relatively young age (40). Endocrine amyloidosis – amyloid deposits in certain endocrine tumors # Medullary carcinoma of thyroid Tumor derived from C cells → overproduction of calcitonin → amyloid is derived from calcitonin and deposited in the tumor. # Type II diabetes Insulin resistance of tissues → overproduction of insulin by pancreas → burn out of pancreas → amylin1 is a byproduct → deposits in the pancreas => interferes with insulin sensing by ȕ FHOOV. 3. HEREDITARY AMYLOIDOSIS # Familial Mediterranean fever: » Autosomal recessive » Pyrin (a gene) inhibits the function of neutrophils → acute inflammation → gain-of-function mutation – overproduction of IL-1→ SAA (acute phase protein) is secreted by the liver → AA amyloid is derived from it. » This condition is characterized by periodic attacks of fever accompanied by inflammation of serosal membranes (peritoneum, pleura). # Familial amyloidotic polyneurophathies: » Autosomal dominant. » Deposition of amyloid in the peripheral and autonomic nerves. » Amyloid deposition – mutant TTR (transthyretin, a plasma protein). # Senile systemic amyloidosis (amyloid of aging): » Systemic deposition of amyloid in elderly people. » Usually involves the heart. » The amyloid is composed of normal TTR molecules. MORPHOLOGY # No distinctive pattern of organ distribution, but generalizations can be made. When amyloid is accumulated (always in EC) in large amount, the organ is frequently enlarged, with firm consistency and gray in color. Major organs involved: Kidneys : Most common and severe involvement. - Abnormally large, pale, gray and firm. - Deposition mainly in glomeruli. Spleen : Enlarged (200-800 gr). - Deposits are limited to the splenic follicles, but may affect the splenic sinusoids and extend to the splenic pulp. - Firm, pale, gray, waxy appearance. Liver : - Massive enlargement, up to 9 kg. - Deposits first appear in the space of Disse, then on hepatic parenchyma and sinusoids. Heart: Minimal to moderate enlargement. - Gray-pink subendocardial elevations, mainly between myocardial fibers Other organs : Most commonly in adrenal, thyroid and pituitary. - Starts at epithelial cells and progresses to parenchyma. - No disturbance of function

Answer 32

EXOGENOUS PIGMENTS Carbon: Phagocytosed by alveolar macrophages, and transported to the lymph nodes (tracheobronchial) Anthracosis – blackening of the lymph nodes and pulmonary parenchyma. Heavy accumulation may indicate emphysema (destruction of tissue responsible for maintaining physical shape of the alveoli and lungs), or fibroblastic reaction (coal workers' pneumonia). ENDOGENOUS PIGMENTS Lipofuscin : Brownish-yellow, insoluble pigment, derived from peroxidation of lipids of membranes. Mostly accumulates in elderly people, mainly in the heart, liver and brain. Not harmful to the cell. Indication for past free radical injury. Brown atrophy – large amount of lipofucsin in atrophied tissue. Melanin: Brown-black pigment, produced in melanocytes in epidermis by tyrosinase enzyme. Once synthesized, melanin is transferred to keratinocytes, which accumulate it (also macrophages). Serves as a screen against harmful UV radiation. Sun tanning will cause increased pigmentation; albinism and vitiligo will cause decreased pigmentation. Bilirubin: Yellowish pigment, end product of heme degradation. When accumulated, stains mucous membranes, sclera and organs (under pathological conditions) => JAUNDICE Hemosiderin : Golden-yellow to brown pigment, derived from Hb and contains iron. Consists of aggregates of ferritin (hemosiderin granules) Identified by Purssian blue staining Local excess of iron => hemosiderin results from hemorrhage (example: common bruise) Colors of the bruise reflect metabolism of Hb: - Red-blue: hemoglobin, as a result of RBCs lysis. - Green-blue: Hb is catabolized by lysosomes to billiverdin (green-blue) and billirubin, - Golden-yellow: hemosiderin (the iron of Hb). Hemosiderosis => when there is systemic overload of iron, hemosiderin is deposited in many organs (first seen in liver, bone marrow, spleen, and lymph nodes). Occurs due to: 1) Increased absorption of dietary iron. 2) Impaired utilization of iron. 3) Hemolytic anemia. 4) Transfusions. Hereditary hemosiderosis => mutation in Hfe gene (chromosome 6) "bronzed diabetes" – occurs in micronuclear cirrhosis, diabetes mellitus and skin pigmentation

Answer 33

# The abnormal deposition of Ca2+ salts together with small amounts of other minerals, PATHOLOGIC CALCIFICATION such as iron and Mg2+ in a tissue. # Two forms of calcification exist: 1) Dystrophic calcification – occurs in the absence of Ca2+ derangement (normal level of serum Ca2+). 2) Metastatic calcification – deposition of Ca2+ salts due to hypercalcemia. DYSTROPHIC CALCIFICATION # The calcification occurring in dying/dead cells as a response to cell injury. (common in caseous necrosis, but occurs in all types of necrosis). # Ca2+ levels in the serum are NOT elevated. # Pathogenesis – formation of crystalline Ca2+-phosphate Initiation: Extracellular – occurs in membrane-bound vesicles, accumulating Ca2+ and phosphate, derived from degenerating cells. Intracellular – occurs in the mitochondria of cells that have lost their ability to regulate IC Ca2+ . » Propagation of crystal formation depends on [Ca2+] and [PO4-] in the extracellular space, presence of mineral inhibitors, and rate of collagenization. # Seen in aortic valves (aortic stenosis) and atherosclerosis. METASTATIC CALCIFICATION # Occurs due to hypercalcemia that can be caused by: » Endocrine dysfunction – increased secretion of PTH due to tumors. » Bone destruction – due to increased turnover (Paget's disease), immobilization, and tumors1 . » Vitamin D related disorders – intoxification (hypervitaminosis), sarcoidosis (macrophages that activate vitamin D precursors). » Renal failure – phosphate retention leads to secondary hyperparathyroidism. » Excess Ca2+ intake. # Morphology – occurs throughout the body, mainly affecting kidneys2 , lungs3 and gastric mucosa.

Answer 34

# Inadequate removal of the substance that is produced in a normal or increased rate ABNORMAL INTRACELLULAR ACCUMULATIONS (example: fatty change in liver). # Genetic or acquired defects in folding, packaging, transport or secretion of a normal or abnormal endogenous substance. # Accumulation of an exogenous substance since the cell lacks the enzymatic machinery to degrade it, or the ability to transport it out of the cell. LIPID ACCUMULATION (fatty change – steatosis) # Any abnormal accumulation of TAGs within parenchymal cells of organs of fat metabolism, mainly in the liver, can also be seen in the heart, kidney and skeletal muscle. # May be caused by: toxins, malnutrition, diabetes mellitus, obesity or anoxia. # FFAs are usually transported into hepatocytes, where they: » Esterified into TAGs. » Converted into cholesterol or phospholipids. » Oxidized into ketone bodies. # TAGs exit hepatocytes by forming complexes with apolipoproteins, creating the lipoprotein complexes that can enter circulation; defects at any stage of this process result in lipid accumulation: » Hepatotxins (alcohol) Alter mitochondrial and sER function Inhibit FA oxidation CCl4/protein malnutrition => Decreased synthesis of apoproteins » Anoxia (extreme hypoxia) => Total decrease in oxygen level Inhibit FA oxidation Morphology => Appears as clear vacuoles within parenchymal cells, Can be visualized by special staining - Sudan IV/oil red O => far appears orange-red - PAS => glycogen appears red-violet Liver appears yellow in color, enlarged (3-6 kg), and soft & greasy in consistency. # In the heart, lipid deposition can appear in two forms: » Specific => zebra-like pattern of yellow myocardium, alternated by bands of healthy, red-brown myocytes; usually as a result of prolonged, moderate hypoxia (anemia). » Uniformly affected myocytes => produced due to profound hypoxia. Cholesterol: » Important component of cell membrane. » Ensures synthesis of steroids, bile acids and vitamin D. » When there is cholesterol overload, macrophages phagocytose the lipids, and become filled with small lipid vacuoles to form FOAM CELLS. » Xanthomas => clusters of foamy macrophages found in sub epithelial c. tissue of the skin or in tendons. » Atherosclerosis => smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries are filled with lipid vacuoles, Such cells have a foamy appearance (foam cells). Some of these fat-laden cells may rupture, releasing lipids into the extracellular space. » Cholesterolosis => This refers to the focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder. » Niemann-Pick disease, type C. This lysosomal storage disease is caused by mutations affecting an enzyme involved in cholesterol trafficking. PROTEIN ACCUMULATION # usually appear as eosinophilic droplets of abnormal proteins deposit primarily in extracellular spaces # In the kidney, proteins like albumin, which are filtered through the glomerulus, are normally reabsorbed by pinocytosis in the proximal tubule. In disorders with heavy protein leakage across the glomerular filter there is increased reabsorption of the protein into vesicles, and the protein appears as pink hyaline droplets within the cytoplasm of the tubular cell. # Accumulation of newly synthesized immunoglobulins that may occur in the RER of some plasma cells, forming rounded, eosinophilic Russell bodies. # Liver – Mallory bodies ("alcoholic hyaline") => eosinophilic cytoplasmic inclusion (crystals) in hepatocytes, composed of aggregated intermediate filaments that are resistant to degradation. # α1-antitrypsin deficiency results in the buildup of partially folded intermediates, which aggregate in the ER of the liver and are not secreted. The resultant deficiency of the circulating enzyme causes emphysema. # Brain – Alzheimer's disease => neurofibrillary compounds of aggregated proteins, containing microtubule-associated proteins and neurofilaments. CARBOHYDRATES ACCUMULATION # Excessive IC deposits of glycogen due to abnormalities in glucose or glycogen metabolism. # Glycogen masses appear as clear vacuoles within the cytoplasm. Staining with PAS reaction imparts a rose-to-violet color to the glycogen # Glycogen storage disease – enzymatic defects in the synthesis or breakdown of glycogen, result in massive storage with secondary cell injury and death. # In untreated diabetes mellitus, glycogen accumulates in renal tubules, hepatocytes, cardiac myocytes and pancreatic B cells.

Answer 35

# Morphology: NECROSIS A form of cell injury that results in the pathologic premature death of cells in the living tissue, which may lead to the death of the organ. This type of cell death is characterized by loss of membrane integrity and leakage of cellular contents → elicit inflammation Necrosis is mediated by the following processes: » Protein denaturation – due to low pH formed by hypoxia-induced glycolysis. » Disruption of the plasma membrane » Enzymatic digestion – *Autolysis: by intracellular enzymes, derived from lysosomes *Heterolysis: by enzymes derived from extrinsic sources (the dying cells induce an inflammatory reaction, attracting leukocytes which release enzymes). » Cytoplasmic changes: increased eosinophilia (loss of basophilic RNA, attachment of eosin to denatured proteins) » Nuclear changes: basophilia of chromatin may fade (karyolysis), nucleus may shrink and increased basophilia (pyknosis), nucleus may undergo fragmentation (karyorrhexis) » Necrotic cells may be replaced by myelin which will be phagocytosed/degraded to FA. FA may be calcified. ORMS OF NECROSIS 1. Coagulative necrosis Ischemia→ infarction=necrosis Red (hemorrhagic) infarct *loosely organized organ reentry of blood White infarct *arterial occlusion » Characteristic of ischemic infarcts in all solid organs EXCEPT THE BRAIN » Tissue cells are dead, but the architecture is preserved (for several days). » Firm texture. » Denaturation of proteins predominates (of both structural proteins and enzymes => NO PROTEOLYSIS => eosinophilia (eosin binds to denatured proteins). » Eventually cells are digested by leukocytes, cellular debris removed by phagocytes Gangrenous necrosis » Usually affects lower limbs, initiated due to loss of blood supply, secondary to coagulative necrosis (particularly in diabetics). » Wet gangrene – in moist tissues => when bacterial infection develops coagulative necrosis is modified by the liquefactive action of the bacteria. » Dry gangrene – in lower extremities => caused by coagulative necrosis without liquefaction. Liquefactive necrosis » Characteristic of bacterial/fungal infections => stimulates the accumulation of inflammatory cells => enzymes of leukocytes digest “liquify” the tissue. » Hypoxic death of cells in CNS evokes liquefactive necrosis (microglial cells which contain hydrolytic enzymes). Also seen in abscesses (neutrophils) & pancreatitis. » Dead cells are completely digested, resulting in the transformation of the tissue into a liquid viscous mass. » Loss of basophilia due to degradation of proteins and RNA. » If the process was initiated by acute inflammation => pus formation. Caseous necrosis » The tissue appears white and friable "cheese-like" consistency, because of fungal infection, but mainly because of mycobacterium tuberculosis. » Tissue architecture is completely obliterated, has amorphous granular appearance (cells are not completely digested), cellular outlines cannot be distinguished. » enclosed within a distinctive inflammatory border. This appearance is characteristic of a focus of inflammation known as a granuloma. Granulomatous reaction – the necrotic area is composed of cellular decries enclosed by multinucleated giant cells (fused macrophages); may also contain epithelial cells, T cells and fibroblasts. Fat necrosis » Necrotic adipose tissue, caused by the release of activated pancreatic lipases from acinar cells and ducts into the pancreatic tissue => pancreatitis => leakage of pancreatic enzymes to the peritoneal cavity, liquefying the membranes of fat cells in the peritoneum » Digestion of TAGs (in cell membrane) => FFAs are released (trauma/lipase) and combine with Ca2+ => formation of grossly visible chalky white areas (SAPONIFICATION). » Characteristic of: Trauma to fat (car accident f.ex.) and pancreatitis mediated damage of peripancreatic fat. Fibrinoid necrosis » Usually seen in immune reactions involving blood vessels damage. » Complexes of antigen-antibody are deposited on the wall of the vessel, together with fibrin (leaked out of the vessel due to increased permeability), resulting in a bright pink and amorphous appearance in H&E stains, called "fibrinoid". » Malignant hypertension and vasculitis result in the leaking of proteins into the vessel wall.

Answer 36

# It is the net result of degradation action of enzymes on lethally injured cells. HYPOXIC CELL INJURY # Causes of hypoxic cell injury: » Ischemia – diminished blood flow to a tissue, usually due to obstruction of arterial blood. » Diminished O2 carrying capacity because of anemia (reduction in number of RBCs or Hb molecules) or CO poisoning (due to affinity of CO to Hb). » Decreased perfusion – in CHF (congestive heart failure), shock, hypertension. » Poor oxygenation of blood – in pulmonary diseases. Hypoxic cell injury eventually results in membrane damage: » Mitochondrial membrane damage – reduction in ATP production, and release of pro-apoptotic enzymes to the cytosol. » Plasma membrane damage – loss of osmotic balance, influx of fluids and ions, loss of cellular contents. » Lysosomal membrane damage – leakage of digestive enzymes into the cytoplasm Hypoxia → Mitochondrial damage *Formation of high conduction channels “mit. Permeability transition pores” → membrane potential lost → failure of oxidative phosphorylation → ATP depletion AND formation of ROS leakage of proapoptotic molecules to cytosol AND Diffusion of cyt-C to cytosol → stimulation of caspases → apoptosis Reactive oxygen species (ROS) are produced normally in cells during mitochondrial respiration and energy generation, but they are degraded and removed by cellular defense systems. When the production of ROS increases or the scavenging systems are ineffective, the result is an excess of these free radicals, leading to a condition called oxidative stress. Mitochondrial damage → ATP depletion Hypoxia / toxins (cyanide) / disrupted ETC (mit damage)→ ATP depletion: *Anaerobic glycolysis → decrease in glycogen stores and lactic acidosis → pH↓ → chromatin clumping AND decreased enzymatic activity *Na+/K+ pump failure→ IC Na+ ↑ → water retention → cell & ER swelling → loss of microvilli and detachment of ribosomes → reduced protein synthesis => damage to cellular components by activation 2+ *Ca2+ pump failure → Increased IC Ca of enzymes (proteases, caspases, phospholipases). CELL DEATH # Occurs when severe injury or prolonged stimulus are applied. » Swelling of mitochondria and lysosome. » Extensive damage to plasma membrane. » Massive Ca2+ influx. IC enzymes are released from necrotic cells into the circulation due to loss of membrane integrity: » Myocardial enzymes AST – aspartate aminotransferase LDH – lactate dehydrogenase CK – creatine kinase troponin » Liver enzyme Alanine aminotransferase Alkaline phosphatase(bile) Gamma glutamyl transferase The vulnerability of cells to hypoxic injury varies among different cell types: » Neurons – 3-5 minutes; purkinje cells of cerebellum & hippocampus are much more sensitive. » Myocardial and hepatic cells – 1-2 hours. » Skeletal muscle cells – several hours. MORPHOLOGY OF HYPOXIC NECROSIS # Hypoxic necrotic cells show increased eosinophilia => eosin binds to denatured cytoplasmic proteins, loss of basophilia due to lack of RNA in cytoplasm. # The cell may have a more glassy, homogenous appearance due to loss of glycogen particles. # When enzymes have digested the cytoplasmic organelles, the cytoplasm becomes vaculated. # Dead cells may be replaced by large masses of phospholipids => myelin figures, derived from damaged cellular membranes. # Eventually, dead cells may become calcified. # By electron microscopy, necrotic cells are characterized by: » Discontinuous membranes (plasma, organelles). » Mitochondrial dilation. » Lysosomal disruption. » Cytoplasmic myelin figures. » Nuclear changes: 1) Pyknosis – nuclear shrinkage and increased basophilia due to DNA condensation. 2) Karyorrhexis – fragmentation of pyknotic nucleus. 3) Karyolysis – fading of chromatin basophilia due to DNAse activity.

Answer 37

# IC changes: CELL INJURY Occurs when the adaptive capability of the cell is exceeded. Within a certain limit, cell injury is reversible, but a severe or persistent stress results in irreversible injury and eventually cell death. Cellular function may be long lost before cell death occurs, and morphologic changes of cell injury lag far behind both (myocardial cells become noncontractile after 1-2min of ischemia, die after 20-30min, appear dead after 2-3h at least). The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. Thus, low doses of toxins or a brief duration of ischemia may lead to reversible cell injury, whereas larger toxin doses or longer ischemic intervals may result in irreversible injury and cell death. The consequences of an injurious stimulus depend on the type, status, adaptability, and genetic makeup of the injured cell. The same injury has vastly different outcomes depending on the cell type; thus, striated skeletal muscle in the leg accommodates complete ischemia for 2 to 3 hours without irreversible injury, whereas cardiac muscle dies after only 20 to 30 minutes. The nutritional (or hormonal) status can also be important; clearly, a glycogen-rich hepatocyte will tolerate ischemia much better than one that has just burned its last glucose molecule. Genetically determined diversity in metabolic pathways can also be important. For instance, when exposed to the same dose of a toxin, individuals who inherit variants in genes encoding cytochrome P-450 may catabolize the toxin at different rates, leading to different outcomes. REVERSIBLE CELL INJURY The cell can return to its normal state if the stress is removed. This happens typically in the early stages/mild form of injury. Significant structural/functional abnormalities may be present, there’s no severe membrane damage/nuclear dissolution. Types of reversible cell injury: ♥Cellular swelling / hydropic change/vacuolar degeneration The failure of energy dependent ion pumps, leading to inability to maintain homeostasis: ATP depletion → ion pump failure → failure of ionic and fluid hemostasis f.ex.: IC Na+ increase → water retention → swelling Cellular swelling is the first manifestation of almost all forms of injury to cells, but it is difficult to appreciate it with the light microscope; it may be more obvious at the level of the whole organ. When it affects many cells in an organ it causes some pallor, increased turgor and increase in weight of the organ. Microscopic examination may reveal small, clear vacuoles within the cytoplasm (these are distended and pinched-off segments of the ER). ♥Fatty change (steatosis) It is mainly seen in cells that are either involved or dependent on fat metabolism like hepatocytes and cardiac myocytes. Occurs in hypoxic injury and various forms of toxic or metabolic injury. Fatty change is manifested by the appearance of lipid vacuoles in the cytoplasm of parenchymal cells, which unite to form a large lipid droplet, displacing the nucleus to the periphery. Some cells may rapture, and their vacuoles unite to form fatty cysts. Injured cells may show increased eosinophilic staining, which becomes more pronounced as the cell progresses to necrosis. The mechanism underlying fatty change is the inadequate removal of fat from the cell. Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver. Free fatty acids from adipose tissue or from the food are normally transported into hepatocytes, where they are esterified to triglycerides, converted into cholesterol, phospholipids or oxidized into ketone bodies. Some fatty acids are synthesized from acetate. In order to leave the cell, triglycerides should form complexes with apoproteins to form lipoproteins. Excess accumulation of triglycerides may result from defects at any step from fatty acid entry to lipoprotein exit Hepatotoxins (e.g. alcohol) change the function of mitochondria and sER, and along with anoxia they impair the oxidation of fatty acids; Examples of fatty change: *Mild fatty change in the liver may not affect the gross appearance. With increasing accumulation, the liver enlarges and becomes yellow. It may reach 3-6 kg and appear bright yellow, soft and greasy. *In the heart, lipid is found in the form of small droplets, occurring in one of 2 patterns: 1. Specific location – results from moderate, prolonged hypoxia, creating bands of yellow myocardium alternating with bands of healthy tissue. 2. Uniformly affected myocytes – results from profound hypoxia or toxic injury. sER is involved in the metabolism of various chemicals. Cells exposed to these chemicals show hypertrophy of the ER. barbiturates are metabolizes in liver by cytochrome P-450. Development of tolerance to the drug is due to this hypertrophy and increased P-450 enzymatic activity. In addition, products formed by the ox. metabolism include reactive ox. species(ROS) which may injure the cell » Plasma membrane alteration: blebbing, blunting, distortion of microvilli, loosening of IC attachment. » Mitochondrial changes: swelling and appearance of phospholipid-rich densities. » Dilation of ER with detachment of ribosomes and siddocoation of polysomes » Nuclear alteration with clumping of chromatin. Plasma may conatin phospholipid masses – myelin figures – derived from damaged cellular membranes » IRREVERSIBLE CELL INJURY ♥Inability to reverse mitochondrial damage ♥Profound membrane dysfunction Can be necrosis or apoptosis Necrosis- a spectrum of morphological changes that follow cell death in living tissues due to progressive degradative action of enzymes on lethally induced cells. The enzymes can come from the damaged cells itself “autolysis” (lysosomal f.ex.), from inflammatory cells “heterolysis”. Morphology: PATHOMECHANISM (causes) OF CELL INJURY Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components. The most important targets of injurious stimuli are (1) mitochondria, the sites of ATP generation (2) cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depend (3) protein synthesis (4) the cytoskeleton (5) the DNA 1. Mitochondrial damage Hypoxia / toxins / increased cytosolic Ca2+/ ROS / radiation → mit damage *Formation of high conduction channels “mit. Permeability transition pores” → membrane potential lost → failure of oxidative phosphorylation → ATP depletion AND formation of ROS leakage of proapoptotic molecules to cytosol AND Diffusion of cyt-C to cytosol → stimulation of caspases → apoptosis 2. ATP depletion Hypoxia / toxins (cyanide) / disrupted ETC (mit damage)→ ATP depletion: *Anaerobic glycolysis → decrease in glycogen stores and lactic acidosis → pH↓ → chromatin clumping AND decreased enzymatic activity *Na+/K+ pump failure→ IC Na+ ↑ → water retention → cell & ER swelling → loss of microvilli and detachment of ribosomes → reduced protein synthesis *Ca2+ pump failure → Increased IC Ca2+ => damage to cellular components by activation of enzymes (proteases, caspases, phospholipases). 3. Disturbance in Ca2+ hemostasis Ischemia/toxin → release of sequestered Ca2+ from mit and SER → increased IC Ca2+ *increased mit. Permeability transition pores → apoptosis *Activation of enzymes (ATPase, phospholipase, protease and endonuclease). 4. Membrane damage *Ischemia/toxin/lytic complement components? → Damage to plasma and lysosomal membranes *Loss of osmotic balance (influx/efflux of fluid and ions) AND loss of cellular content. 5. Damage to DNA and misfolding of proteins 6. Oxidative stress ROS are oxygen derived free radicals which are special molecules that have a single unpaired electron in their outer orbit- not stable and thus very reactive. They can convert proteins, carbs and lipids to free radicals themselves (chain reaction). Examples- O2- (superoxide) H2O2 (hydrogen peroxide), OHReduction and oxidation reactions / Ionizing radiation / Inflammation reaction / transition metals like iron and copper participate in “Fenton reactions”→ ROS → oxidative stress *Oxidation of lipids → peroxidase formation in the different membranes *Oxidation of proteins → enzymes lose function, abnormal folding *DNA damage

Answer 38

ADAPTATION Reversible changes in the size, number, phenotype or function of the cell in response to change in the environment, to achieve a new steady state and preserve its function. PHYSIOLOGICAL responses of the cell to normal stimulation by hormones or endogenous mediators => closing/opening of ion channels, enlargement of the breast and uterus during pregnancy PATHOLOGICAL responses of the cell to stress that allows it to modulate its structure, thus escape injury => atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia

Answer 39

# Caspase antagonist is a protein called FLIP. Some viruses produce a FLIP homolog and ADAPTATION Basic principles: ♥ An organ is in homeostasis with the physiologic stress placed on it. ♥ An increase, decrease, or change in stress on an organ can result in growth adaptations. Adaptation any response of a cell to stimuli (stress) to achieve a new steady state and preserve its function. PHYSIOLOGICAL responses of the cell to normal stimulation by hormones or endogenous mediators => closing/opening of ion channels, enlargement of the breast and uterus during pregnancy PATHOLOGICAL responses of the cell to stress that allows it to modulate its structure, thus escape injury => atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia ATROPHY A decrease in the size of an organ in response to a decrease in stress. E.g.: * Decreased hormonal stimulation (in menopause –physiologic) * Disuse (immobilization of a limb to permit healing of a fracture) * Decreased nutrient supply “cachexia” * Decreased blood supply * Denervation- pathologic * Aging (senile atrophy) Although some of these stimuli are physiologic and some are pathologic, the fundamental cellular changes are identical. They represent a retreat by the cell to a smaller size at which survival is still possible; a new equilibrium is achieved between cell size and diminished blood supply, nutrition, or trophic stimulation. *Decreased protein synthesis (due to reduced metabolic activity) and decreased protein degradation Mechanism- a decrease in the size and number of cells ♥ Decrease in cell number Occurs via apoptosis (programmed cell death) ♥ Decrease in cell size Occurs via *Ubiquitin-proteasome degradation of the cytoskeleton Intermediate filaments of the cytoskeleton are "tagged" with ubiquitin and destroyed by proteasomes. *Autophagy of cellular components- process in which the starved cell eats its own components in an attempt to survive. Generation of autophagic vacuoles with lysosomes whose hydrolytic enzymes breakdown cellular components APOPTOSIS Cell death- The morphologic hallmark of cell death is loss of the nucleus, which occurs via nuclear condensation (pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis), leading the cytoplasm to become more eosinophilic. The two mechanisms of cell death are necrosis and apoptosis. Apoptosis: energy (ATP)-dependent, genetically programmed cell death, characterized by nuclear dissolution without complete loss of membrane integrity. Apoptotic bodies fall from the cell and are removed by macrophages; apoptosis is not followed by inflammation. Whereas necrosis is always a pathologic process, apoptosis serves many normal functions. Examples: Physiological 1. Endometrial shedding during menstrual cycle 2. Removal of cells during embryogenesis 3. T cell-mediated killing of virally infected cells 4. Cell loss in proliferating cell populations (intestinal crypt epithelia). 5. Cells that have served their purpose (RBCs, neutrophils in an acute .)inflammatory response – deprived of survival signals like GF 6. Elimination of potentially harmful self-reactive lymphocytes Pathological elimination of cells that are genetically altered or injured beyond repair, keeping extent of tissue damage to a minimum 1) DNA damage that cannot be repaired – radiation, cytotoxic anticancer drugs, extreme temp, hypoxia, directly/through free radicals 2) Misfolded proteins – accumulation of misfolded proteins causes ER stress that induces apoptosis (unfolded protein response), part of Alzheimer, Huntington, Parkinson. 3) Cell injury due to infections, mainly by viral infections. 4) Pathologic atrophy in parenchymal organs after duct obstruction (pancreas, parotid gland, kidney) Mechanism Apoptosis is mediated by caspases that activate proteases (break down the cytoskeleton) and endonucleases (break down DNA). Caspases are activated by multiple pathways: 1. Intrinsic mitochondrial pathway Loss of stimulation of growth factors/agents that damage DNA/acc of misfolded proteins → Inactivation of antiapoptotic proteins (Bcl-2, Bcl-xL) and activation of pro-apoptotic proteins Bax, Bak) → Channels are formed in the mitochondrial membrane → Cytochrome c leaks from the inner mitochondrial matrix into the cytoplasm → Caspases are activated (cytochrome C + Apaf-1 activate caspase 9 → Cytoskeletal and nuclear fragmentation 2. Extrinsic death receptor pathway *FAS ligand binds FAS death receptor on the target cell, activating caspases (e.g., negative selection of thymocytes in thymus). *Tumor necrosis factor binds to receptor on the target cell, activating caspases. 3. Cytotoxic CD8+T cell-mediated pathway *Perforins secreted by CD8+ T cell create pores in membrane of target cell. *Granzyme from CD8+ T cell enters pores and activates caspases. *CD8+ T-cell killing of virally infected cells is an example Regulation of apoptosis is mediated by the Bcl-2 protein family, which includes both pro- and anti-apoptotic proteins, and by p53 protein. prevent cell apop # When DNA is damaged, p53 accumulates in cell, arrests cell in G1 phase for repair, if damage is too great, it triggers apop by activating Bax, Bak and increase synthesis of pro-apop members of Bcl-2 family INVOLUTION Developmental loss Examples of involution: » Involution of the uterus – after birth the uterus returns from its hypertrophic state to its normal size. » Involution of the thymus – during puberty the gland begins to atrophy, and is gradually replaced by fat.

Answer 40

# Homeostasis – a process in which the cell regulates its internal environment by HOMEOSTASIS OF THE CELL continuous exchange of nutrients, fluids and temperature (heat) with the external environment. # Stress – any stimulus that interrupts with the homeostasis of the cell, which can be physiological or pathological. TYPES OF STRESS mnemonic: higc pain # Hypoxia – interferes with aerobic oxidative respiration; it can be caused by *Ischemia- reduced arterial or venous blood flow (atherosclerosis…) *Hypoxemia- reduced amount of oxygen in blood PiO2 (inspired) → PAO2 (alveolar)→ PaO2 (arterial)→ SaO2 (RBC) hypoventilation, high altitude → lack of lung perfusion, obstructive disease, lack of surfactant… (pneumonia) *Anemia/CO poisoning- reduction of the oxygen carrying capacity. Infectious agents – viruses, bacteria, fungi etc. # Genetic defects – congenital malformations (sickle cell), damaged DNA, misfolded proteins. # Chemical agents – substances that are osmotically active, such as glucose or salts, which cause movement of fluids into or out of the cell, others: pollutants, co, asbestos, high amount of ox. # Physical agents – such as trauma, extreme temperatures, radiation, atmospheric pressure etc. # Aging – leads to alterations in the ability of the cell to replicate and repair itself. # Immunologic reactions – autoimmune reactions, allergic reactions. # Nutritional imbalance – when the diet lacks certain nutritional values (proteins, vitamins). THE CONCEPT OF ADAPTATION An increase, decrease, or change in stress on an organ can result in growth adaptations. # Reversible changes in the size, number, phenotype or function of the cell in response to change in the environment, to achieve a new steady state and preserve its function. The responses of the cell can be either physiological or pathological: » Physiological adaptation – the responses of the cell to normal stimulation by hormones or endogenous chemicals. » Pathological adaptation – the responses of the cell to stress, allowing the cell to modulate its structure and function to avoid cell injury. These adaptations can be: hyperplasia, hypertrophy, metaplasia, atrophy and dysplasia. CELLULAR INJURY When the cell is exposed to severe stress that exceeds its adaptive capability, cell injury may occur. The injury can be acute or chronic, and these are further subdivided as follows: Acute can be divided into: based on nature and severity of stress AND basal cellular metabolism and nutrient supply? ♥Reversible – the cell can return to its normal state if the stress is removed. Early stages/mild form of injury, Significant structural/functional abnormalities may be present, there’s no severe membrane damage/nuclear dissolution. Morphological correlates: 1. Cellular swelling- failure of energy dependent ion pumps, leading to inability to maintain homeostasis. ATP depletion → ion pump failure → failure of ionic and fluid hemostasis f.ex.: IC Na+ increase → water retention → swelling → loss of microvilli → absorption↓ →bulbes formation due to cytoskeletal failure → rER swelling → ribosomes detach → protein synthesis↓ 2. Fatty change- occurs in hypoxic injury and in various forms of toxic/metabolic injury. Manifested by lipid vacuoles in cytoplasm. Abnormal accumulation of TAGs within parenchymal cells, observed most frequently in the liver (major organ of fat metabolism), but also in the heart and kidney ♥Irreversible – the cell will eventually die. Necrosis (always pathological)/apoptosis (no GF, DNA/proteins damage). Characterized by – inability to correct mitochondrial dysfunction, and profound disturbance in membrane function. The cell's fate can be: 1. Necrosis 2. Apoptosis Chronic: The causes of injury are the various types of stress mentioned earlier, which induce distinctive alterations that include only the organelles: » Autophagy – lysosomal digestion of the cell's own components, considered to be a survival mechanism in nutrient deprived cells. » Hypertrophy of sER – occurs in cells that are exposed to certain chemical agents, such as barbiturates. (Hepatocytes detoxification). » Mitochondrial alterations – change in the number, size and shape of mitochondria. » Cytoskeletal abnormalities – occur due to certain drugs that interfere with the normal function of cytoskeleton (disrupt polymerization, cause accumulation of fibrillar material, defective mobility of organelles).

Answer 41

# Benign epithelial neoplasms are very common properly develop from stem cells reside in the BENIGN AND PREMALIGNANT EPITHELIAL LESIONS epidermis and hair follicles. They grow to a limited size and generally do not undergo malignant transformation. SEBORRHEIC KERATOSIS # Presents as raised round, discolored plaques on the extremities or face made of proliferating basal epidermal cells Characterized by keratin pseudocysts on epidermis see also sometimes hyperkeratosis common tumor in the elderly Usually these lesions are of little clinical importance. In rare cases see abundant such as lesions may appear as a paraneoplastic syndrome most common are the GI tract carcinoma association which produce GF that stimulate epidermal proliferation. # Pathogenesis – activating mutations in Fibroblast Growth Factor receptor . ACTINIC KERATOSIS # This lison usually a result of chronic exposure to sunlight, and is associated with hyperkeratosis hence actinic keratosis. Pathogenesis –. Mostly associated with TP53 mutation age fair skin n sun exposure (inducing tp53 mutation). has the potential to become malignant (SSC) therefore must be removed . # Morphology – Usually are less than 1 cm in diameter, brown or red in color, and rough. Epidermis – show cytological atypia in lower part of epidermis; parakeratosis of stratum corneum can also be seen .Dermis – actinic elastosis. Instead of collagen see elastic fibers become homogenous appearance on HE … SEBACEOUS ADENOMA # Rear benign, self-limited growth, that appear in the head and neck region of older individuals. Present as flesh-colored papules-elevated less than 5 mm lesion. Pathophys Association with Muir-Torre syndrome, a rare autosomal dominant cancer syndrome, and with internal malignancy, mainly colon carcinoma. Both cases are considered subtypes of hereditary nonpolyposis colorectal carcinoma syndrome, characterized by loss of a DNA mismatch repair protein. Morphology – lobular proliferation of sebocytes that maintain an organoid appearance. with expansion of germinative basaloid cell layers at periphery MALIGNANT EPIDERMAL TUMORS SQUAMOUS CELL CARCINOMA # Malignant proliferation of squamous cells. Presents as an red scaling may ulcerate , nodular mass, usually appear on sun-exposed sites in older people typically the face (classically involving the lower lip) With higher incidence in men than in women. Predisposing factors exposure to sunlight, albinism, and xeroderma pigmentosum. Additional risk factors include immunosuppressive therapy, toxin exposure - arsenic exposure, and chronic inflammation (e.g., scar from burn, chronic ulcers etc..) Pathogenesis – Exposure to UV light Causes mutation in TP53, HRAS and loss of function in Notch receptors, which regulates differentiation of normal squamous epithelia. Also has Immunosuppressive effect on skin by impairing antigen presentation by Langerhans cells. Morphology – Characterized by atypical cells at all levels of the epidermis Invasive tumors, defined by penetration of the basement membrane. Show variable degrees of differentiation, ranging from tumors with cells arranged in orderly lobules that exhibit extensive keratinization to neoplasms consisting of highly anaplastic cells with foci of necrosis and only abortive, singlecell keratinization (dyskeratosis). See inflammatory reaction aroun nodules in dermis Clinical features – Treatment is excision; rarely metastasize; the likelihood of metastasis is related to the thickness of the lesion and degree of invasion into the sub cutis. Mucosal squamous cell carcinoma (oral, pulmonary, esophageal) are much more aggressive BASAL CELL CARCINOMA # Malignant proliferation of the basal cells of the epidermis Most common cutaneous malignancyA slow-growing tumor that Rarely metastasize Pathogenesis – Tends to occur at sites subjected to chronic sun exposure associated with a tumor suppressor mutation that regulates the Hedgehog pathway, causes familial basal cell carcinoma and also in sporadic see mutations in hedgehok path. Mutations in p53 are also common in familial or sporadic carcinomas. Morphology – Presents as an elevated nodule with a central, ulcerated crater surrounded by dilated (telangiectasia) vessels 'pink, pearl-like papule' Classic location is the upper lip. Tumor cells resemble the epidermal basal cells from which they originate. On histo see horizontal growth along-epithelodermaljunction and vertical growth into dermis crate island of malignant cells may be bordered by palisading, around it see inflammation and it destroy surrounding dermis as it replace it… Clinical features – Should be radically removed extensive local invasion of bone or facial sinuses may occur. Actinic keratosis is a precursor lesion of squamous cell carcinoma and presents as a hyperkeratotic, scaly plaque, often on the face, back, or neck. Keratoacanthoma is well-differentiated squamous cell carcinoma that develops rapidly and regresses spontaneously; presents as a cup-shaped tumor filled with keratin debris

Answer 42

# A brown, uniformly pigmented, small (<5mm), solid regions of elevated skin (papules) Melanocytes are responsible for skin pigmentation and are present in the basal layer of the epidermis. Derived from the neural crest. Synthesize melanin in melanosomes using tyrosine as a precursor molecule Pass melanosomes to keratinocytes Melanocytic nevus is the benign tumor of melanocytes Nevus = congenital. Malignant melanoma is a malignant tumor of melanocytes MELANOCYTIC NEVI with well defined, rounded borders. Initially composed of oval cells that grow in nests along the dermoepidermal junction => JUNCTIONAL NEVI Most junctional nevi grow into the underlying dermis as nests or cords of cells => COMPOUND NEVI In older lesions, the epidermal nests may be lost completely to leave pure INTRADERMAL NEVI. The majority of benign nevi show an activating mutation in BRAF, or less commonly in RAS. BRAF – a gene encoding Ser/Thr kinase which is involved in directing cell growth. changes of morphology of cells as evidence of cellular senescence Superficial nevus cells – larger and less mature, tend to produce melanin and grow in nests. Deeper nevus cells – smaller and more mature, produce little to no pigment and grow in cords or single cells; the deepest nevus cells grow n fascicles. DYSPLASTIC NEVUS Dysplastic nevi consist mainly of compound nevi and Marked by Cytological atypia (consisting of irregular nuclei and hyperchromasia) result from BRAF or RAS mutations May occur sporadically or in a familial form (autosomal dominant inheritance).appearance of dysplastic nevi mainly Familial are considered as markers for risk to develop melanoma . Morphology – Larger than most acquired nevi (>5mm), may occur in large numbers come as flat macules to slightly raised plaques, show variable pigmentation and irregular borders. accure on sun expose n non expose surfaces Nevus cell nests within the epidermis may be enlarged and fusion with adjacent nests.As a result, the nevus cells begin to replace the normal basal cells at the dermoepidermal junction- lentiginous pattern Dermal changes as host respond see Lymphocytic infiltration into the superficial dermis. melanin phagocytosis by dermal macrophages Linear fibrosis surrounding epidermal nests of melanocytes. MELANOMA # Malignant neoplasm of melanocytes; most common cause of death from skin cancer # Pathogenesis – Sunlight exposure plays the important role - Most melanomas occur sporadically also hereditary predisposition – dysplastic nevus syndrome (autosomal dominant disorder characterized by formation of dysplastic nevi that may progress to melanoma). Mutations in the gene of p16 gene that encodes a cyclin-dependent kinase inhibitor regulating the G1-S transition; this mutation id found in 40% of familial melanomas and less commonly in sporadic cases the gene is silenced by methylation. Somatic activating mutations in the protooncogenes BRAF and NRAS are common in melanomas of bout kinds Growth pattern- Radial growth is the initial tendency of a melanoma to grow horizontally within the epidermis (in situ) and superficial dermal layers => during this stage no metastasizes, and do not induce angiogenesis. Vertical growth: the melanoma grows into the deeper dermal layers, lacking cell maturation- with greater metastatic potential => metastases involves regional lymph nodes, liver, lungs, brain etc. Morphology –show large variation of pigmentation (black, brown, red etc..) The borders are irregular and notched. Malignant cells grow in poorly-formed nests or ad individual cells at all levels of the epidermis Melanoma cells are larger than nevus cells, containing large nuclei with chromatin clumped at the periphery of the nucleus, with prominent eosinophilic nucleoli (described as "cherry red"). Superficial spreading melanomas are associated with lymphocytic infiltrate. Clinical features – Mostly arise in the skin, yet may also involve oral and anogenital mucosal surfaces, esophagus, meninges, and the eye. Signs of melanoma – ABCs of melanoma – Asymmetry, Border, Color, Diameter, Evolution (change of an existing nevus). Probability of metastasis is predicted by measuring the depth of invasion in mm of the vertical growth phase nodule from the top of the granular call layer of the epidermis (Breslow thickness)

Answer 43

# Sarcoma vs. Carcinoma : carcinoma easily will be separated into parenchyma & CLASSIFICATION AND GRADING OF SOFT TISSUE TUMORS Soft tissue – The bulk of the body is composed of the cells forming tissues that are considered "soft" tissues or connective tissues. (Any non-epithelial tissue except bone, cartilage, CNS, hematopoietic and lymphoid tissues).These embryological derived from the mesoderm. Hence, they are often called me-senchymal tissues. Classification of soft tissue tumors: stroma. In sarcoma both paranchyma & stroma are derived from the same origin = cannot be separated. Tumors of the peripheral nerves be-long here despite their derivation from the neuroectoderm! Currently we assume they originate from tissue-specific Mesenchymal stem cells and not from malignant transformation of adult tissue cells . MSCs, are multipotent stromal cells that can differentiate into a variety of cell types creating mesenchymal tissue MSCs do not differentiate into hematopoietic cells got self-renewing asymmetric division and found in body : placenta umbilical cord blood, adipose tissue, adult muscle, corneal stroma or the dental pulp of deciduous baby teeth, but do not have the capacity to reconstitute an entire organ. Metaplasia is common in soft tissue tumors Soft tissue tumors are rarely malignant (represent less than 1% of all invasive malignancies), but they cause 2% of all cancer deaths, reflecting their lethal nature. Soft tissue tumors can arise in any location, but 40% occur in the lower extremities. Soft tissue sarcomas usually are treated with wide surgical excision (frequently limbsparing), with irradiation and systemic therapy reserved for large high-grade tumors. Prognosis of soft tissue: Diagnostic classification- histology, immunohistochemistry, electron microscopy, cytogenetics and molecular genetics are important in assigning the correct diagnosis. Keeping in mind the high metaplastic appearance… Histological diagnosis = pattern recognition help in estimate tumer type patterns apper chrecteristicly with different tumers Spindle cell/epitheloid/pleiomorphic/small blue cell /biphasic Grading Differentiation! How well it resembles the origin cell. Staging = the stage! Location. # Staging- use TNM system as size and depth of invesion looked in T the N for nodal involvement and the M for metastasis With tumors larger than 20 cm, metastases develop in 80% of cases; by contrast, for tumors 5 cm or smaller, metastases occur in only 30% of cases. It is rare for adult sarcomas to metastasize to lymph nodes. Note that in STT the dipper ones more aggressive then superficial.. Grading- Grading based on a scale of I to III, relating to the degree of differentiation, the mitotic activity and of the extent of necrosis. 1. Differentiation (1-3 score) less diffrant. Higher score 2. Mitotic count (1-3 score) 3. Necrosis (1-3 score) higher score more necrosis Total sum = from 1-3 by addition of scores in each category as 3 grade got higst summed up score Grade help to indicate the probability of distant metastases and reaction to treatment… TUMORS OF ADIPOSE TISSUE LIPOMA Benign tumors of fat.Most common soft tissue tumors in adult. # Most lipomas are solitary lesions, mobile, slowly enlarging, painless masses ( Multiple lipomas may suggest the presence of rare heredity syndromes). Can be classified based on their histologic features or chromosomal rearengment: » Conventional lipoma- (the most common subtype) are soft, yellow, wellencapsulated masses of mature adipocytes; they can vary considerably in size and no pleomorphism. » Myolipoma – a benign tumor that consists of fat cells with variable number of muscle cells. » Spindle cell lipoma – slow-growing subcutaneous tumors, mainly in the back, neck and sholders of older men. » Myelolipoma – a benign tumor composed of mature adipocytes and hematopoietic cells. » Pleomorphic lipoma – characterized by giant cells that resemble small flowers, with overlapping nuclei. » Angiolipoma – subcutaneous nodule with vascular structure; they are commonly painful. LIPOSARCOMA Malignant neoplasms of adipocytes usually occur in 50-60 years old. Most liposarcomas arise in deep soft tissues or in the retroperitoneum. Can be sub classified: » Well-differentiated liposarcoma – malignant lesions that arise in the retroperitoneum, commonly associated with amplification of a region in the long arm of chromosome 121 . » Dedifferentiated liposarcoma – consists of a well-differentiated liposarcoma adjacent to a more poorly differentiated tumor. » Myxoid (round cell) liposarcoma – associated with translocation between chromosomes 12 and 16, which affects the transcription factor that plays a role in normal adipocyte differentiation. More aggressive pleomorphic variant, which tend to recur after excision and metastasize to lungs. Morphology – Well circumscribed lesion. » Myxoid liposarcoma characterized by abundant, mucoid extracellular matrix. » Lipoblasts are present  indicative of fatty differentiation. They have cytoplasmic lipid vacuoles that scallop (צדפה (the nucleus TUMORS AND TUMOR-LIKE LESIONS OF FIBROUS TISSUE I. REACTIVE PROLIFERATIONS # Nodular fasciitis –rapidly growing reactive lesion of self-limited fibroblastic proliferation that probably resulted from trauma(Rarely recurs after excision) and is superficial » Morphology – Tightly woven uniform spindle cells and collagen are seen (=stroiform arrangement) A few lymphocytes & vascular channels are present. » Can be up to several cm in diameter and appears nodular Typically occurs in adults on the volar aspect of the forearm, chest or back Myositis ossificans » Distinguished from other types of fibroblastic proliferations by the presence of metaplastic bone. » Characterized by the ossification of muscle. Develops in the proximal muscles of the extremities in athletic adolescents and young adults after trauma. » Initially, the involved area is swollen and painful, and eventually develops into a hard, painless, well-demarcated mass. Critical to distinguish from extra skeletal osteosarcoma. II. FIBROMATOSES # Benign soft tissue tumors the lesions are locally aggressive, but DO NOT metastasizes. Many cases recur after surgical removal. Can be divided into 2 groups: » Superficial fibromatoses – arise in the superficial fascia2 , can be associated with trisomy 3 & 8, but usually are harmless. » Deep fibromatoses – include the desmoid tumor that arise in the abdominal wall and mesentery, and muscles of the trunk and extremities, as isolated lesions or as a component of Gardner syndrome3 ; tend to grow in a locally aggressive manner, Morphology – » The tumors are gray-white, firm to rubbery, poorly demarcated, infiltrative masses (1- 15cm). » histology consistent with : contain abundant dense collagen. with low cellularity , a proliferation of well-differentiated fibroblasts that tend to grow in an infiltrative fashion III. FIBROSARCOMA # Malignant neoplasms composed of fibroblasts. Tend to grow slowly And Typically found in the deep tissues of the thigh, knee and retroperitoneal area. Recur locally after excision. (in 50% of cases) Can metastasize, usually to the lungs. Morphology – soft, unencapsulated, infiltrative masses, usually with areas of hemorrhage and necrosis. Histologic examination  discloses all degree of differentiation.

Answer 44

# Skeletal muscle neoplasms are almost all malignant.rheabdomyoma is rear bingeing skeletal SKELETAL MUSCLE TUMORS .m. tumor most often found in heart. RHABDOMYOMA # rear benign hamartomatous tumor of striated muscle. Can be cardiac or extra cardiac  most often found in the heart. Can be classified as adult type, fetal type and genital type. Very rear but Most frequent primary tumor of the heart in infants and children RHABDOMYOSARCOMA # Skeletal muscle malignant neoplasm Usually appears in children and adolescents. Occur most commonly in the head and neck region or the urogenital tract . # often chromosomal translocation are found, mainly t(2,13)4 . # Morphology – Can be sub classified into morphological types embryonal, alveolar and pleomorphic variants. Tumors that arise next to the bladder or vagina are soft, gelatinous, grape-like masses (sarcoma botryoides); in other cases the tumor is poorly defined. Rhabdomyoblast is the cell that appears in all types, and exhibits granular, eosinophilic cytoplasm rich in thick and thin filaments. These cells can be round or elongated2 IHC: desmin, aktin  Clink.: aggressive; chemotherapy often effective, especially in children (cure) SMOOTH MUSCLE TUMORS LEIOMYOMA Benign smooth muscle tumors. Common, well-defined neoplasms that arise most commonly in the uterus. These tumors are monoclonal and are associated with chromosomal rearrangement of chromosomes 6 and 12 Morphology – Very well-defined, gray-white masses with whorled cut surface. Can be intramural (within the myometrium), submucosal (directly beneath the endometrium), or subserosal5 (directly beneath the serosa). Large neoplasms may develop ischemic necrosis with areas of hemorrhage and cystic softening; after menopause, they may become collagenous and even calcified. LEIOMYOSARCOMA Occur in adults, more commonly in females. Usually exist as SOLITARY tumors, usually occur in postmenopausal women (in contradiction to leiomyoma) Present as firm, painless masses. Common sites of development are skin, deep soft tissues of the extremities and retroperitoneum. Metastasize typically to the lungs. Leiomyosarcoma of the uterus usually arise de novo from mesenchymal cells of the myometrium, and NOT from pre-existing leiomyomas. Morphology – Soft, hemorrhagic and necrotic. They show spindle cells with cigar-shaped nuclei arranged in interwoven fascicles. Present cytological atypia and mitotic activity. Present a wide range of cell differentiation, from close resemblance to leiomyoma to anaplastic tumors. PERIPHERAL NERVE TUMORS # In most tumors, the neoplastic cells show evidence of Schwann cell differentiation. These tumpors usually occur in adults.They are frequently associated with familial tumor syndromes neurofibromatosis type 1 (NF1) and type 2 (NF2) SCHWANNOMA AND NEUROFIBROMATOSIS TYPE 2 # Schwannomas are benign encapsulated tumor composed of Schwann cells that may occur in soft tissues, internal organs or spinal nerve roots .Causing local compression of the involved nerve, or the compression of adjacent structures Most Schwannomas are sporadic; 10% inherited associated with NF2 or Schwannomatosis .The presence of bilateral vestibular Schwannomas is the hallmark of NF2. Affected patients carry a dominant loss-of-function mutation of the merlin8 gene on chromosome 22 Schwannomatosis is a familial condition associated with multiple Schwannomas in which vestibular nerve is absent Morphology – Well-defined, encapsulated Firm, gray masses. That are attached to the nerve, but can be separated from it. Histo-Biphasic tumor: Antoni A – dense areas; bland spindle cells arranged into intersecting fascicles.Often align to produce nuclear palisading, resulting in alteration bands of nuclear and a nuclear areas called Verocay bodies. Antoni B – loose meshwork of cells and stroma Thick-walled hyalinized vessels often are present NEUROFIBROMA # Benign peripheral nerve sheath tumors. # Subdivided into 3 types: » Localized cutaneous neurofibroma – arise as superficial nodular or polypoid tumor. These occur either as solitary sporadic lesions or as multiple lesions in the context of NF1 » Plexiform neurofibroma – grow diffusely within a nerve or a nerve plexus; associated with type 1 neurofobromatosis (NF1); may evolve to a malignant tumor; involve multiple fascicles of individual affected nerves, residual axons are found embedded within the diffuse neoplastic Schwann cell proliferation » Diffuse neurofibromas – infiltrative proliferation; large subcutaneous masses. Often associated with NF1; often found in the dermis and subcutis of the skin. Morphology – not encapsulated (unlike Shwannomas). May appear circumscribed (localized cutaneous neurofibroma) or diffuse. In contrast with Schwannomas, neoplastic Schwann cells are mixed with other cell types (mast cells, fibroblast-like cells and perineurial-like cells). Stroma contains loose wavy collagen bundles/dense collagen MALIGNANT PERIPHERAL NERVE SHEATH TUMOR # Highly malignant sarcomas, which are locally invasive. # Seen in adults, typically show evidence of Schwann cell derivation and sometimes arise from transformation of a plexiform neurofibroma (50% arise from NF1) Morphology – » Large, poorly defined tumor masses. » Tumors are highly cellular, exhibiting malignancy properties (anaplasia, necrosis, infiltrative growth pattern, pleomorphism, high proliferative activity) » Low power magnification shows alternating areas of high and low cellularity  marble-like appearance NEUROFIBROMATOSIS TYPE 1 # Autosomal dominant disorder caused by mutation in the tumor suppressor neurofibromin found of chromosome 17. # Neurofibromin is a negative regulator of Ras. Patients exhibit learning disabilities, seizures, skeletal abnormalities, vascular abnormalities with arterial stenoses, pigmented nodules of the iris (Lisch nodules), pigmented skin lesions. SYNOVIAL SARCOMA The cell of origin is unclear (non-joint origin!!), but it is most certainly NOT cells of the synovium; less than 10% are intra-articular. Mostly affect persons in their 20-40 years # Usually develop in deep soft tissues around the large joints of the extremities, mainly the knee joint. # Most synovial sarcomas show t(X, 18)9 . # Morphology – » The tumor can be monophasic (only one cell type – spindle cell), or biphasic (both cell types). » Nonophasic tumors may be mistaken with fibrosarcomas or malignant peripheral nerve sheath tumor, differential diagnosis is done by immunohistochemistry showing a positive test result for keratin and epithelial membrane antigen. » Tumor cells can be of two types: 1) Spindle cell (fibrous type cell) – arranged in cellular fascicles that surround the epithelial cells. 2) Epithelial-like cell – cuboidal to columnar, form glands or grow in solid cords or aggregates. » Common metastatic site are the lungs, bones and regional lymph node

Answer 45

# Skeletal muscle neoplasms are almost all malignant.rheabdomyoma is rear bingeing skeletal SKELETAL MUSCLE TUMORS .m. tumor most often found in heart. RHABDOMYOMA # rear benign hamartomatous tumor of striated muscle. Can be cardiac or extra cardiac  most often found in the heart. Can be classified as adult type, fetal type and genital type. Very rear but Most frequent primary tumor of the heart in infants and children RHABDOMYOSARCOMA # Skeletal muscle malignant neoplasm Usually appears in children and adolescents. Occur most commonly in the head and neck region or the urogenital tract . # often chromosomal translocation are found, mainly t(2,13)4 . # Morphology – Can be sub classified into morphological types embryonal, alveolar and pleomorphic variants. Tumors that arise next to the bladder or vagina are soft, gelatinous, grape-like masses (sarcoma botryoides); in other cases the tumor is poorly defined. Rhabdomyoblast is the cell that appears in all types, and exhibits granular, eosinophilic cytoplasm rich in thick and thin filaments. These cells can be round or elongated2 IHC: desmin, aktin  Clink.: aggressive; chemotherapy often effective, especially in children (cure) SMOOTH MUSCLE TUMORS LEIOMYOMA Benign smooth muscle tumors. Common, well-defined neoplasms that arise most commonly in the uterus. These tumors are monoclonal and are associated with chromosomal rearrangement of chromosomes 6 and 12 Morphology – Very well-defined, gray-white masses with whorled cut surface. Can be intramural (within the myometrium), submucosal (directly beneath the endometrium), or subserosal5 (directly beneath the serosa). Large neoplasms may develop ischemic necrosis with areas of hemorrhage and cystic softening; after menopause, they may become collagenous and even calcified. LEIOMYOSARCOMA Occur in adults, more commonly in females. Usually exist as SOLITARY tumors, usually occur in postmenopausal women (in contradiction to leiomyoma) Present as firm, painless masses. Common sites of development are skin, deep soft tissues of the extremities and retroperitoneum. Metastasize typically to the lungs. Leiomyosarcoma of the uterus usually arise de novo from mesenchymal cells of the myometrium, and NOT from pre-existing leiomyomas. Morphology – Soft, hemorrhagic and necrotic. They show spindle cells with cigar-shaped nuclei arranged in interwoven fascicles. Present cytological atypia and mitotic activity. Present a wide range of cell differentiation, from close resemblance to leiomyoma to anaplastic tumors. PERIPHERAL NERVE TUMORS # In most tumors, the neoplastic cells show evidence of Schwann cell differentiation. These tumpors usually occur in adults.They are frequently associated with familial tumor syndromes neurofibromatosis type 1 (NF1) and type 2 (NF2) SCHWANNOMA AND NEUROFIBROMATOSIS TYPE 2 # Schwannomas are benign encapsulated tumor composed of Schwann cells that may occur in soft tissues, internal organs or spinal nerve roots .Causing local compression of the involved nerve, or the compression of adjacent structures Most Schwannomas are sporadic; 10% inherited associated with NF2 or Schwannomatosis .The presence of bilateral vestibular Schwannomas is the hallmark of NF2. Affected patients carry a dominant loss-of-function mutation of the merlin8 gene on chromosome 22 Schwannomatosis is a familial condition associated with multiple Schwannomas in which vestibular nerve is absent Morphology – Well-defined, encapsulated Firm, gray masses. That are attached to the nerve, but can be separated from it. Histo-Biphasic tumor: Antoni A – dense areas; bland spindle cells arranged into intersecting fascicles.Often align to produce nuclear palisading, resulting in alteration bands of nuclear and a nuclear areas called Verocay bodies. Antoni B – loose meshwork of cells and stroma Thick-walled hyalinized vessels often are present NEUROFIBROMA # Benign peripheral nerve sheath tumors. # Subdivided into 3 types: » Localized cutaneous neurofibroma – arise as superficial nodular or polypoid tumor. These occur either as solitary sporadic lesions or as multiple lesions in the context of NF1 » Plexiform neurofibroma – grow diffusely within a nerve or a nerve plexus; associated with type 1 neurofobromatosis (NF1); may evolve to a malignant tumor; involve multiple fascicles of individual affected nerves, residual axons are found embedded within the diffuse neoplastic Schwann cell proliferation » Diffuse neurofibromas – infiltrative proliferation; large subcutaneous masses. Often associated with NF1; often found in the dermis and subcutis of the skin. Morphology – not encapsulated (unlike Shwannomas). May appear circumscribed (localized cutaneous neurofibroma) or diffuse. In contrast with Schwannomas, neoplastic Schwann cells are mixed with other cell types (mast cells, fibroblast-like cells and perineurial-like cells). Stroma contains loose wavy collagen bundles/dense collagen MALIGNANT PERIPHERAL NERVE SHEATH TUMOR # Highly malignant sarcomas, which are locally invasive. # Seen in adults, typically show evidence of Schwann cell derivation and sometimes arise from transformation of a plexiform neurofibroma (50% arise from NF1) Morphology – » Large, poorly defined tumor masses. » Tumors are highly cellular, exhibiting malignancy properties (anaplasia, necrosis, infiltrative growth pattern, pleomorphism, high proliferative activity) » Low power magnification shows alternating areas of high and low cellularity  marble-like appearance NEUROFIBROMATOSIS TYPE 1 # Autosomal dominant disorder caused by mutation in the tumor suppressor neurofibromin found of chromosome 17. # Neurofibromin is a negative regulator of Ras. Patients exhibit learning disabilities, seizures, skeletal abnormalities, vascular abnormalities with arterial stenoses, pigmented nodules of the iris (Lisch nodules), pigmented skin lesions. SYNOVIAL SARCOMA The cell of origin is unclear (non-joint origin!!), but it is most certainly NOT cells of the synovium; less than 10% are intra-articular. Mostly affect persons in their 20-40 years # Usually develop in deep soft tissues around the large joints of the extremities, mainly the knee joint. # Most synovial sarcomas show t(X, 18)9 . # Morphology – » The tumor can be monophasic (only one cell type – spindle cell), or biphasic (both cell types). » Nonophasic tumors may be mistaken with fibrosarcomas or malignant peripheral nerve sheath tumor, differential diagnosis is done by immunohistochemistry showing a positive test result for keratin and epithelial membrane antigen. » Tumor cells can be of two types: 1) Spindle cell (fibrous type cell) – arranged in cellular fascicles that surround the epithelial cells. 2) Epithelial-like cell – cuboidal to columnar, form glands or grow in solid cords or aggregates. » Common metastatic site are the lungs, bones and regional lymph node

Answer 46

# The functional unit of the kidney is the nephron, which is composed of the glomerulus and a STRUCTURE OF THE NEPHRON tubular system, in which the filtered fluid is converted into urine. The glomerular capillary wall is the filtration unit, and is composed of 3 layers: 1) Fenestrated endothelium – each pore is 70-100nm in diameter. 2) Glomerular basement membrane – consists of 3 sub layers => lamina rara interna and lamina rara externa10, between them is the lamina densa 3) Visceral epithelium – composed of podocytes that possess interdigitating processes adherent to the lamina rara externa create by their processes 20-30nm wide filtration slits that are covered by a slit membrane. Podocyte slit diaphragm are an important diffusion barrier for plasma proteins and synthesis of the GBM components. The glomerular structure is supported by mesangial cells, lying between the capillaries, which have contractile, proliferative abilities, laying down CT and secretion of active mediators. # The selective permeability depends on the size of the molecule, the charge (cationic are more permeable) of molecule CLINICAL MANIFESTATION OF RENAL DISEASE can be grouped into reasonably well-defined syndromes Azotemia is an elevation of blood urea nitrogen and creatinine levels reflects a decreased glomerular filtration rate (GFR) Prerenal azotemia is seen when there’s hypo perfusion of the kidney -decrease in GFR Post renal azotemia – urine flow is obstructed below the level of the kidney Uremia when azotemia gives rise to clinical manifestations metabolic and endocrine alterations incident to renal damage Major syndromes: * Nephritic syndrome: due to glomerular injury (most common - post streptococcal glomerulonephritis); visible/microscopic hematuria, some level of oligouria and azotemia and hypertension. * Nephrotic syndrome: heavy proteinuria (>3.5g/day), hypoalbunemia, severe edema, hyperlipidemia and lipiduria. * Asymptomatic hematuria: non-nephrotic proteinuria, usually due to mild glomerular abnormalities. * Rapidly progressive glomerulonephritis: nephritic synd that progress to rena failure in weeks to months * Acute kidney injury: dominated by acute oliguria or anuria and azotemia. May result from glomerular injury, intestinal injury, vascular injury or acute tubular injury. * Chronic kidney disease: prolonged symptoms and signs of uremia, due to progressive scarring in the kidney. Urinary tract infection: characterized by bacteriuria and pyuria. May be symptomatic or asymptomatic, may affect the kidney (pyelonephritis) or the bladder (cystitis) only. * Nephrolithiasis (renal stones): manifested by renal colic-cherecter abd. Pain , hematuria (without casts) and recurrent stone formation. MECHANISM OF GLOMERULAR INJURY Primary glomerular diseases- the kidney is the predominant organ involved (e.g minimal change GN). In Secondary glomerular diseases- injury is caused by a systemic disease (SLE, hypertension, diabetes mellitus, Alport syndrome). Most types of primary glomerular diseases, and many of the secondary diseases, are caused by immune reactions. Which come in 2 types : 1.antibody-associated # Circulating immune complexes Injury resulting from deposition of soluble circulating antigen-antibody complexes in the glomerulus. Complexes are formed due to exposure to antigens that DO NOT originate in the glomerulus. The deposition of these complexes produces injury through the activation of the complement system and recruitment of leukocytes. The glomerular lesions usually consist of leukocytes infiltration into glomeruli, and proliferation of endothelial, mesangial and epithelial cells. in situ immune complexes Injury by antibodies reacting in situ within the glomerulus, either with glomerular antigens or with molecules planted within the glomerulus. The antibodies react directly with antigens fixed or planted in the glomerulus. Planted antigens include nucleosomal complexes in patients with SLE, bacterial products egendostroptosin expressed by group A streptococci, IgG which tend to deposit in the mesangium and the immune complexes themselves. in most cases planted antigens induce a granular pattern under immunofluorescence microscopy. Antibodies against glomerular cell components In anti-glomerular basement membrane (GBM) glomerulonephritis, autoantibodies are produced against the GBM14.Deposition of anti-GBM antibodies appears linear in immunoplerescence. The GBM antigen responsible for the production of these antibodies is a domain in collagen type IV of the GBM. Constitute less than 1% of glomerulonephritis cases, its results include severe glomerular damage- with necrosis, crescents and rapidly progressive. Anti-GBM may cross react with the basement membrane of the alveoli resulting in both kidney and alveoli lesions known as Goodpasture syndrome. 2.cell-mediated Glomerular injury is caused by sensitized T cells, and may explain incidents in which there were no deposits of antibodies or immune complexes.Even so, it has been difficult to establish the exact role of T cells or cell-mediated immune response in any form of glomerulonephritis. Mediators of immune injury # Complement-leukocyte mediated injury – activation of complement generates chemotactic agents (mainly C5a) that help recruit neutrophils; the neutrophils release proteases, oxygen-derived free radicals that cause cell damage and arachidonic acid metabolites which contribute to reduction in GFR. Complement dependent injury (when there are no neutrophils) – activation of the membrane attack complex (C5-C9), which causes the creation of pores in the GBM. And up-regulates TGF-β receptors on podocytes (stimulates synthesis of ECM). Monocytes and macrophages – infiltrate the glomerulus during the immune response and release a vast number of biologically active molecules. # Platelets – aggregate in the glomerulus during the immune response and release prostaglandins and GF. # Resident glomerular cells(mesangial,epithelial, endothelial) – can be stimulated to secrete mediators # thrombin – produces as a consequence of intraglomerular thrombosis cause leukocytes infiltration and glomerular cell proliferation. OTHER THEN IMMUNE MECHANISMS: 1) Podocyte injury: # reflected by morphologic changes including; effacement of foot processes, vacuolization, retraction ad detachment of cells from the GBM. clinical signs: proteinuria ( mainly due to loss of the normal slit membrane). 2) Nephron loss: # maladaption occurs in the remaining nephrons, for example: hypertrophy  causig an increase in the single nephron GFR, and capillary hypertention. The remaining nephrons become maladaptive which leads to further endothelial lesions and podocyte inury, increase in protein permeability and accumulation of proteins and lipids in the mesangial matrix. The final outcome is sclerosis of a portion (segmental) or complete sclerosis of the glomeruli.

Answer 47

# Characterize by proteinuria lead to hypoalbuminemia and edema. Glomerular disorders(in BM or THE NEPHROTIC SYNDROME podocyte) characterized by increased permeability to plasma proteins (mainly albumin)- proteinuria (> 3.5 g/day) resulting in cherecter clinical manifestations: 1) Massive proteinuria – daily protein loss in the urine of 3.5g or more. 2) Hypoalbuminemia – serum albumin concentration of less than 3g/100 ml. 3) Generalized edema – also called anasarca, results from decreased plasma oncotic pressure. Usually starts with periorbital edema, the edema is an character clinical manifestation 4) Hyperlipidemia and lipiduria – caused by increased hepatic lipoprotein synthesis. may be due to hypoalbuminemia that triggers synthesis of lipoprotein or massive proteinuria causes loss of an inhibitor of their synthesis. 5) Hypercoagulable state—due to loss of antithrombin III Derangement of the capillary wall  increased permeability  leakage of plasma proteins into filtrate  proteinuria  serum albumin  hypoalbuminemia  plasma ocnotic pressure  secretion of rennin by the renal juxtamedullary cells (due to decrease in intravascular volume)  angiotensin-aldosterone axis stimulation  retention of salt & water by the kidney  edema # In children, nephritic syndrome is usually the primary illness , while in adults it is usually a secondary manifestation to a systemic disease May caused 2ndry to diabetes or systemic amyloidosis MINIMAL-CHANGE DISEASE (lipoid nephrosis) # Seen mainly in young children (also may be in adult) Most common cause of nephrotic syndrome in children usually idiopathic (may be associated with Hodgkin lymphoma) Pathogenesis – characterize by damage to podocyte layer of glomerular filtration apparatus lead to proteinuria the damage caused by T-cell derived cytokines that damages the podocyte foot processes. Morphology – Characterized by glomeruli that have normal appearance (in light microscopy), but show disappearance of podocytes foot processes (in electron microscopy) No immune complex deposits; negative immunofluorescence. The cells of the proximal convoluted tubules are heavily laden with protein droplets and lipids. The cytoplasm of the podocytes appears flattened; the epithelial cells undergo vacuolization and occasional focal detachment. Clinical features – leads to nephrotic syndrome, there’s no hypertension, and usually renal function is preserved. Protein loss is usually confined to smaller proteins- selective proteinuria (albumin); response to steroid therapy -corticosteroid treatment is used. MEMBRANOUS NEPHROPATHY (membranous glomerulonephritis) A progressive disease, most common for ages between 30-60 years Characterized by the presence of sub epithelial immune complexes deposits along GBM in early stages, the glomeruli appear normal, but later the show diffuse thickening of the capillary wall. One of the major causes of nephrotic syndrome. In most cases it is an idiopathic (primary) disease. Can be secondary to: Infections (chronic hepatitis B/C, syphilis). Solid Malignant tumors, mainly melanoma, and carcinoma of lungs and colon. SLE and autoimmune conditions. Drugs (penicilamine, non-steroidal anti-inflammatory agents). Pathogenesis – a form of chromic immune complex glomerulonephritis, induced by antibodies reacting with intrinsic or planted glomerular antigens; a podocyte antigen, the phospholipase A2 receptor, is the antigen that is most often recognized by the antibodies. Morphology –Diffuse subepithelial immune deposits separate the GBM by small protrusions18, resulting in thickening of the GBM H&E- LM. Due to immune complex sub epithelial deposition along GBM see granular appearance in IF. in EM sub epithelial deposits, spike and dome pattern the podocytes show effacement of foot processes Clinical features – development of nephrotic syndrome (some may have a lesser degrees of proteinuria) Only 40% suffering from progressive disease will have renal failure after 2-20 years. Poor response to steroids FOCAL & SEGMENTAL GLOMERULOSCLEROSIS It is characterized by sclerosis affecting some, but not all glomeruli (focal involvement), and involving only segments of each affected glomerulus (segmental involvement). May be primary, accounts for 20%-30% of nephritic syndrome Usually idiopathic-May be secondary to: 1) May be associated with HIV, heroin use, and sickle cell disease 2) As a maladaptation after nephron loss. 3) In inherited or congenital forms resulting from mutations affecting cytoskeletal or related proteins expressed in podocytes (podocin). Pathogenesis – The pathogenesis of primary FSGS is unknown, may be the progression of minimal-change disease ,Injury to the podocytes is thought to be the initiating event of primary FSGS. Deposition of hyaline masses in the glomeruli  entrapment of plasma proteins and lipids in foci of injury where sclerosis has developed. Morphology – » Light microscopy The affected glomeruli exhibit segmental increased mesangial matrix, obliterated capillary lumens, and deposition of hyaline masses (hylinosis) and lipid droplets. » Florescence No immune complex deposits but Nonspecific trapping of immunoglobulins, mainly IgM, and complement proteins C3 in areas of hylinosis. » Podocytes exhibit disappearance - effacement of foot processes. » Progression of the disease leads to global sclerosis of the glomeruli with tubular atrophy and interstitial fibrosis. Collapsing glomerulopathy – collapse of the entire glomerular tuft and podocyte hyperplasia. May be in primary cases, or associated with HIV. Clinical features – higher incidence of hematuria and hypertension, non-selective proteinuria, poor response to corticosteroids therapy, development of end-stage renal failure (in 50% of the cases). MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS Characterized by alterations in the GBM and mesangium result from proliferation of glomerular cells. Patient may exhibit nephrotic or nephritic picture. Or sub nephrotic proteinuria # Pathogenesis – There are two major types of MPGN (MPGN type 1 & Dense deposit disease {once called type 2}), with type I more common (80%). » Type I – sub endothelial deposit associated with HBV and HCV » Type II – Type II (dense deposit disease)—intra membra no us; associated with C3 nephritic Factor (autoantibody that stabilizes C3 convertase, leading to over activation of Complement, inflammation, and low levels of circulating C3) Morphology – » Large glomeruli with lobular appearance. Proliferation of mesangial and endothelial cells. GBM is thickened and glomerular capillary wall has a "tram track" appearance, this “splitting” of the GBM is due to extension of processes of mesangial and inflammatory cells into the GBM and deposition of mesangial matrix. Type I more prominent train trak appearance then type 2 # Clinical features – Poor response to steroids; progresses to chronic renal failure # Note membranous GN is the cause when you see lupus patient with nephrotic synd. but most common lupus kidney is the membranous glomeruloproliferative nephritis comes with nephritic synd.

Answer 48

# Glomerular disorders cherectrize by glomerular inflamtion (damaging THE NEPHRITIC SYNDROME endothelium-GBM-mesangial cells) Main feature of syndrome include hematuria oliguria & azotemia and hypertension # Clinical manifestations include acute onset of: 1) Hematuria – with dysmorphic red cells and red cell casts in the urine This inflammatory reaction injures the capillary walls permitting blood to pass into the urine 2) some degree of oliguria and azotemia Oliguria (low output of urine).Azotemia (high levels of nitrogen containing compounds). As result of reduced GFR 3) Hypertension result from fluid retention & sum release of renin from ischemic kidneys. 4) +/- not severe proteinuria/edema(periorbital) # Histologically 1. Proliferation of the cells within the glomeruli 2. Inflammatory leukocytes infiltrate ACUTE POSTINFACTIOUS (POSTSTREPTOCOCCAL) GLOMERULONEPHRITIS one of the more frequently occurring glomerular disorders This glomerulonephritis usually develops following a streptococcal infection (beta-hemolytic, group A –nephritogenic strain carry M protein).although may develop following other infections usually seen in children but also may see in adult Children rarely (1%) progress to renal failure.Some adults (25%) develop rapidly progressive glomerulonephritis (RPGN). Pathogenesis- 1 to 4 weeks after the initial infection group A streptococcal nephritogenic infection (localized to the pharynx or skin) see m Prot. Molc mimicry result in autoreactive AB against glomerular components as GBM . glomerular deposition of immune complexes with activate the alternative complement pathway lead to infiltration of leukocytes (C5a attract neutrophils etc.…) resulting in proliferation of and damage to glomerular cells pathogenesis include streptococcal exotoxin B (Spe B) SpeB may induce immune-complex-mediated glomerulonephritis as SpeB deposits colocalizes with complement and IgG and is present in the sub epithelial humps that are the hallmark lesion of PSGN Nephritogenicity may be related to its plasmin-binding activity of bough that would induce inflammatory reactivity and glomerular basement membrane (GBM) degradation as, plasmin receptor of strep. co-localizes in glomeruli mesangial cells with plasmin, but not with IgG or complement .bout SPEB70, 71 and NAPlr72 are capable of inducing chemotactic (monocyte chemoattractant protein 1) and IL-6 moieties in mesangial cells #Morphology LM- diffuse increased cellularity - proliferation and swelling of endothelial and mesangial cells plus infiltrating neutrophils and monocytes. sometimes there is necrosis of endothel cell and mass named crescents is visable in part of glomeruli IF -Granular IgG and C3c within the capillary walls +/- mesangial deposition EM -Intramembranous or most often, subepithelial “humps” #Clinical features – onset of fever, nausea and nephritic syndrome that is characterized by mild oliguria, azotemia and hypertension, BUT with gross hematuria cola urine color .Serum complement levels are low, streprococcal antibodies may be detected. IgA NEPHROPATHY Characterized by the deposition of IgA in the mesangium. The most common cause of recurrent microscopic/ gross hematuria appearance. This condition usually affects children, and begins as an episode of gross/microscopic hematuria within 1-2 days of a nonspecific upper respiratory tract infection. Pathogenesis –In genetically susceptible individuals mucosal infection may lead to increased IgA production21, some of which is abnormal, and deposition of IgA or IgA-containing immune complexes in the mesangium  activate complement (alternative)  cause glomerular injury. Also in liver disease defect in hepatobiliary clearance on IgA complexes (secondary IgA nephropathy). Morphology – LM: vary considerably may see focal proliferative GN /mesangioproliferative GN /crescentic GN IF: mesangial deposition of IgA, often with C3 EM: electron-dense deposits in the mesangium # Clinical- most often affects children and young adults50% present with gross hematuria after an infection of the respiratory tract hematuria typically lasts for several days in recurrent episodes over very long period of time there is risk to develop chronic renal failure -in 25% to 50% of cases over a period of 20 years HEREDITARY NEPHRITIS A group of hereditary glomerular disease caused by mutation in the genes encoding for GBM proteins. Most common is the Alport syndrome, in which nephritis is accompanied by sensory hearing loss and eye disorders22 Pathogenesis – the GBM is composed of type IV collagen; which is a heterotrimer composed of α3, α4, α5 chains. Mutation in one of the α chains (crucial for lens, cochlea and glomerulus) will cause Alport syndrome. Morphology – glomeruli appear normal until late in course, when secondary sclerosis may occur. In some cases, interstitial cells appear foamy as a result of accumulation of fats and mucopolysaccharides (foam cells) as a reaction to proteinuria. With progression, glomerulosclerosis; vascular sclerosis; tubuar atrophy and interstitial fibrosis are typical changes. GBM is thin at first, and late in course the GBM develops irregular foci of thickening with pronounced splitting and lamination of the lamina densa  basketweave appearance # Clinical course – most common form of inheritance is X-linked (mutation in α5 chain)  males are affected more frequently and sevearly female carrier asymptomatic rarely, inheritance may be autosomal recessive/dominant (defects in α3/4 chains). At age of 5 to 20 see gross or microscopic hematuria and proteinuria renal failure develops between 20 and 50 years of age

Answer 49

Glomerulum-capillary network, glomeruli-corpuscle RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS  A clinical syndrome leading to renal failure in short time ~weeks and may arise from different types of glomerulonephritis.  Characterized by: » Progressive loss of renal function with Severe oliguria and azotemia » Laboratory findings of nephritic syndrome » Histologically, formations of crescents are seen between Bowman's capsule and the glomerular capillary network, due to proliferation of parietal epithelial cells Etiology may be learned from immunofluorescence pattern: ANTI-GLOMERULAR BASEMENT MEMBRANE CRESCENTIC GLOMERULONEPHRITIS  Characterized by linear deposits in immunofluorescent of IgG and C3 on the GBM.  May be idiopathic but in some cases see AB deposits on BM of alveolar capillaries if such as patient with hematuria and hemoptysis its Goodpasture syndrome24. Classic seen in young adult male.  Morphology: Kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surface. Glomeruli show segmental necrosis and crescents appearance In time, may undergo scarring glomerulosclerosis develops IMMUNECOMPLEX MEDIATED CRESCENTIC GLOMERULONEPHRITIS  Granular pattern of staining is characteristic finding in immunofluorescent  Rapid progressive GN with Crescents may be the complication of any immune-complex nephritides most common associated with post streptococcal GN, diffused proliferative GN such as most common SLE-kidney , IgA nephropathy and Henoch-Schonlein purpura  Morphology: Segmental necrosis and crescents are present. In contrast with Anti-GBM Crescentic Glomerulonephritis, segments of glomeruli without necrosis show the underlying immune complex GN. PAUCI-IMMUNE CRESCENTIC GLOMERULONEPHRITIS  Defined as no anti-GBM antibodies / immune complex deposition are detected not in IF nor EM. Although Segmental necrosis and crescents are seen.  In many cases, the condition is limited to the kidney and is therefore called idiopathic. Antineutrophil cytoplasmic antibodies (ANCA) typically are found in the serum  in some cases crescentic GN is a component of systemic vasculitis (e.g. microscopic polyagniitis pANCA or Wegener granulomatosiscANCA) Chug Strauss got eosinophilia and asthma and granulomatous inflammation that polyangitis don’t have even both come with pANCA

Answer 50

# A purulent inflammation of the kidney and renal pelvis, caused by bacterial infection may origin A group of inflammatory diseases that primarily involve the tubules and interstitium. The glomeruli may be spared or affected only late in course. » Pyelonephritis as you talk on bacterial infection of upper urinary tract prominently involving The renal pelvis25 , most common form of TIN. The term interstitial nephritis relating to TIN nonbacterial origin mostly results from drugs, metabolic disorders (hypokalemia), viral infection and immune reaction. ACUTE PYELONEPHRITIS from lower part of UT or from blood hematogenous less common -molnar Pathogenesis – Principal causative agents are enteric G(-) rods, mainly E.coli, but also Klebsiella, Enterococcus faecalis. With outflow obstruction26 , bladder dysfunction- vesicoureteral reflux 3 , catheter see infection may ascend… # Morphology – Abscess with pus may be seen on cut surface, histo see mix inflammatory infiltrate marked by neutrophils in tubular sys. Interstitum and b.v. -glomeruli are spared the affected areas show abscess loss of parenchymal structures note it isn’t diffused .one complication is papillary necrosis(ischemic and supportive); there are 3 predisposing conditions for this: diabetes, urinary tract obstruction and analgesic abuse Clinical features – Presents with fever, flank pain, and leukocytosis in addition to symptoms of cystitis urgent frequent small amount of urine CHRONIC PYELONEPHRITIS In case of recurrent injury see morphology of chronic inflammation including scarring and deformities of pelvic calycal system uneven interstitial fibrosis Chronic inflammatory infiltrate of lymphocytes, plasma cells, and neutrophils. Dilation/contraction of tubules, with atrophy of the lining epithelium. Dilated tubules contain colloid casts similar to thyroid appearance thyroidization. #Can be divided into two forms: 1) Chronic obstructive pyelonephritis – recurrent infections superimposed on obstruction lesions, leading to recurrent renal inflammation scarring, eventually causing chronic pyelonephritis. 2) Chronic reflux-associated pyelonephritis (reflux nephropathy) – results from superimposition of UTI on congenital vesico-urethral reflux and intrarenal reflux. The damage may cause scarring/atrophy unilaterally or bilaterally Clinical features – hypertension, asymmetrical contraction of the kidneys, polyuria eventually, secondary glomerulosclerosis (with proteinuria) UROCYSTITIS Infection of the bladder Presents as dysuria(burning sensation), urinary frequency, urgency, and suprapubic pain; systemic signs (e.g., fever) are usually absent. Patho mechanisems: o infections Principal causative agents are enteric G(-) rods, mainly E.coli, but also Klebsiella, Staphylococcus saprophytics—increased incidence in young, sexually active women Proteus mirabilis—alkaline urine with ammonia scent Enterococcus faecalis. Types may be : Acute Chronic Granulomatous o Vesico-ureteral reflux o Urinary outflow disability- Causes include prostatic hyperplasia; bladder stones; tumors neurologic disease, diabetic bladder Fistula formation- Abnormal connection formed between the bladder and the surrounding organs may create from Malignant tumors Postirradiating necrosis Crohn dissease Cervical carcinoma /Rectum carcinoma Laboratory findings1Urinalysis—cloudy urine with pyuria > 10 WBCs/high power field (hpf) 2Dipstick—Positive leukocyte esterase (due to pyuria) and nitrites (bacteria convert nitrates to nitrites) 3. Culture—greater than 100,000 colony forming units (gold standard) Note! Sterile pyuria is the presence of pyuria (> 10 WBCs/hpf and leukocyte esterase) with negative urine culture. Suggests urethritis due to Chlamydia trachomatis or Neisseria gonorrhoeae (dominant presenting sign of urethritis is dysuria)

Answer 51

# Acute drug-induced interstitial nephritis is associated with the usage of drugs: synthetic DRUG-INDUCED INTERSTITIAL NEPHRITIS penicillin’s (methicillin, ampicillin), synthetic antibiotics (rifampin), diuretics (thiazides), nonsteroidal anti-inflammatory agents –analgesic use etc. Pathogenesis: » The onset of the nephropathy is NOT dose-dependent; the drug induces an immune reaction. » The drug acts as an hapten, during secretion by the tubules it covalently bunds to a tubular cell component and becomes immunogenic  IgE and cell mediated immune response damage the tubules. » IgE levels are elevated, suggesting type I hypersensitivity, and mononuclear or granulomatous infiltrate suggests a T-cell mediated, type IV hypersensitivity. Morphology – the interstitium shows profound edema and infiltration by eosinophils and also lymphocytes and macrophages seen –interstitial inflammation; Glomeruli are normal, except in cases caused by non-steroidal anti-inflammatory agents in which hypersensitivity leads to podocyte foot disappearance  nephritic syndrome. Clinical features – the disease begins 2-40 days after exposure to the drug, characterized by fever, eosinophilia, a rash in some cases, and renal finding that include hematuria, minimal proteinuria, and leukocyturia. In 50% of cases – increase in serum creatinine, oliguria(less than 400 ml/day) may develop into renal failure if remove drug see recovery although it may take several months ACUTE TUBULAR INJURY Most common cause for acute renal injury characterized by destruction of tubular epithelial cells, followed by acute renal failure (oliguria, proteinuria, blood retention of urea and creatinine) Cuases for acute renal injury range from: ischemic injury, glomerular rapid progress-acute tubular injury –interstitial nephritis like drug induced… Pathogenesis – result from ischemia/nephrotoxic to renal tubols » toxic acute tubular necrosis-after ingestion or inhalation of toxic substance ethylene glycol, mercury, lead, carbon tetrachloride, methyl alcohol, nephrotoxic drugs greatest characterized by proximal tubular epithelium necrosis due to interference of ingested toxic agents (poisons, organic solvents, drugs, heavy metals) with epithelial cell metabolism. Necrotic cells fall into the tubule lumen, obliterating it, and determining acute renal failure (oligo-anuria). Basement membrane is intact, so the tubular epithelium regeneration is possible » ischemic acute tubular necrosis- also called acute vasomotor nephropathy; due to inadequate renal blood flow, often from marked hypotension and shock (acute pancreatitis, severe trauma); ischemia causes vasoconstriction, which leads to reduced glomerular filtration rate and oliguria Intrarenal vasoconstriction - mediated by sublethal endothelial injury - release of endothelin (vasoconstrictor), decreased production of NO and prostaglandins - reduced glomerular plasma flow, and blood supply to tubular sys. Tubular cells: Ischemic tubular cells express chemokines, cytokines promoting interstitial inflammation. Ischemia change cell express of pumps na not absorbed and tubologlomerular feedbeck n vasoconstriction ischemia damage also BM so cell detachment n debris obligating tubular system more breakdown of tubule lead to beck leak of filtrate to interstitium… Morphology – ischemic ATI varies from cell swelling to focal tubular epithelial necrosis and apoptosis mainly in the straight proximal tubule and the ascending thick limb. Tubular injuries show thinning or loss of proximal tubule brush border, vacuolization of cells, sloughing of tubular cells into the urine. Proteinaceous casts are found in distal tubules and collecting duct along with hemoglobin. Edema is seen in the intestitium along with inflammatory infiltrates (PMN leukocytes, lymphocytes and plasma cells). Later - epithelial regeneration (flattened epithelium, dilated tubular Lumina, large nuclei with prominent nucleoli and mitotic activity) Toxic acute tubular necrosis is characterized by proximal tubular epithelium necrosis (no nuclei, intense eosinophilic homogenous cytoplasm, but preserved shape) Basement membrane is intact, The interstitium and glomeruli are not affected Clinical course –patient suffers from oliguria/anuria and decreased GFR; electrolyte abnormalities; acidosis; uremia DIFFUSE CORTICAL NECROSIS The pathological progression of ATN, resulting from diminished renal arterial perfusion due to vascular spasm, microvascular injury or DIC. Can occur as a result of: » In adults => pregnancy, HIV, shock, trauma, SLE, sickle cell anemia. » In neonates => congenital heart disease, anemia, placental hemorrhage. DCN can be classified into 5 forms: 1) Focal => the kidneys show focal necrosis of glomeruli without thrombosis, and patchy necrosis of tubules. 2) Minor => larger areas of necrosis are evident with vascular and glomerular thrombosis. 3) Patchy => patches of necrosis occupy 2/3 of the cortex. 4) Gross => almost the entire cortex is involved; thrombosis of the arteries is more widespread. 5) Confluent => the kidneys show widespread glomerular and tubular necrosis with no arterial involvement. Morphology – » Grossly, the kidney appears red (congested) with yellowish-white spots (infarcts). » Microscopically, one can see ischemic necrosis, massive leukocytes infiltration in deeper areas (in contact with the medulla), and thrombosis (intravascular and intraglomerular).

Answer 52

# The main importance of cysts is their differentiation from kidney tumors. In contrast to renal CYSTIC DISEASE OF THE KIDNEY SIMPLE CYST Generally non harmful lesions that occur in multiple or single cystic commonly, they are 1-5cm in diameter, usually confined to the cortex. tumors, the cysts have smooth contours, are almost always avascular and produce fluid rather than solid tissue under ultrasonography. Dialysis- associated acquired renal cysts are present in both cortex and medulla and occur in kidneys of patients with end-stage kidney diseases who have undergone prolonged dialysis-see shrunk kidney with cyst unlike polycystic diseas …. Those patient at highr risk to develop renal cell carcinoma at the effected kidney AUTOSOMAL DOMINANT (ADULT) POLYCYSTIC KIDNEY DISEASE Characterized by multiple expanding cysts on both kidneys that eventually destroy the parenchyma. Caused by heterogeneous28 inheritance of: » PKD1 – the defective gene in 85%-90% of the cases, encodes for Polycysticn-1 (a cell membrane protein) is involved in cell-cell or cell-matrix interactions » PKD2 – the defective gene in 10%-15% of the cases and encodes for ycystin-2 functions as a Ca2+ membrane channel. Both polycystin molecules are believed to act together by forming a heterodimer, thus mutation in either of the genes gives rise to the same phenotype. Although Patients with PDK2 mutations have a slower rate of disease progression. Morphology – » The kidneys may reach an enormous size-palpable abdominally as masses extending into the pelvis. » with numerous dilated cysts.The pressure of the expanding cyst leads to ischemic atrophy of renal substance. » The cysts may arise at any level of the nephron; tubules, collecting ducts and occasionally Bowman’s capsule. » Clinical features – usually does not produce symptoms until the age of 40; symptoms include flank pain, hematuria, hypertension and urinary infection; Asymptomatic liver cysts occur in one third of patients. Aneurysms in circle of Willis, with resultant subarachnoid hemorrhage, may be associated with this disease. AUTOSOMAL RECESSIVE (CHILDHOOD) POLYCYSTIC DISEASE Rear AR inherited form of polycystic disease accruing in childhood with different genetic background Characterized by multiple closed cysts that are NOT in continuity with the collecting system. This disease results from mutations in PKHD1 gene found on chromosome 6, encodes for fibrocysin. A receptor-like protein that may be involved in tubulogenesis and/or in the maintenance of duct-lumen architecture. Morphology –bilateral numerous small cysts in both the cortex and medulla, giving the kidney a sponge-like appearance. The cysts are lined with cuboidal cells, reflecting their origin from the collecting tubules. In most cases, the disease is associated with epithelium-lined cysts in the liver, and proliferation of portal bile ducts. Perinatal, neonatal, infantile and juvenile subtypes have been defined, depending on the time of presentation and the presence of associated hepatic lesions. Clinical features – most common forms are perinatal and neonatal; manifestations usually present at birth, and new-born babies die quickly of hepatic or renal failure, while patients who survive develop liver cirrhosis (congenital hepatic fibrosis). MEDULLARY CYSTIC DISEASE There are 2 types: 1) Medullary sponge kidney Characterized by cystic dilatation of the collecting tubules in one or both kidneys. Relatively common innocuous condition occasionally associated with nephrolithiasis (formation of kidney stone). 2) Nephronophthisis medullary cystic disease complex Group of autosomal recessive disorders resulting in chronic renal disease beginning in childhood almost always associated with renal dysfunction. Characterized by corticomedullary cysts, atrophy and interstitial fibrosis "Phthisis" (Greek): dwindling or wasting away Pathogenesis – associated with several mutations in different genes -NPHP genes produce nephrocystins in cilia / basal body structures Morphology – small contracted kidneys. Numerous small cysts, lined by cuboidal epithelium, are found mainly in the cortico-medullary junction. Other less specific pathologic changes are chronic tubulointerstitial nephritis with tubular atrophy and progressive interstitial fibrosis. Clinical features – initial manifestations are polyuria and polydipsia (excessive thirst), a consequence of diminished tubular function; diagnosis is difficult since there are no serologic markers, and the cysts are too small to recognize in radiologic imaging. The 2nd type has 4 variants, based on the time of onset: infantile, juvenile (most common), adolescent and adult. Usually associated with extra-renal manifestations, most often appear as retinal abnormalities; retinitis pigmentosa and early onset of blindness in the most severe form. HYDRONEPHROSIS The dilation of the renal pelvis and calyces, with accompanying atrophy of the parenchyma, caused by obstruction to the outflow of urine-may occur at any level of the urinary tract; from the urethra to the pelvis. The most common causes of obstruction are: » Congenital – atresia33 of the urethra, valve formations in either ureter or urethra, renal artery compressing the ureter, renal ptosis with torsion, bending of the ureter. » Acquired – foreign bodies (stone). Tumors; benign prostatic hyperplasia/ carcinoma, bladder tumors (papilloma and carcinoma), inflammation (of the prostate, ureter, urethra). Neurogenic spinal cord damage with paralysis of the bladder. Pregnancy. #Pathogenesis –Even with complete obstruction, glomerular filtration persists for some time because of continued filtration, the affected calyces and pelvis become dilated. Initial functional disturbances are manifested by impaired concentration ability, and later glomerular filtration starts to diminish. The obstruction leads to increased pressure in the tubular system, and the filtrate subsequently diffuses back into the interstitium and perirenal spaces and from there it returns to the lymphatic and venous system the high pressure generated causes the compression of the renal vasculature, resulting in arterial insufficiency and venous stasis. The obstruction also triggers an interstitial inflammatory reaction, eventually leading to interstitial fibrosis. Morphology – display morphologic changes that vary with the speed and degree of obstruction 1) Partial (temporary) obstruction – the kidney may be massively enlarged (up to 20cm), the renal parenchyma atrophied with obliteration of the papillae and flattening of the pyramids. 2) Complete obstruction – glomerular filtration is compromised at an early stage, so renal function may cease even when dilation is relatively slight; in severe cases, coagulative necrosis of the renal papillae may occur. #MICRO-Lesions show tubular dilation followed by atrophy and fibrous replacement of the tubular epithelium. With sudden and complete obstruction there may be coagulative necrosis of the renal papillae. In severe cases, the glomeruli also become atrophic and disappear converting the entire kidney into a thin shell of fibrous tissue. Clinical features – bilateral and complete obstruction produces anuria (if it's below the bladder the main symptom is bladder distention); incomplete bilateral obstruction causes polyuria rather than oliguria due to defects in tubular concentrating mechanisms. Unilateral obstruction may be silent for a long period unless the other kidney for some reason is not functioning. NEPHROLITHIASIS (kidney stones) #Urolithiasis is the formation of stone at any level in the urinary collecting system, most often in the kidney. #more common in men, Risk factors include high concentration of solute in the urinary filtrate and low urine Volume as Precipitation of a urinary solute may accrue as a stone Clinical features – Presents as colicky pain with hematuria and unilateral flank tenderness Stone is usually passed within hours; if not, surgical intervention may be required. Large stones can be present in the renal pelvis without producing any symptoms, but small stones may pass into the ureter and produce typical intense pain that often radiates to the groin=> renal colic often by this time there is gross hematuria. #Stones appear in different compositions: 1.Calcium oxalate and/ or calcium phosphate composition- Most common type; usually seen in adults. The cause of stone formation is often obscure the most common cause of stone formation is increased urine concentration of the constituents of the stone, so it exceeds their solubility in the urine (supersaturation). In this case most patient present idiopathic hypercalciuria which is not associated with hypercalcemia. Although hypercalcemia and its related causes must be excluded. Also seen with Crohn disease-oxalate increase from resorption of intestine… Treatment is hydrochlorothiazide (calcium-sparing diuretic). 2.Ammonium magnesium phosphate/ Struvite stones - Second common type, common cause is infection with urease-positive organisms (proteus vulgaris or Klebsiella bacteria’s) alkaline urine leads to formation of stone. Classically, results in staghorn calculi in renal calyces Treatment involves surgical removal of stone (due to size) and eradication of pathogen (to prevent recurrence). 3.Uric acid stones- Third most common stone (5%) and the only radiolucent (invisible in imaging), Risk factors include hot climates leading to low urine volume, and acidic pH patients exhibit low ph. urine which favors the formation of the uric acid stones without neither hyperuricemia nor increased urine urate.. seen in patients with gout-hyperuricemia or disease with increase cellular turnover n uric acid production such as leukemia or myeloproliferative disorders patient are at increases risk. Treatment involves hydration and alkalization of urine (potassium bicarbonate); allopurinol is also administered in patients with gout. 4.Cysteine stones- Rare cause of nephrolithiasis; usually seen in children associated with genetical defects the renal transport of certain amino acids (including cysteine) results in decreased tubules reabsorption of cysteine- cystinuria. May form staghorn calculi; treatment involves hydration and alkalization of urine.

Answer 53

HYDRONEPHROSIS The dilation of the renal pelvis and calyces, with accompanying atrophy of the parenchyma, caused by obstruction to the outflow of urine-may occur at any level of the urinary tract; from the urethra to the pelvis. The most common causes of obstruction are: » Congenital – atresia33 of the urethra, valve formations in either ureter or urethra, renal artery compressing the ureter, renal ptosis34 with torsion, bending of the ureter. » Acquired – foreign bodies (stone). Tumors; benign prostatic hyperplasia/ carcinoma, bladder tumors (papilloma and carcinoma), inflammation (of the prostate, ureter, urethra). Neurogenic spinal cord damage with paralysis of the bladder. Pregnancy. #Pathogenesis –Even with complete obstruction, glomerular filtration persists for some time because of continued filtration, the affected calyces and pelvis become dilated. Initial functional disturbances are manifested by impaired concentration ability, and later glomerular filtration starts to diminish. The obstruction leads to increased pressure in the tubular system, and the filtrate subsequently diffuses back into the interstitium and perirenal spaces and from there it returns to the lymphatic and venous system the high pressure generated causes the compression of the renal vasculature, resulting in arterial insufficiency and venous stasis. The obstruction also triggers an interstitial inflammatory reaction, eventually leading to interstitial fibrosis. Morphology – display morphologic changes that vary with the speed and degree of obstruction: 1) Partial (temporary) obstruction – the kidney may be massively enlarged (up to 20cm), the renal parenchyma atrophied with obliteration of the papillae and flattening of the pyramids. 2) Complete obstruction – glomerular filtration is compromised at an early stage, so renal function may cease even when dilation is relatively slight; in severe cases, coagulative necrosis of the renal papillae may occur. #MICRO-Lesions show tubular dilation followed by atrophy and fibrous replacement of the tubular epithelium. With sudden and complete obstruction there may be coagulative necrosis of the renal papillae. In severe cases, the glomeruli also become atrophic and disappear converting the entire kidney into a thin shell of fibrous tissue. Clinical features – bilateral and complete obstruction produces anuria (if it's below the bladder the main symptom is bladder distention); incomplete bilateral obstruction causes polyuria rather than oliguria due to defects in tubular concentrating mechanisms. Unilateral obstruction may be silent for a long period unless the other kidney for some reason is not functioning. (cont, there is more need to check more)

Answer 54

NEOPLASIA OF THE KIDNEY Benign tumors, such as small(less then 0.5cm) cortical papillary adenomas are common and have no clinical significance. # Most common malignant tumor of the kidney is renal cell carcinoma althow tumors of lower urinary tract are even more common RENAL CELL CARCINOMA # Malignant tumor Derived from renal tubular epithelium, thus these tumors are located mainly in the cortex. the most common metastasis are to the lungs and bone. Represent 80%-85% of all primary malignant tumors of the kidney, occur most commonly at the age of 60-70. Men are more commonly affected than women. Risk factors: smoking, obesity, hypertension, exposure to cadmium and persons who acquire polycystic disease as a complication of chronic dialysis. Clinical features – The clinical triad of renal cell carcinomas; painless hematuria, palpable abdominal mass if large enough, dull flank pain. Extra-renal manifestations Fever, weight loss, or paraneoplastic syndrome e.g., polycythemia (due to increased amount of erythropoietin secreted by the tumor) renin or ACT H may also be present. Involvement of the left renal vein by carcinoma blocks drainage of the left spermatic vein leading to varicocele. Right spermatic vein drains directly into the IVC; hence, right-sided varicocele is not seen. Staging:T—based on size and involvement of the renal vein (occurs commonly and Increases risk of hematogenous spread to the lungs and bone) N—spread to retroperitoneal lymph nodes The 3 most common forms are; clear cell carcinoma, papillary renal cell carcinoma and chromophobe renal carcinoma. CLEAR CELL CARCINOMAS Most common type (70%-80% of cases).Derived from the proximal convoluted tubule. Located predominantly in cortex Morphology – » Gross appearance – Gross exam reveals a solitary large spherical yellow mass with areas of cystic softening or hemorrhage. » The tumor may invade into the renal vein and grows as a solid column within it and may extend all the way to the inferior vena cava or right atrium. » Microscopically – tumor cells appear with clear cytoplasm demarcated by their cell membrane (vacuolated-lipid Leiden accumulate glycogen and lipids). With small round, uniform nuclei. Majority of the cases arise sporadically (non-inheritant), but may arise in familiar forms.bouth associated with loss of VHl (3chromosome) tumor suppressor gene, which leads to increased IGF-l (promotes growth) and increased HIF(hypoxia-induced transcription factor) (increases VF.GF and PDGF). » Hereditary tumors arise in younger adults and are often bilateral, von Hippel-Lindau disease is an autosomal dominant disorder associated with inactivation of the VHL gene leading to increased risk tor hemangioblastoma of the cerebellum and renal cell carcinoma. » Sporadic associated with cigarette smoking PAPILLARY RENAL CELL CARCINOMAS # Comprises 10%-15% of renal cancers. Derived from the proximal convoluted tubule. Show papillary growth pattern, and are frequently multifocal and bilateral. Papillary renal cell carcinoma can be sporadic or familial: Familial form – characterized by increased dosage of the MET gene35, located on chromosome 7 (due to trisomy or tetrasomy), along with activating mutations of the MET gene. » Sporadic form – characterized by larger amount of chromosome 7, resulting in increased dosage of the product of MET gene, but it lacks the mutations in the gene itself. Morphology: Unlike clear cell carcinomas, papillary carcinomas are frequently multifocal in origin and less yellow no lipid accumulation.. Consists of papillae covered by eosinophilic cells arranged in an irregular, pseudostratified manner and fibromuscular core . CHROMOPHOBE RENAL CARCINOMAS # Least common type, represent 5% of renal carcinomas.Arise from intercalated cells of the collecting ducts. Characterized by having multiple losses of complete chromosomes, mainly 1, 2, 6, 10, 13, 17 and 21 => hypo ploidy. Gross appearance tends to be tan-brown. The tumor cells have abundant eosinophilic cytoplasm with a distinct cell membrane. The nuclei are surrounded by halos of clear cytoplasm. WILMS TUMOR (nephroblastoma) Wilms' tumor (nephroblastoma) is a malignant mixed tumor containing metanephric blastema36, stromal and epithelial derivatives. It is the most frequent renal tumor in children before age of 5 years (peak of incidence at age of 2 ) Etiology of Wilms' tumor (nephroblastoma): mutations of WT1 gene on chromosome 11 and nephroblastematosis (persistence of renal blastema in kidney tissue). show association 2 syndromes: WAGR syndrome—Wilms tumor, Aniridia, Genital abnormalities, and mental and motor Retardation. Beckwith-Wiedemann syndrome—Wilms tumor, neonatal hypoglycemia, Muscular hemi hypertrophy, and organomegaly (including tongue) Morphology: In most cases, it is unilateral. The tumor tends to be encapsulated and vascularized. The tumor consists in tumor epithelial component (abortive tubules and glomeruli) surrounded by metanephric blastema and tumor immature spindled cell stroma. The stroma may include differentiated (muscle, cartilage, bone, fat tissue, fibrous tissue) or anaplastic elements. The tumor compresses the normal kidney parenchyma and may metastasize to the lungs. TUMORS OF URINARY COLLECTING SYSTEM UROTHELIAL (TRANSITIONALCELL) CARCINOMA # urinary collecting system from renal pelvis to urethra is lined with transitional epithelium Malignant tumor arising from the transitional epithelium Most common type of lower urinary tract cancer; usually arises in the bladder Tumors are often multifocal and recur Generally seen in older adults; affect men about three times as frequently as women # classically presents with painless hematuria Major risk factor is exposure to β-naphthylamine, cigarette smoking, chronic cystitis, schistosomiasis, cyclophosphamide # tumors are classified papillary urothelial neoplasms of low malignant potential (PUNLMP) Low grade urothelial carcinoma (papillary/flat; invasiv /non invasiv) High grade urothelial carcinoma (papillary/flat; invasiv /non invasiv) Arises via two distinct pathways » Flat—develops as a high-grade flat tumor and then invades; associated with early P53 mutations » Papillary—develops as a low-grade papillary tumor that progresses to a high-grade Papillary tumor and then invades; not associated with early p53 mutations SQUAMOUS CELL CARCINOMA Malignant proliferation of squamous cells, usually involving the bladder Arises in a background of squamous metaplasia (normal bladder surface is not lined by squamous epithelium) Risk factors include chronic cystitis (older woman). Schistosoma hematobium Infection (Middle East male), and long-standing nephrolithiasis. ADENOCARCINOMA Malignant proliferation of glands, usually involving bladder Arises from a urachal remnant connection of fetal bladder to yolk sack (tumor develops at the dome of the bladder), cystitis glandularis-columnar metaplasia in respond to chronic inflammation , or exstrophy (congenital failure to form the caudal portion of the anterior abdominal and bladder walls open bladder to world )

Answer 55

one of the three subtypes of arteriosclerosis-thickening of arteries patho gr. (which are atherosclerosis, Monckeberg's arteriosclerosis and arteriolosclerosis). 1) Arteriolosclerosis –intima involve affects small arteries and arterioles, got 2 types hyaline thickening or proliferative (hyperplastic) changes; usually associated with hypertension or diabetes mellitus. 2) Mönckeberg medical calcific sclerosis – calcific deposits that involve the tunica media of medium-sized muscular arteries, but does not affect the blood flow since it does not involve the tunica intima. 3) Atherosclerosis – the thickening and hardening of large to medium size arteries as a result of the accumulation of fatty material (cholesterol, TAGs). ATHEROSCLEROSIS Involves large- and medium-sized arteries; abdominal aorta, coronary artery, Popliteal artery, and internal carotid artery are commonly alfected. An atherosclerotic plaque/atheroma is a Intimal plaque that obstructs blood flow Consists of a necrotic lipid core (mostly cholesterol) with a fibromuscular cap often undergoes dystrophic calcification The atherosclerotic plaques obstruct the blood flow, as well as weakening the underlying media-impaired blood diffusion . These plaques can also rupture, causing acute thrombosis-reveling lipid negative charged core RISK FACTORS FOR ATHEROSCLEROSIS # Nonmodifiable: 1. Age – the accumulation of atherosclerotic plaques progresses with age, but becomes clinically manifest in middle age or later. 2. Gender – premenopausal women are relatively protected against atherosclerosis; after menopause, the incidence of atherosclerosis-related diseases increases with age. 3. Genetics – familial predisposition to atherosclerosis and ischemic heart disease (IHD) is multifactorial, and related to hypertension, diabetes mellitus, and familial hypercholesterolemia. Modifiable: 1. Hyperlipidemia – the major component associated with increased risk is LDL cholesterol, which delivers cholesterol to peripheral tissues; in contrast, HDL mobilizes cholesterol from tissues, as well as developing and existing atheroma’s, back to the liver for excretion in the bile => higher LDL levels, together with decreased HDL, constitute a risk factor for formation of atheroma’s; 2. Hypertension – both systolic and diastolic levels are important contributors to premature atherosclerosis. 3. Cigarette smoking – increase the incidence and severity of atherosclerosis => prolonged smoking of 1 pack daily increases the death rate from IHD by 200%. 4. Diabetes mellitus – induces hypercholesterolemia. 5. Lipoprotein A – altered form of LDL that contains the apolipoprotein B100 link to apolipoprotein A => high levels are associated with higher risk of coronary and cerebrovascular diseases, independent of cholesterol or LDL levels. 6. Other factors – lack of exercise, stressful lifestyle, and obesity. Hyperhomocystinemia –are caused by low folate and vitamin B intake. PATHOGENESIS Response-to-injury hypothesis – atherosclerosis is a chronic inflammatory response of the arterial wall to endothelial injury. consists of a raised lesion with a soft, yellow core of lipids (mainly cholesterol and cholesteryl esters), covered by a firm, white fibrous cap-fibromuscular cap Lesion progression occurs by: Process start as early as teenage years with fatty stripes formation created from Damage to endothelium allows lipids to leak into the intima. Accumulation of lipoproteins, mainly LDL, on the vessel wall just under endothel in intimal level. Lipids are oxidized and then consumed by macrophages via scavenger receptors, resulting in foam cells. Monocyte from blood are origin of MFactor release from activated platelets, macrophages and vascular wall cells, denoting processes of Inflammation and healing leads to deposition of'extracellular matrix and proliferation of smooth muscle.

Answer 56

the formation of atherosclerotic intimal plaques. atherosclerosis is the result of response to endothelial injury with chronic inflammation (lymphocytes and macrophages) ,fibro proliferative process- recruited and proliferating smooth muscle cells which has become excessive and in its excess this protective response has become the disease stat At early stage, the intimal plaque includes aggregates of foam cells (macrophages accumulating lipids)and not so elevated- Fatty streaks; with progression to fibrofatty pluqe see the atheroma modifies collagen synthesized by smooth muscle cells producing a fibrous cap, but retain the lipid-laden core which may become dystrophically calcified over time. Next such as advanced pluqe may : Rupture- surface of the atheroma exposes the blood stream to highly thrombogenic substances, inducing thrombus formation that can partially or completely occlude the lumen => the thrombi may become organized and incorporated into the growing plaque. Atheroembolism – plaque rupture releases debris into the blood stream, producing microemboli. Aneurysm formation – atherosclerotic-induced pressure, and loss of elasticity, causes weakness of the vessel wall and development of aneurysms. Grow till create critical stenosis - ischemic injury to organs PATHOGENESIS OF ATHEROGENESIS ENDOTHELIAL INJURY Early lesions begin at the site of intact but dysfunctional endothelium, there is increased endothelial permeability, enhanced leukocyte adhesion and altered gene expression. # Endothelial dysfunction can be caused by : 1) Toxins from cigarette smoke, homocysteine and infectious agents. 2) Hemodynamic disturbance-Atherogenesis occurs at the openings of existing vessels, branch points, as along the posterior wall of the abdominal aorta => where there are disturbed flow patterns .Laminar flow leads to the induction of genes whose products (antioxidant superoxide dismutase) actually protect against atherosclerosis. 3) Lipids (hypercholesterolemia- The dominant lipids in atheromas are cholesterol and cholesteryl ester)Lipoprotein abnormalities increase the risk of atherosclerosis, and include increased LDL level, decreased HDL level increased level of abnormal lipoprotein A,may be Genetic defects39 or Acquired disorders that cause hypercholesterolemia, such as diabetes mellitus and hyperthyroidism. Accumulation of lipoproteins within the intima, which are then oxidized through the action of oxygen free radicals => oxidized LDL40 is ingested by macrophages through a scavenger receptor, leading to foam cells formation. 4) Inflammation a. Endothelial cells express adhesion molecules that encourage leukocyte adhesion => VCAM-1 binds monocytes and T cells. b. Monocytes transform into macrophages and engulf lipoproteins, including oxidized LDL (foam cells) => progressive accumulation of lipids results in activation of macrophages and production of cytokines that increases leukocyte adhesion c. T cells that are recruited to the intima interact with macrophages and generate inflammation.As a result of the chronic inflammatory state, activated leukocytes and vascular wall cells release GFs that promote smooth muscle proliferation and ECM synthesis. SMOOTH MUSCLE PROLIFERATION # Smooth muscle proliferation and ECM deposition convert the fatty streak into a mature atheroma. The smooth muscle cells produce ECM, mainly collagen, which stabilizes the atherosclerotic plaque. Smooth muscle cells derived from the intima, as well as recruited from circulating precursors. Several GFs take part in the proliferation of the smooth muscle cells: platelet-derived growth factor (PDGF) fibroblast growth factor (FGF), and transforming growth factor alpha (TGFα). MORPHOLOGY OF ATHEROSCLEROSIS Fatty streaks – composed of lipid-filled macrophages (foam cells), but they are not significantly raised Atherosclerotic plaque –Atheromatous plaques appear white-yellow may be hard n calcified . vessels more prone to plaque formation are abdominal aorta, coronary arteries, popliteal arteries, internal carotid arteries, and the vessels of circle of Willis. An eccentric lesion under microscope composed of The fibrous cap is composed of smooth muscle cells and dense collagen; in shoulder of cap there is a more cellular area (containing macrophages, T cells and smooth muscle cells), and deep to the fibrous cap is a necrotic core (containing Intracellular and extracellular lipids, debris from dead cells, foam cells and plasma proteins).The cholesterol content of the plaque is usually present as crystalline aggregates => washed out during normal tissue processing => empty "clefts" are left => neovascularization (proliferating small blood vessels) seen in periphery of plaque

Answer 57

HYPERTENSION Hypertension – Increased blood pressure; may involve pulmonary or systemic circulation ,Systemic HTN is defined as pressure over 140/90 mm Hg (normal < 120/80 mm Hg) and its Divided into primary or secondary types based on etiology #The blood pressure depends on the regulation of cardiac output-systolic (p) and total peripheral resistance-diastolicb.p. (regulated by arterioles ) hence Contributors to hypertension: 1) Reduced renal Na+ excretion – causes an obligatory increase in fluid volume and increased cardiac output, resulting in elevated blood pressure. 2) Vascular change – vasoconstriction or structural changes in the vascular wall that result in increased resistance( Aortic rigidity) PATHOGENESIS OF HYPERTENSION Primary (essential) hypertension- HTN of unknown etiology accunts for about 95% of cases, although viewed as multifactorial condition involving inheritance and environment: 1) Risk factors include age, race (increased risk in African Americans, decreased risk in Asians) 2) Genetic factors – defects in the genes encoding components of RAS, familial history of hypertensive disease . 3) Environmental factors – stress, obesity, smoking, physical inactivity and heavy consumption of salt # Secondary hypertension-It is secondary to a known underlying cause. » Renal artery stenosis is a common cause, Stenosis decreases blood flow to glomerulus. Responds by secreting renin, which converts Angiotensinogen to angiotensin .Angiotensin I is converted to angiotensin 11 (ATII) by angiotensin converting enzyme ATII raises blood pressure by (I) contracting arteriolar smooth muscle,increasing total peripheral resistance and (2) promoting adrenal release of aldosterone, which increases resorption of sodium in the distal convoluted tubule (expanding plasma volume). Leads to HTN with increased plasma renin and unilateral atrophy (due to low blood flow) of the affected kidney important causes of stenosis include atherosclerosis (elderly males) and fibromuscular dysplasia (young females) » Adrenals or other endocrine organ disorders: 1) Conn syndrome (primary hyperaldosteronism) – the overproduction of aldosterone, mainly due to adrenal adenoma. 2) Cushing syndrome – excess production of cortisol that enhances the vasoconstrictive effect of epinephrine.,hyperthyroidesiem 3) Diabetes mellitus – when complicated by diabetic glomerulonephritis HYPERTENSIVE VASCULAR DISEASE # Hypertension can cause cardiac hypertrophy and heart failure (hypertensive heart disease), aortic dissection, renal failure and cerebrovascular hemorrhages-strokes. Hypertensive vascular disease, induced by hypertension: » In large to medium size .a. see increased tendency to atherogenesis plus risk to develop aortic dissection and cerebrovascular hemorrhages There are 2 form of small b.v. hypertension related diseases » Hyaline arteriolosclerosis – homogenous, pink proteinaceous thickening of the walls of arterioles with loss of underlying structural detail and narrowing of the lumen => plasma components leak across the vascular endothelium,. Also seen in diabetic both lead to nephrosclerosis glomerular scarring… link to bening HT » Hyperplastic arteriolosclerosis – related to more acute blood pressure elevations, associated with "onionskin", concentric, laminated41 thickening of the walls of arterioles with luminal narrowing => the hyperplastic changes are accompanied by fibrinoid deposits and vessel wall necrosis. Complications of hypertension Progressive heart failure = left ventricular hypertrophy adaptation to pressure overload (left ventricule) ↓ concentric (compensated) ↓ dilatative (decompensated) Cerebrovascular stroke - atherosclerosis - reversible ischemic attack - haemorrhagic infarction (encephalomalacia) - apoplexia (Pathology) sudden loss of consciousness, often followed by paralysis, caused by rupture or occlusion of a blood vessel in the brain (primary hemorrhage) Charcot–Bouchard aneurysms (also known as miliary aneurysms or microaneurysms) are aneurysms of the brain vasculature which occur in small blood vessels (less than 300 micrometre diameter). Charcot–Bouchard aneurysms are most often located in the lenticulostriate vessels of the basal ganglia and are associated with chronic hypertension. Charcot–Bouchard aneurysms are a common cause of cerebral hemorrhage. cerebral haemorrhage and subarachnoid haemorrhage due to ruptured berry aneurysms Berry aneurysm: A small aneurysm that looks like a berry and classically occurs at the point at which a cerebral artery departs from the circular artery (the circle of Willis) at the base of the brain. Berry aneurysms frequently rupture and bleed. in patients with benign hypertension Renal demage - nephrosclerosis - Hyperplastic arteriolosclerosis

Answer 58

ANEURYSMS #Localized abnormal ballon like dilation of a blood vessel or the heart,anyrisem complication pockets of stasis lead to subsequent thrombosis, embolization and also potential to rupture : » True aneurysm – when an aneurysm involves all 3 layers of the arterial wall (atherosclerotic, syphilitic and congenital aneurysms, and ventricular aneurysms). » False aneurysm (pseudoaneurysm) – a breach in the vascular wall leading to an extravascular hematoma that freely communicates with the intravascular space – pulsating hematoma. E.g. ventricular ruptures after MI, contained by a pericardial adhesion. #shape and size: » Saccular aneurysm – a spherical outpouching, involving only a portion of the vessel wall, which vary from 5-20cm in diameter and usually contain thrombi. » Fusiform aneurysm – a circumferential dilation up to 20cm dimeter, commonly seen involve extensive portions of the aortic arch, abdominal aorta, and the iliac artery. » Mycotic aneurysm – as result of endocarditis embolization of septic embolus nearby supportive process etc. …caused by infection that weakens the wall of the artery, with rupture and thrombosis as major complications. The etiology of depends on the site of its occurrence in the aorta. Causes of aortic aneurysm include: » inherited syndromes- lead to abnormal c.t. synthasis such as Marfan syndrome, EhlersDanlos syndrome type 4.usually appear in the root of ascending aorta » non- inflammatory aneurysms are associated with congenital conditions (bicuspid aortic valveroot of aorta) and acquired conditions (hypertension- ascending aortic aneurysm). the pathogenesis of the aneurysms is due to medial degeneration of the elastic aortic wall may demonstrate degrees of cystic, medial degeneration » inflammatory destruction: a) Secondary to syphilis/bacterial infection - Characteristic of the tertiary stage of syphilis see in the ascending aorta. Inflammation Involves small vessels all over the body, particularly the vasa vasorum => Hyperplastic thickening of vasa vasorum => reduced blood flow to aorta => ischemic medial injury => aneurysm. The involved vessels develop obliterative endarteritis => luminal narrowing and obliteration, scarring of the vessel wall, and a dense surrounding rim of lymphocytes and plasma cells that may extend into the media (syphilitic aortitis). Major complication is dilation of the aortic valve root, resulting in aortic valve Insufficiency, other complications include compression of mediastinal structures (e.g., airway or esophagus) and thrombosis/embolism. b) noninfectious aortitis as Atherosclerosis –dominant factor for abdominal aortic aneurysm. As Severe atherosclerosis lead to destruction and thinning of the aortic media, compromise nutrient and waste diffusion from the vascular lumen into the wall => degeneration and necrosis of media => dilation of the vessel. More see occurs due to an altered balance of collagen degeneration and synthesis mediated by local inflammatory infiltrates and their proteolytic enzymes.e.g Elevated matrix metalloproteinases (MMPs) levels, together with decreased levels of tissue inhibitor of metalloproteinases (TIMPs). There are 2 important variants of AAA: 1) Inflammatory AAA – characterized by dense periaortic fibrosis, containing lymphocytes and macrophages infiltrate. 2) Mycotic AAA – atherosclerotic lesions infected by circulating organisms due to bacteremia. Clinical Presentation as pulsatile abdominal mass that grows with time complication: Rupture into the peritoneal cavity with massive hemorrhage. Embolism from the atheroma or mural thrombus lead to Obstruction of a branch vessel, resulting in downstream tissue ischemia (for example, obstruction of the iliac arteries can cause ischemic damage to the legs). Compression of local structures (e.g., ureter) AORTIC DISSECTION Occurs when there is a tear in intima allow blood to penetrate through the wall of the aorta may completely rapture the aorta as deadly hemorrhage or propagate within media as blood filled channel – intramural hematoma . For this development must have 2 factors the very high pressure flow –hence accurse in proximal 10 cm of aorta and preexisting weakness of media layer, Aortic dissection is not necessarily associated with aortic dilation. Pathogenesis – Aortic dissection occurs in 2 groups: » About 90% of cases Men aged 40-60 with the existence of hypertension. Hypertension is the major risk factor => hypertrophy of the media => ECM degeneration and loss of smooth muscle cells. More aorta is very large and thick b.v. must use vasa vasurum for nutrients vasa vasurum hyaline arteriolosclerosis impaired blood supply and weakens wall » Younger patients with systemic or localized abnormalities of c. tissue (for example, Marfan /ehaler danols synd.4). Inherited or acquired c. tissue disorders abnormal ECM, such as Marfan syndrome (most common) no fibrillin no elastic weak media, Ehlers-danlos syndrome, vitamin C deficiency, copper metabolic defects. Morphology –The tear is usually found in the ascending aorta within 10cm of the aortic valve. in a few cases, the channel origin in intimal lesion free area ruptures back into the lumen of the aorta in origin of atherosclerotic plaque , creating a "double-barreled aorta". Histologically the dissecting intramural hematoma spreads along the laminar planes between the middle and outer thirds of media, pre-existing lesion to wall not identified in most cases but cystic medial degeneration (CMD) separation of the elastic and smooth muscle cell elements of the media by cystic spaces filled with proteoglycan-rich ECM. Clinical features – » Aortic dissections can be classified as: 1) Proximal lesions (type A dissections) – involve the ascending aorta (DeBakey type I), 2) Distal lesions (type B dissections) – usually begin distal to the subclavian artery (DeBakey type III). » Aortic dissections are characterized by the sudden onset of excruciating pain, beginning in the anterior chest, radiating to the back between the scapula’s, and moving downwards as the dissecting progresses. » complications 1. Cardiac tamponade (hemorrhage into the pericardial sac). Most common cause of death 2. Extension of the dissection and compression of the outlets to the great arteries of the neck, renal, mesenteric or iliac arteries impairing their blood flow. 3. The channel can rupture through the adventitia and into mediastinum, causing a massive fetal hemorrhage

Answer 59

VENOUS DISORDERS VARICOSE VEINS # Abnormally dilated and tortuous (twisted) veins, produced by prolonged increase in intramural pressure and loss of vessel wall support. The superficial veins of upper and lower leg are usually involved.with about 20%of man and 1/3 of woman will develop it # Morphology – » Wall thinning at the points of maximal dilation with smooth muscle hypertrophy and intimal fibrosis.Elastic tissue degeneration. » Spotty medial calcifications (phlebosclerosis). » Venous valve deformities (rolling and shortening). Clinical features – » Venous valves become incompetent upon widening, leading to stasis and edema causing pain and thrombosis » Persistent edema => secondary ischemic skin changes the skin is pale and often hairless, cool, thickened nail => stasis dermatitis of skin reddish purple and scaleded venus stasis result in increase pressure in microcirculation and ulcerations.Poor wound healing + superimposed infections = chronic varicose ulcers. Esophageal varices – » Occurs due to portal vein hypertension, usually due to cirrhosis, but also because of portal vein obstruction or hepatic vein thrombosis. » Liver cirrhosis => portal vein hypertension => opening of porto-systemic shunts => increased blood flow to veins of the gastro-esophageal veins (esophageal varices), to the veins of the rectum (hemorrhoids), and to the periumbilical veins (caput medusa). » The rupture of the esophageal varices can lead to massive upper GI hemorrhage that can be fatal. # Hemorrhoids – Varicose dilation of the hemorrhoidal venous plexus at the anorectal junction. Can be caused by pregnancy, chronic constipation or strain of defecation. THROMBOPHLEBITIS AND PHLEBOTHROMBOSIS Definitions – » Thrombophlebitis – an inflammation of the veins caused by a blood clot. » Phlebothrombosis – blood clots formed in the veins. In most cases (>90%), these conditions involves the deep veins of the leg, but they can also appear in the periprostatic veins (in males), the pelvic venous plexus (in females), the large veins in the skull and the dural sinuses. deep venous thrombosis is caused by :stasis e.g. bad care patient ,procoagulative state –contraceptives, vascular wall injury such in venipuncture or infection Virchow’s triad, Peritoneal infections can lead to portal vein thrombosis. Thrombi in the leg tend to produce few, if any, symptoms => local manifestations (Distal edema, cyanosis, superficial vein dilation, and pain- homans test: foot dorsiflexion cuff .m. compress vain and cause pain) can be entirely absent. Thromboembolisem-95%of pulmo. Embolism are result of DVT risk to complication… SUPERIOR & INFERIOR VENA CAVAL SYNDROMES SVC syndrome –commonly caused by certain neoplasms (Bronchogenic carcinoma, mediastinal lymphoma.)Which their location compress or invade the SVC. The resulting obstruction produces marked dilation of the veins of the head, neck and arms, accompanied by cyanosis. Pulmonary vessels can also become compressed, resulting in respiration distress. IVC syndrome – Caused by : Certain neoplasms, such as hepatocellular carcinoma and renal cell carcinoma, show tendency to grow within veins or by thrombus from the hepatic(Budd–Chiari syndrome), renal, or lower extremity veins or other tumors compressing IVC.. The obstruction of IVC induces marked lower extremity edema, distension of the superficial collateral veins of the lower abdomen, and in case of renal vein involvement, massive proteinuria. VASCULAR TUMORS #Vascular neoplasms can be derived from endothelial cells, or from cells that surround and/or support the blood vessels. Vascular tumors can be either benign hemangiomas, intermediate lesions that are locally aggressive, or highly malignant angiosarcomas. #General distinction between benign and malignant tumors: » Benign tumors – produce obvious vascular channels filled with blood cells, lined by a monolayer of normal endothelial cells (without atypia). » Malignant tumors – cellular with cytological anaplasia (including mitotic figures), and usually do NOT form well-organized vessels BENIGN TUMORS AND TUMOR LIKE CONDITIONS Hemangioma -A common benign tumor of infancy and childhood characterized by increase number of normal or abnormal vessels filled with blood. Usually spontantusly regress with age . » Cherectarly appear as localize lesion in head and neck skin or oral mucosa/tongue but may appear internally if so ~ 1/3 of it seen in the liver .When involving large portions of the body-more extensive lesions named => angiomatosis. » Clinical variants: 1) Capillary hemangioma – most common consists of closely packed thin capillaries and scant stroma lined by flattened one layer endothelium; can occur in the skin, subcutaneous tissues, mucous membranes of the oral cavity and lips, liver, spleen and kidneys. 2) Cavernous hemangioma – characterized by large vascular channels, separated by c. tissue stroma, and most frequently involves deep structures (liver, pancreas, spleen and brain); they appear as red-blue soft masses, 1-2cm in diameter. Glomus tumor (glomangioma) - Benign painful tumor Arises from modified smooth muscle cells of glomus body, a specialized arteriovenous anastomosis involved in thermoregulation . » Most commonly found in the distal portions of the digits, especially under the fingernails. » The tumors are round, slightly elevated, red-blue, firm nodules, consist of masses of glomus specialized tissue. Histologically resemble cavernous hemangiomas branching vascular channels separated by stroma containing glomus cells in nests, aggregates Glomus cells are arranged around vessels. Vascular ectasias -Local dilation of preexisting vessels: » Telangiectasia – permanent dilation of preformed small blood vessels ( capillaries, venules or arterioles) not a tumor just structure abnormality. Hereditary hemorrhagic telangiectasia – an autosomal dominant disorder that creates telangiectasia malformations present at birth usually distributed over the skin and mucous membranes their rupture can cause nosebleeds epistaxis , GI bleeding and hematuria. » Nevus flammeus – the ordinary birth mark, flat lesion ranging in color from light pink to deep purple. May regress with time Port wine stain is a special form of nevus flammeus that tends to grow with the child, thickens the skin surface and has no tendency to fade. » Spider telangiectasia – a non-neoplastic vascular lesion consists of a radial array of subcutaneous arteries or arterioles, surrounding a central core; associated with hyper estrogenic states such as pregnancy or cirrhosis. Bacillary angiomatosis -Reactive vascular proliferation due to opportunistic infection by Bartonella family of gram( – ) bacteria’s . Most commonly affects immunocompromised individuals (especially those with HIV) » Can occur in any cutaneous site as red papules and nodules which are widely distributed Rarely occurs in mucosa or internal organs e.g. bone and brain. » Histologically, there is capillary proliferation with epithelioid endothelial cells showing nuclear atypia and mitoses; the lesions contain stromal neutrophils, nuclear dust and purplish granular material (representing the causal bacteria). INTERMEDIATE-GRADE TUMORS Kaposi sarcoma (KS) -Vascular neoplasm that develops from the cells lining the lymph vessels or blood vessels, and appears as tumors on the skin or on mucosal surfaces (for example, inside the mouth). Strong association to AIDS » Pathogenesis – the tumor is caused by infection with human herpes virus 8 (HHV-8), which is also called KS-associated herpesvirus (KSHV). Virus synth homologue prot to cyc. D and suppress P53 induction of apoptosis » Types of KS: 1) Chronic KS – also called classic KS Mostly affects older men of eastern European or Mediterranean origin, not associated with HIV. It is characterized by red to purple nodules, usually on distal lower extremities, and is typically asymptomatic and localized. 2) Lymphadenopathy KS – also called African or endemic KS Most common in people living in equatorial Africa, and is also not associated with HIV. Patients present with lymphadenopathy, which occasionally involves the viscera, and is extremely aggressive. 3) Transplant-associated KS Occurs in transplant patients whose immune system have been suppressed to avoid organ rejection. It tends to be aggressive with nodal, mucosal and visceral involvement. 4) AIDS-associated (epidemic) KS Can involve lymph nodes and viscera, and is considered an "AIDS defining" illness => when a person infected with HIV develops KS, that person officially has AIDS. » Morphology – consist of 3 stages of progression :  Patches – solitary or multiple red-purple macules, confined to the distal lower extremities, with irregular dilated b.v. and chronic inflammatory infiltrate in-between b.v.  Plaques – larger and raised, composed of dermal accumulation of vascular channels lined by spindle cells, with RBCs, hemosiderin-filled macrophages, lymphocytes and plasma cells scattered among them.  Nodules– the lesions become nodular and more distinctly neoplastic, composed of sheets of proliferating spindle cells in the dermis or subcutaneous tissue, with marked hemorrhage, hemosiderin and lymphocytes. MALIGNANT TUMORS Angiosarcoma » Malignant endothelial neoplasm, varying from highly differentiated to anaplastic tumors. » Usually involves the skin, soft tissue, breast and liver. » Hepatic angiosarcoma is associated with carcinogen exposure, especially arsenic, thorium dioxide (thorotrast), and polyvinyl chloride. » Lymph angiosarcoma arises from lymphatic vessels. » Morphology –  Begin as small, sharply demarcated, red nodules.  Become large masses of red-tan to white-gray tissue. » Clinical features – they are locally invasive and can metastasize. Hemangiopericytome » Rare tumors derived from pericytes. » Occur as slowly enlarging, painless masses. » Most common on lower extremities. » Consist of numerous branching capillary channels and gaping sinusoidal spaces, enclosed within nests of spindle shaped cells.

Answer 60

LYMPHANGITIS Lymphangitis, bacterial infection of the lymphatic vessels. Acute inflammation elicited by bacterial infections that spread into and throughout the lymphatics. Main causative agents are group A, β-hemolytic streptococci. The condition is most commonly caused by streptococcus or staphylococcus organisms The affected lymphatics are dilated, and filled with exudate of neutrophils and monocytes. Lymphangitis most commonly develops after cutaneous inoculation of microorganisms that invade the lymphatic vessels and spread toward the regional lymph nodes. The inflamed lymph vessels are visible as red streaks under the skin that extend from the site of infection to the groin or armpit with painful enlargement of the draining lymph nodes (acute lymphangitis). If the bacteria are not contained within the lymph nodes, they may pass into the venous circulation, resulting in bacteremia or sepsis. Reminder: The major function of the lymphatic system is to resorb fluid and protein from tissues and extravascular spaces. The absence of a basement membrane beneath lymphatic endothelial cells affords the lymphatic channels a unique permeability, allowing resorption of proteins that are too large to be resorbed by venules. Lymphatic channels are situated in the deep dermis and subdermal tissues parallel to the veins and have a series of valves to ensure one-way flow. Lymph drains via afferent lymphatics to regional lymph nodes and then by efferent lymphatics to the cisterna chyli and the thoracic duct into the subclavian vein and venous circulation LYMPHEDEMA Edema upon impaired lymphatic dranage , Lymphedema is traditionally classified into two forms: primary, which is genetic, and secondary caused by an acquired defect in the lymphatic system Primary lymphedema – occurs as isolated congenital defect, or as the familiar Milroy disease A familial, autosomal-dominant disorder, it is often caused by anaplastic lymphatic channels. The disorder manifests at birth or later, up to age 1 year., resulting from lymphatic agenesis or hypoplasia. Secondary (obstructive) lymphedema – accumulation of interstitial fluid due to blockage of normal lymph vessels; the obstruction can be the result of malignant tumors, therapeutic or post-inflammatory thrombosis and scarring. Commonly associated with obesity, infection, neoplasm, trauma, and therapeutic modality: I. Filariasis-The most common cause of secondary lymphedema worldwide is filariasis, a disease caused by the parasite Wucheria bancrofti which are widely distributed in tropical and subtropical regions of the world and are transmitted to man by mosquitoes infecting lymphnodes and may result in some of the untreated cases in the condition known as elephantiasis, which is typically associated with the gross expansion of the tissues of the legs and scrotum. II. Malignancy and cancer treatment- In the industrialized world, the most common causes of secondary lymphedema are malignancy and its treatment. This means that the disease can arise from obstruction from metastatic cancer or primary lymphoma or can be secondary to radical lymph node dissection and post-irradiation fibrosis Commonly affected area is the axillary region after mastectomy and radical dissection for breast cancer. III. Other causes- Morbid obesity frequently causes impairment of lymphatic return and commonly results in lymphedema. # Lymphedema increases the hydrostatic pressure in the lymph vessels, causing accumulation of lymph fluid in various spaces => chyloud ascites (abdomen), chylothorax, and chylopericardium.

Answer 61

HEART FAILURE Occurs when the heart is unable to pump blood at the rate necessary to supply the requirements of the metabolizing tissues Forward failure, and inadequate cardiac output, is almost always accompanied by backward failure, an increased congestion of the venous circulation => the failing ventricle is unable to eject the blood delivered to it, resulting in increased EDV, leading to increased diastolic pressure and elevated venous pressure. The cardiovascular system can adapt to reduced myocardial contractility in a few ways: 1) Activation of neurohumoral systems – release of epinephrine to increase heart rate and contractility, activation of rennin-angiotensin system, and release of atrial natriuretic peptide (ANP) that causes vasodilation, natriuresis and dieresis to relieve pressure overload states. 2) The Frank-Starling mechanism – increase of EDV causes stretch of cardiac muscle fibers and dilation of the ventricle, and results in more forceful contraction to elevate cardiac output 3) Myocardial structural changes – including hypertrophy to increase the mass of the contractile tissue (adult cardiac myocytes are unable to proliferate) => the capillary bed does not always increase with coordination to the increased oxygen demands of the hypertrophic cells, causing an ischemic injury LEFT-SIDED HEART FAILURE Usually occurs due to ischemic heart disease (IHD), systemic hypertension, mitral or aortic valve disease, and primary diseases of the myocardium. The result is damming of blood within the pulmonary circulation, and diminished peripheral blood pressure and flow. Morphology – » The left ventricle is usually hypertrophied and dilated. » Secondary enlargement of the left atrium can reduce stroke volume, and lead to stasis and thrombus formation. » Rising pressure in the pulmonary veins results in pulmonary congestion and edema. Histologically => interstitial transudate alveolar septal edema, and intra-alveolar edema. Capillary leakage hemoglobin is converted to hemosiderin => heart failure cells (macrophages containing hemosiderin). Clinical features – breathlessness (dyspnea), cough, orthopnea in later stages (dyspnea when lying down), enlarged heart, tachycardia, a 3rd heart sound (S3), mitral regurgitation and systolic murmur (due to displacement of the papillary muscle laterally). RIGHT-SIDED HEART FAILURE Usually the consequence of left-sided heart failure; Pressure increase in the pulmonary circulation => increase burden on the right side of the heart. Isolated right-sided heart failure occurs in case of: 1) Patients with intrinsic disease of lung parenchyma and/or pulmonary vasculature that result in chronic pulmonary hypertension => COR PULMONALE 2) Patients with pulmonic or tricuspid valve disease. Isolated right-sided heart failure is characterized by » Liver –congestion (nutmeg liver) => centrilobular necrosis and more peripheral yet reversible fatty change ,upon chronic injury risk to develop cardiac cirrhosis => the central areas become fibrotic. » Portal system elevated pressure also result in congested enlarged spleen may see more brown color again view hemosiderin accumulation. » Pleural and pericardial spaces – accumulation of fluid (effusion) in the pleural and pericardial spaces. » Subcutaneous tissue – peripheral edema pitting edema symmetric both lower extremities.

Answer 62

ISCHEMIC HEART DISEASE A group of related syndromes resulting from myocardial ischemia, most common cause for the reduction in coronary blood flow is atherosclerotic disease. Hence risk to develop IHD are same as ones of develop AS (age, gender, metabolic state, smoking etc.) IDH can also be the result of increased demand (increased heart rate, hypertension), or of diminished oxygen-carrying capacity (anemia, CO poisoning). The clinical manifestations of IDH are angina pectoris, acute myocardial infarction, chronic IHD and sudden cardiac death. ANGINA PECTORIS It is a periodic chest pain caused by reversible myocardial ischemia. Pressing retrosternal pain not related to breading, no elevation in myocardial enzymes opposing to MI, character ECG changes may seen (coronary/hyper acute t waves or ST alteration or both) and relief upon nitroglycerin administration… There are 3 variants of AP: 1) Typical (stable) AP  Episodic chest pain50 result of reversible injury to myocyte (swelling hallmark) associated with increased myocardial oxygen demand (tachycardia, hypertension =exertion/emotional stress etc.)  Usually occurs due to fixed atherosclerotic narrowing (>70%) of one or more coronary arteries => myocardial oxygen supply is sufficient no stress , but cannot be increased to meet the adequate demand.  Can be relieved by drugs that cause peripheral vasodilation, as nitroglycerin administration lead to immediate relief- vasodilation of mainly veins as reduced preload thus o2 demand ... 2) Prinzmetal (variant) AP  Episodic-less then 20 min chest pain unrelated to exertion, occurring at rest due to Short term complete occlusion of blood supply like in coronary artery spasms/repeated complete obstructive thrombus who partially lysed and reformed, usually take place near an existing atherosclerotic plaque, although normal vessels can also be affected.  Can be relieved by vasodilators such as nitroglycerin and Ca2+ channel blockers. ECG ST elevation transmural ischemia ,deadly may lead to arrhythmia and cardiac arrest. Main patient present it are male smoker 3) Unstable AP (crescendo angina)  AP show also at rest from incomplete occlusion of coronary, It is associated with atherosclerosis/plaque disruption and superimposed thrombosis, embolization… risk to progress to potentially irreversible injury ischemia.- It is called pre-infarction angina  Characterized by increasing frequency of pain => episodes tend to be more intense and long lasting than stable AP. ACUTE CORONARY SYNDROME Refers to any of the 3 catastrophic outcomes of IHD see picture upon coronary atherosclerosis and typical AP may develop chronic ischemic heart diseas or progress to acute coronary syndrome. 1. Unstable AP 2. Acute MI-previously non major occlusive plaque build thrombose and see acute unset sever ischemia 3. Sudden cardiac death-usually refer to sudden collapse of circulation as from arrhythmia without prominent myocardial damage Associated with coronary thrombosis/embolisem-acute pluqe changes,vasoconstriction such upon agonist of epi ,platelet local realis, endothelin other vasoconstrictor realis upon endothelial imbalance ext. endothelin and cocaine usage. Symptoms include angina pectoris but sever, shortness of breath, nausea and sweating and sympathetic dominance .

Answer 63

ETIOLOGY OF MYOCARDIAL INFARCTION MI, or common name heart attack, is necrosis of heart muscle resulting from ischemia. The major underlying cause is atherosclerosis (as see disruption of plaque and thrombogenesis); therefore the frequency of MI rises progressively with age and occurrence of risk factors to atherosclerosis; women are protected against MI during their reproductive years. Other risk factors that contribute to MI are hypertension, smoking, diabetes mellitus, gender (men are more affected). PATHOGENESIS Most MIs are caused by acute coronary artery thrombosis, resulting from disruption of an atherosclerotic plague and formation of thrombus. In limit to sub endocardial infarctions, the cause is usually increase in demand such as arrhythmia/hypertension under settings of diffused coronary atherosclerosis  ischemic necrosis of the myocardium ,most distal to the epicardial vessels Occurrence of MI without occlusive atherosclerotic disease(~10% of MI ) include Vasospasms (prinzmetal AP , elevated catecholamine or exogenous cocaine),mural thrombose/ valve vegetation leading to thromboembolism in coronaries Ischemia without atherosclerosis or thromboembolic disease can be caused by disorder of small intramyocardial arterioles, including vasculitis (Kawasaki diseas a vasculitis in small children preferentially involving coronaries), amyloid deposition or stasis (e.g. sickle cell disease). Sequence of events in coronary artery occlusion: » Atheromatous plaque is disrupted -> sub endothelial collagen and necrotic plaque are exposed to the blood » Platelets aggregate and activated -> release of thromboxane A2, ADP and serotonin -> vasospasm, Coagulation begins with exposure of TF and platelet surface… » Thrombus evolves to completely occlude vessel # Myocardial response to ischemia – » aerobic glycolysis ceases -> inadequate production of ATP, and accumulation of toxic products (lactic acid)  loss of contractility, myofibrillar relaxation, glycogen depletion, cellular and mitochondrial swelling. These changes are REVERSIBLE » severe prologue ischemia ( more then 20-40 minutes) causes irreversible injury and death of myocytes as coagulation necrosis , irreversible injury usually appear initially in the sub endocardial zone since it’s the last area to receive blood from the epicardial vessels and it has a high intramural pressure -> Infract usually achieves its full extent within 3-6 hours (transmural infract) MORPHOLOGY Patterns of infraction – location , size and morphology depend on the size and duration of involved vessel; rate of development; metabolic demands of the myocardium. Usually in MI atria’s are speared Epicardial vessels are interconnected by collateral circulation; in case of epicardial occlusion, collateral dilation can provide adequate perfusion. Microscopic infract – small vessel occlusion, no changes on ECG. Occurs in vasculitis, embolization/ mural thrombi, vessel spasm … In most patients, the distribution of infarcts is as follows: » Left anterior descending (LAD) artery (most common 40%) infarct involves the anterior left ventricle, anterior 2/3 of septum and the apex. Left coronary occlusion is typically fatal (“widow maker”). » Right coronary artery (RCA) 2nd common  infarct involves the posterior left ventricle, posterior septum and right ventricle. RV papillary .m. » Left circumflex artery (LCX) -> infarct involves the lateral left ventricle. Myocardial necrosis eventually proceeds to scar formation without any significant regeneration. The gross and microscopic appearance of MI depends on the interval of time since the original injury (coagulative necrosis -> acute & chronic inflammation -> fibrosis : 1. In 1st day- initial 1st min come with loss of function no visible change may end as arrhythmia/cardiogenic shock if large effected area, next 4-24 hr. development of coagulative necrosis lose nuclei look dark on macro due to stagnated trapped blood again danger of necrosis conductive sys. And arrhythmia. 2. In first week- events of inflammation take place ,initial 3 days neutrophils infiltrate if transmural infract may involve epicardium as fibrinous pericarditis, following days till full week past see macrophages come to clean inflammatory debris n initiate granulation tissue formation so this stage myocardium most weak and danger of rapture as complication papillary .m. rapture=mitral insufficiency/vent. Wall rapture and cardiac tamponade !macro appearance in 1st week as yellow pallor appearance micro see inflamtory infiltrate inbt necrotic myocytes 3. Till end of month follow infarction-from 1-3 week see granulation tissue micro fibroblast depositing collagen and new blood vessels leading to red border around infract macro morphology as new blood vessel formed from preexisting ones on edges of necrotic tissue ,till end of month scar (main collagen 1) replace the myocardium risk for anyurisem and turbulencestasis-new thrombose etc.… Infracts older than 3 hours can be stained by a substrate51 for LDH – leaks from cell at the area of necrosis. The infracted area is pale CLINICAL FEATURES Severe chest pain radiating to neck, jaw, left arm, lasts a few minutes-hours (in contrast with angina pectoris); pain isn’t relieved by nitroglycerin or rest. Pulse is rapid and weak; patients are nauseated, Dyspnea is common due to impaired contractile ability -pulmonary congestion and edema,SNS sings In severe MI cardiogenic shock develops # Lab findings – leaked enzymes – myoglobin, cardiac troponin may raise 5 fold almost absolute for MI less other stuff as inflammation but if absent for sure this isn’t MI raise after 4 hr. from event peak in 24 hr and fall after about a week , creatine kinase useful for detection of 2ndery event as take ~6hr to raise and peak in 24 and fall in about 72 hr. , LDH # Reperfusion injury- Reperfusion when injury is still reversible can preserve cell viability. Perfused myocardium appear hemorrhagic and show an eosinophilic contraction band necrosis. » Return of blood means return of oxygen and inflammatory cells lead to Free radicals which far more injure myocytes » Myocardial ischemia contributes to arrhythmias by causing electrical instability of ischemic regions of the heart -> ventricular fibrillation -> sudden death. During ischemia IC Ca levels are significantly increased, after reperfusion more ca but no pump capacity , contraction of myofibrils is uncontrolled -> cell death see contraction band necrosis pattern CONSEQUENCES OF MYOCARDIAL INFARCTS Contractile dysfunction – resulting in hypotension, pulmonary vascular congestion, and pulmonary transudation into the pulmonary interstitial and alveolar spaces. Arrhythmias – sinus bradycardia, heart block, tachycardia, ventricular premature contractions, and ventricular fibrillation. Myocardial rupture – complications include rupture of the wall with hemopericardium and cardiac tamponade; rupture of the septum with left to right shunt; and papillary muscle rupture resulting in mitral regurgitation. Pericarditis – develops within 2-3 days after MI and usually spontaneously resolves. Dressier syndrome rear AI pericarditis appearing about 6 week follow transmural infarction as result of exposure of pericards AG to immune system Infarct expansion Chamber dilation – wakening of necrotic muscle results in its thinning and dilation of the infarct region. Mural thrombus – local loss of contractility, causing stasis, with endocardial damage, causing thrombogenic surface; can result in the formation of mural thrombus and thromboembolism. Ventricular aneurysm – usually results from anterolateral infarction with the formation of thin scar tissue, may lead to mural thrombus, arrhythmias and heart failure. Papillary muscle dysfunction

Answer 64

HYPERTENSION (topic 80) Hypertension – a chronic medical condition in which the blood pressure in the arteries is elevated, requiring the heart to work harder than normal to circulate the blood through the vasculature. Regulation of blood pressure depends on the regulation of cardiac output (affected by blood volume), and total peripheral resistance (regulated by arterioles via neurological and hormonal inputs). The kidneys, and to some extent the adrenal glands, are responsible for blood pressure regulation, mainly by the rennin-angiotensin system (RAS). Hypertension can cause cardiac hypertrophy and heart failure (hypertensive heart disease), aortic dissection, and renal failure. CARDIAC HYPERTENSION Cardiac myocytes are terminally differentiated cells, which lack the capacity to divide -> hyperplasia CANNOT occur. Instead, increased work will induce an increased mass and heart size -> hypertrophy The pattern of the hypertrophy reflects the initiating stimulus: » Concentric hypertrophy – develops due to pressure-overloaded ventricles (in hypertension or aortic valve stenosis), with an increased wall thickness that can reduce the volume of the ventricle. » Eccentric hypertrophy – develops due to volume overload (in aortic valve insufficiency), and is characterized by ventricular dilation associated with muscle mass increase. Prolonged hypertrophy can eventually result in myocyte contractile failure, cardiac dilation, CHF and sudden death. Although hypertensive heart disease mostly affect the lecft side of the heart secondary to systemic hypertension, pulmonary hypertension also can cause right-sided hypertensice changes – cor pulmonale SYSTEMIC HYPERTENSION Systemic hypertension occurs when there’s left ventricular hypertrophy without other cardiovascular pathology (valvular stenosis); and evidence of hyertension Morphology – left ventricular hypertrophy, without ventricular dilation (until very late in the process). Heart weight ~500gr, wall thickness >2cm, causing stiffness that impairs diastolic filling; microscopically, there is nuclear enlargement and hyperchromasia, and interstitial fibrosis PULMONARY HYPERTENSION Usually low pressure in pulmonary circulation about 25/10 mmHg and Venus pressure 2-5 mmhg if raise above 25mmhg its an pulmonary hypertension Characterized by atherosclerosis of the pulmonary trunk, smooth muscle hypertrophy of pulmonary arteries, and intimal fibrosis; plexiform lesions–endothelial prolifartion and occlusion of small .a. lumen are seen With severe, long-standing disease Sub classified as primary or secondary based on etiology A. primary-Classically seen in young adult females, Etiology is unknown; some rear familial forms are related to inactivating mutations of BA1PR2, leading to proliferation of vascular smooth muscle. Rare, autosomal dominant with incomplete penetrance Mutations in bone morph genic protein receptor 2 signaling pathway (BMPR2) B. secondary - Due to hypoxemia (e.g., COPD and interstitial lung disease) or increased volume in the pulmonary circuit (e.g., congenital heart disease); may also arise with recurrent pulmonary embolism COR PULMONALE pulmonary hypertensive heart disease- is the enlargement and failure of the right ventricle of the heart as a response to increased vascular resistance (such as from pulmonic stenosis) or high blood pressure in the lungs. Presents with exertional dyspnea or right-sided heart failure # Consists of right ventricular hypertrophy and dilation – frequently accompanied by right heart failure - due to pulmonary hypertension, caused by primary disorders of the lung parenchyma or pulmonary vasculature. Can be either acute or chronic: » Acute – follows massive pulmonary embolism with obstruction of >50% of the pulmonary vascular bed. Thromboembolic obstruction of proximal pulmonary arteries » Chronic – occurs secondary to prolonged pressure overload, caused by obstruction of the pulmonary vasculature, or compression/obliteration of septal capillaries (resulting from emphysema, interstitial pulmonary fibrosis, or primary pulmonary hypertension). Morphology – » In acute cor pulmonale – the right ventricle is dilated, but does not show hypertrophy. » In chronic cor pulmonale – right ventricle hypertrophy. When ventricular failyre develops, ventricle and right atrium are dilated; pulmonary arteries often contain atheromatous plaque

Answer 65

RHEUMATIC FEVER An immunologically-mediated, systemic disease that occurs after group A, β-hemolytic streptococcus pharyngitis about 2-3 weeks after pharyngitis. # Most often affects children 5-15 years old. In only about 3% of infected individuals hence genetic susceptibility is likely to influence (due to the small minority of infected people). Can be prevented by AB penicillin treatment to strep throat infection preventing complications such as scarring of mitral valve which may lead to need in surgery for valve replacement. Pathogenesis – it is a hypersensitivity reaction induced by host antibodies against group A streptococci => some M proteins induce antibodies that cross-react with glycoproteins in the heart and joints, this cross-reactivity is a type II hypersensitivity reaction and is termed molecular mimicry. This Autoimmune attack manifested as systemic disease affecting the connective tissue around arterioles, heart and joints, producing the symptoms of rheumatic fever. Morphology – the classic lesion of rheumatic fever histologic characteristic appearance of Aschoff body => an area of focal interstitial inflammation that is characterized by fragmented collagen and fibrinoid material, by activated macrophages with slander wavy nucleus (Anitschkow cells), and by occasional giant cells . Manifestations of rheumatic fever As jones criteria an diagnostic system in it the Major criteria represent manifestations: Polyarthritis- A temporary migrating inflammation of the large Joints, usually starting in the legs and migrating upwards. Pancarditis- inflammation of all 3 layers of heart : A. endocarditis as small vegetation’s essentially on valves and preferentially on mitral valve impire normal valve closure upon appearance of vegetation later resolve as scar valve stenosis … B. myocarditis- histologic characteristic appearance of Aschoff body, most common cause of death during acute phase C. pericarditis-fibrinous exudate resolve alone Subcutaneous Nodules Erythema marginatum: reddish rash that begins on the trunk or arms as macules with clear center, next spread outward typically spares the face. Sydenham's chorea: A characteristic series of involuntary rapid movements of the face and arms. RHEUMATIC HEART DISEASE Repeated Inflammation of the endocardium due to repited rheumatic fever attecks may result in rheumatic heart disease (RHD). RHD is the consequence of Fibrosis and scarring of the valves: valve leaflets become thick fibrotic and deformed ,commissural fusion or shortening of cusps and thickening of chorda tendinae leads to abnormalities that can result in valve stenosis or regurgitation Manifestation » Mitral valve –stenosis and/or insufficiency. » Aortic valve – usually affected along with the mitral valve, by stenosis or insufficiency. » Tricuspid valve – if affected, it occurs with the involvement of both mitral and aortic valves. » Pulmonary valve – rarely involved.

Answer 66

VALVULAR STENOSIS & INSUFFICIENCY # Stenosis – the failure of a valve to open completely, obstructing forward flow, usually caused by chronic process e.g. calcification or valve scarring. # Insufficiency – the failure of the valve to close completely, allowing backflow, resulting from either intrinsic disease of the valve cusps, or distortion of the supporting structures chords/papillary muscles. # Valvular disease can affect a single valve (most often the mitral valve), or may include more than one valve. # The abnormal flow through diseased valves produces abnormal heart sounds => murmurs. # Valve abnormalities are caused by congenital disorders or by acquired diseases, for example: rheumatic heart disease, infective endocarditis and calcification (aortic valve). # Calcific aortic stenosis – most common degenerative valvular disease, and most frequent cause of aortic stenosis: » Usually age-associated calcification wear and tear damage to valve, appear around age of 60 risk factors are same as for atherosclerosis » Nodular Calcified masses on the outflow side of the cusps causing them to protrude into the aortic sinuses, obstructing normal opening. Note no commissure fusion like in rheumatic fever. » Post inflammatory scaring anther common reason for stenosis as in after rheumatic fever appear usually together with commissural fusion and mitral valve involvement. » In about 1% of all live birth see bicuspid aortic valve (2 leaflet instead of 3) most common congenital valve diseas not rally problem only repercussion is for increased risk to develop aortic calcification stenosis in general and earlier. MITRAL VALVE PROLAPSE # Characterized by myxoid (mucoid) degeneration of one or both leaflets of the mitral valve, making them "floppy" => the leaflets are being pushed back into the left atrium during systole. # Seen more frequently in women. # Morphology – » The affected leaflets are enlarged, thick and rubbery. » Chordae tendinous are elongated, thin and may be ruptured. » Histologically => impaired structural integrity, and increased deposition of mucoid material in center of valve -spongiosa layer one who enclosed by fibrosa layer . # Pathogenesis –primary the cause of degeneration is unknown, but it may be associated with intrinsic defect of c. t tissue (Marfan syndrome/ehelor danols syndrome).2ndry come upon other etiology as ischemic dysfunction. # Clinical features – most patients are asymptomatic, but mitral prolapsed may cause palpitations, breathlessness and atypical chest pain.may be heard as murmur in middle of systole. # Complications rear but in case of sever weakening to valve see sever mitral regurgitation which may lead to left side congestive heart failure risk for ventricular arrhythmias and incres risk for infective endocarditis on injured valve.

Answer 67

ENDOCARDITIS # Inflammation of the endocardium, the inner layer of the heart. # It usually involves the heart valves (native or prosthetic). # Other structures that may be involved are the interventricular septum and the chordae tendinae. # It is characterized by abnormal growth of the endocardium, composed of platelets, fibrin, micro colonies of microorganisms and inflammatory cells. INFECTIVE ENDOCARDITIS # It is defined as an infection of the endocardial surface of the heart. # Characterized by microbial invasion of heart valves or mural endocardium, often includes destruction of the underlying tissue, and results in bulky vegetation’s abnormal masses composed of necrotic debris, thrombus and organisms. # Most cases of endocarditis are caused by extracellular bacteria # Infective endocarditis can be classified into 2 types use as spectrum many cases fall in between..: » Acute endocarditis – due to a destructive infection, caused by a highly virulent organism (Staphylococcus aureus) that attacks a previously normal valve » Subacute endocarditis – infections by organisms of low virulence (streptococcus viridians part of oral flora..) colonizing a previously abnormal heart, especially deformed valves # Morphology – » Both acute and subacute forms are characterized by destructive vegetation’s (abnormal tissue growth) in the heart valves, containing fibrin , inflammatory cells and microorganisms => aortic and mitral valves are the most common sites of infection. » These vegetations can penetrate into the underlying myocardium to produce an abscess cavity (ring abscess). » Fungal endocarditis tends to form larger vegetations than bacterial endocarditis. » Systemic emboli may occur due to the fact that damage endocardium as damage endothelium promote thrombose formation.. » Microscopically, subacute endocarditis contains granulation tissue at the bases of the vegetation => may indicate a chronic process. » Over time, fibrosis, calcification may develop. # Pathogenesis – » Cardiac abnormalities predispose to infections => rheumatic heart disease (RHD), mitral valve prolapsed, bicuspid aortic valve, and calcific valvular stenosis. » Host factors also increase the risk of infective endocarditis. » Endocarditis of previously damaged and abnormal valves is usually caused by Viridians streptococci, while endocarditis of deformed and healthy valves is caused by Streptococcus aureus. # Clinical features – » Fever, fatigue, and flu-like syndrome with more sever abrapt manifestation in acute one. » May see Splenomegaly in the subacute form of infective endocarditis. » In the acute form => rapidly developing fever, chills, weakness and fatigue. » In 90% of patients with left side abnormalities, murmurs are present. » Diagnosis is made on the basis of positive blood cultures and echocardiography findings. » Complications include glomerulonephritis, septicemia, arrhythmias, and systemic embolization. NON-INFECTIVE ENDOCARDITIS # Non-bacterial thrombic endocarditis (NBTE) is characterized by deposition on heart valves of thrombotic small masses composed of mainly fibrin and platelets unlike infective form thes are sterileno microorganism and nondestructive lesions. # Vavular damage is NOT a prerequisite for NBTE, and the condition is usually found on previously normal heart valves. # A wide variety of diseases, associated with debility (exhaustion), may increase the risk of NBTE; therefore, it NBTE is also referred to as MARANTIC ENDOCARDITIS. # Morphology – » Vegetation’s are sterile, small (1-5mm dimeter) thrombotic mases occur around the line of closure of the leaflets or cusps. » They are composed of thrombus without accompanying inflammation of valve itself # Pathogenesis – Typically occurs in hyper coagulative states (DIC), hyper estrogenic states, or underlying malignancy (adenocarcinomas). # Clinical features – embolization may occur to the brain and heart.also may use as surface for infective agents to implant. # Libman-Sacks endocarditis – sterile vegetations that develop on the valves of patients with SLE.upon immune complex deposition on surface may lead to valve serious deformities fibrosis resemble to recurrent rheumatic fever . COMPLICATIONS RELATED TO PROSTHETIC VALVES # There are 2 types of prosthetic valves: » Mechanical valves – Double tilting disc made of pyrolytic carbon.Have excellent durability. Require chronic anticoagulation treatment => increased risk of hemorrhage. Cause hemolysis due to shear stress. » Bioprosthetic valves – Porcine or bovine tissues, or cryopreserved human valves. Do not require anticoagulation. Less durable => can fail due to matrix deterioration. Undergo some degree of stiffening after implantation => may cause stenosis. Calcification is also common. # Prosthetic valves are subjected to infection- strep. Epidermidis most characteristic for transplant valve infection . In mechanical valves, infective endocarditis usually involves the suture line and adjacent perivalvular tissue => may cause the valve to detach (bio valve itself may be infect along surrounding tissue).

Answer 68

MYOCARDITIS # Inflammation of the myocardium with resulting injury by infective agent/ the inflammatory process is the cause of the myocardial injury. # Pathogenesis – » Infections – viruses most common agents (Coxsackieviruses A and B , other enteroviruses and less common CMV) in virus case usually its more the immune respond who responsible to damage, bacteria Lyme diseas and borrhileia burgdorferi (Corynebacterium diphtheria, Neisseria meningococcus), Chlamydial, Rickettsia, fungi (Candida), protozoa (Trypanosoma) => Chagas disease. » Non-infectious causes – systemic diseases of immune origin (SLE, polymyositis). # Morphology: » Macro-The heart may appear normal or dilated. On more advanced stage the ventricular wall appear lose (flabby), and surface may show patchy pallor (paleness) and/or hemorrhage pattern. » Micro- see edema, interstitial inflammatory infiltrate with sings of injury to myocytes. There are 4 patterns of myocarditis: 1) Lymphocytic myocarditis – the most common form lymphocyte infiltrate edema and injured myocytes in focal areas . 2) Hypersensitivity myocarditis – interstitial and characteristic perivascular infiltrates dense with eosinophils. Also see lymphocytes and macrophages. 3) Giant-cell myocarditis – characterized by widespread inflammatory cellular infiltrates, containing multinucleated giant cells (fused macrophages), a more aggressive edge of lymphocytic type with diffused there is extensive necrosis inflammation covering larger areas then lymphocytic. 4) Chagas myocarditis – the myofibers are distended by trypanosomes58, accompanied by inflammatory infiltrate of neutrophils, lymphocytes and macrophages. # Clinical features – can vary from asymptomatic myocarditis, to the onset of heart failure or arrhythmias; other symptoms include fatigue, dyspnea, palpitations, pain and fever. CARDIOMYOPATHIES #A collective name for cardiac muscle diseases that are attributed to intrinsic myocardial dysfunction. #They include myocarditis, immunologic diseases (sarcoidosis), systemic metabolic disorders (hemochromatosis), muscular dystrophies, and genetic disorders of cardiac muscle cells. #In many cases, cardiomyopathies are IDIOPATHIC (unknown cause). #Cardiomyopathies are divided into 2 groups: Primary – the disease is mostly confined to the heart muscle. And Secondary – the heart is involved as part of a general, multi-organ disorder. #Clinical classification divides cardiomyopathies into 3 types: » Dilated cardiomyopathy. » Hypertrophic cardiomyopathy. » Restrictive cardiomyopathy DILATED CARDIOMYOPATHY # Most common cardiomyopathies Characterized by progressive cardiac dilation and contractile dysfunction, usually accompanied with hypertrophy. # Pathogenesis – in primary conformation as the myocardium is the organ principally involved by the diseas : many cases no major underlying reson discovered and it termed as idiopathic dilated cardiomyopathies ,About 25%-35% of the cases have a familial basis, other cases result from toxic exposure (alcoholism), myocarditis, and pregnancy associated changes; » Alcohol and toxic exposure – metabolites of alcohol, especially acetaldehyde, have a direct toxic effect on myocardium. » Genetic influences – most common is autosomal dominant inheritance, but the other forms of inheritance can also occur => most genetic abnormalities involve the myocytic cytoskeleton Peripartum cardiomyopathy – occurs late in gestation or in the first few weeks-months after birth => caused by pregnancy-associated hypertension, volume overload, nutritional deficiency. » Iron overload e.g. hematochromatosis Secondary as myocardial presentation part of systemic disorder common second to other cardiovascular disease: ischemia, hypertension, valvar disease, tachycardia induced # Clinical features – » Can occur at any age, mainly 20-50 years of age.Presents as slowly progressive congestive heart failure. The main defect is ineffective contraction, eventually resulting in ejection fraction of less than 25%. » Secondary mitral regurgitations and abnormal cardiac rhythms are common HYPERTROPHIC CARDIOMYOPATHY # Characterized by myocardial hypertrophy, abnormal diastolic filling- Systolic function is usually preserved, but the heart does not relax, resulting in diastolic dysfunction. ventricular outflow obstruction come in about 1/3 of cases. # Pathogenesis – the manifestation as primary cardiomyopathy shuld be destingushed from ventricular hypertrophy as adaptive respond and disorders influencing ventricular stiffness. In most cases, there is autosomal dominant missense point mutation in one of the several genes encoding the proteins of the sarcomere => β-myosin heavy chain gene is most commonly affected, but also myosin-binding protein C and troponin T. # Morphology - » Massive myocardial hypertrophy without ventricular dilation. The ventricular cavity loses its round shape and is compressed into a "banana-like" shape. » Disproportionate thickening of the septum relative to the walls of the left ventricle => asymmetrical septal hypertrophy. # Clinical features – » Impaired diastolic filling => provides reduced stroke volume despite the hypertrophied LV. Also the severing the situation is patient with outflow obstruction Systolic ejection murmur. » Beside reduced systemic blood supply secondly, the reduced cardiac output results in pulmonary venous pressure, causing dyspnea. » Clinical problems include atrial fibrillation, infective endocarditis of the mitral valve, chronic heart failure, arrhythmias and sudden death. RESTRICTIVE CARDIOMYOPATHY # Characterized by primary decrease in ventricular compliance, resulting in impaired ventricular filling during diastole while the contractile function of the left ventricle is usually unaffected. # Can be idiopathic or associated with systemic diseases that affect the myocardium (fibrosissuch after radiation, amyloidosis, hemochromatosis, and sarcoidosis). # Morphology – The ventricles are of normal size but bi-atrial dilation often seen and The myocardium is firm. Micro interstitial fibrosis may seen or In case of specific cause to the cardiomyopathy, disease-specific features can be seen (amyloid, iron overload etc.). # There are 2 more forms of restrictive cardiomyopathy: 1) Endomyocardial fibrosis – disease of children and young adults in tropic countries, characterized by dense fibrosis of the ventricular endocardium and sub endocardium, extending from the apex to the AV valves. 2) Loffler endomyocarditis – causes endocardial fibrosis with mural thrombi, but it is not geographically restricted. 3) Amyloidosis – deposition of extracellular proteins with the predilection for forming insoluble beta-pleated sheets. Can be a part of systemic amyloidosis, or can be restricted to specific organ.

Answer 69

CONGENTIAL HEART DISEASE # Congenital heart diseases are abnormalities of the heart or great vessels that are present at birth, most of which arise during weeks 3-8 of gestation when major cardiovascular structures develop... # Pathogenesis – » In most cases (~90%) the cause of the abnormality is unknown. » Environmental factors – congenital rubella infection, teratogens exposure etc.. Congenital rubella syndrome (CRS) can occur in a developing fetus of a pregnant woman who has contracted rubella, usually in the first trimester The classic triad for congenital rubella syndrome is:[4]  Sensorineural deafness (58% of patients)  Eye abnormalities—especially retinopathy, cataract, and microphthalmia (43% of patients)  Congenital heart disease—especially pulmonary artery stenosis and patent ductus arteriosus (50% of patients) » Genetic factors – familial forms of congenital heart disease, and certain chromosomal abnormalities (trisomy’s 13, 15, 18 & 21, and Turner syndrome). » Several congenital heart diseases are associated with mutation in transcription factors => TBX560, NKX2.561 » Abnormal development of neural crest cells can cause defects in the formation of the outflow tract => caused by deletions of a segment in the long arm of chromosome 22. # Congenital heart diseases can be divided into 3 groups: 1) Malformations causing a left-to-right shunt 2) Malformations causing a right-to-left shunt. 3) Malformations causing obstruction. LEFT-TO-RIGHT SHUNTS # Shunts permit the flow of blood from the left heart to the right heart.most common CHD. # Manifestation range from asymptomatic to RHF Left-to-right shunts increase pulmonary blood flow, and expose the low pressure & low resistance pulmonary circulation to increased pressure and volume, resulting in right ventricular hypertrophy and eventually right-sided failure , but they are NOT associated with cyanosis as an early feature. 1. Atrial septal defects: abnormal fixed opening in atrial septum not closed by the septum secundum, so a shunt exists across from left to right. # Reminder- septum secundum and premium create foramen inbt right and left atrium in embryo life its open as valve closed on its left side by a flap of tissue derived from the primary septum, which acts as a one way valve that allows right-to-left blood flow keep embryo circulation. At the time of birth, pulmonary vascular resistance drops and systemic arterial pressure rises, causing the pressure in the left atrium to exceed those of the right atrium, resulting in the functional closure of foramen ovale. # There are 3 types of ASD: 1) Ostium secundum ASD – the most common (90%), occurs when septum secundum does not enlarge sufficiently to cover the ostium secundum. Significant large lesion induce vol. overload so right atrial and ventricular dilation, right ventricular hypertrophy, and dilation of the pulmonary artery. 2) Ostium premium ASD – less common (5%), occurs when the septum premium and endocardial cushion fail to fuse; associated with other abnormalities in structures derived from the endocardial cushion (AV valves malformations cleft valves as antr leaflet mitral valve…). 3) Sinus venosus ASD – less common (5%), located near the entrance of SVC. often accompanied by anomalous drainage of the pulmonary veins into the right atrium or SVC. # Clinical features – ASDs initially come as asymptomatic at childhood even large openings do so but with time larger openings may end with pulmonary hypertension with increased pulmonary arterial pressures that eventually led to reversal and right-to-left shunt, resulting in marked right ventricular hypertrophy. # patent foramen ovale –upon incomplete fusion of septum secundumm flap with wall it develops present =Normally, the left atrial pressure keeps the foramen closed, but if right atrial pressures rise with pulmonary hypertension (as with pulmonary embolus), the foramen may open and even allow a thrombus to go from right to left. This is a rare entity called "paradoxical embolus"…… 2. ventricular septal defects # Incomplete closure of the ventricular septum. left-to-right shunts, # The ventricular septum is formed by the fusion of an intraventricular muscular ridge, and a thinner membranous portion that grows from the endocardial cushion. # About 90% of VSD's are in the membranous septum and 10% in the muscular septum. Most VSDs close spontaneously in childhood. # Morphology – » Size and location of defects are variable. » In defects associated with significant left-to-right shunts, the right ventricle is hypertrophied and often dilated. » The diameter of the pulmonary artery is increased due to increased volume ejected by the right ventricle. # Clinical features – small VSDs are asymptomatic, while larger defects cause severe left-to-right shunt, complicated by pulmonary hypertension and congestive heart failure; progressive pulmonary hypertension results in reversal of the shunt and cyanosis 3. Patent ductus arteriosus # The ductus arteriosus, which normally closes soon after birth, remains open, and a left-to-right shunt develops Ductal closure is delayed in infants with hypoxia, resulting from respiratory distress or heart disease. # During intrauterine life, ductus arteriosus allows blood flow from the pulmonary artery to the aorta => bypass the unoxygenated lungs. After brith, ductus arteriosus constrics and becomes ligamentum arteriosum. # Morphology – Ductus arteriosus arises from the left pulmonary artery and joins the aorta just distal to the origin of the left subclavian artery.In PDAs, some of the blood flowing out of the left ventricle is directed back to the lungs => volume overload => dilation of proximal pulmonary arteries, left atrium and ventricle => pulmonary hypertension => right heart hypertrophy and dilation. # Clinical features – PDAs are high pressure shunts, audible as "machinery-like" murmurs; large defects can lead to Eisenmenger syndrome with cyanosis and congestive heart failure. RIGHT-TO-LEFT SHUNTS # Cardiac malformations that are characterized by cyanosis at the time of birth which happened due to direct introduction of poorly oxygenated blood from the right side of the heart, into the arterial circulation. # Clinically present as sever systemic cyanosis with consequence of polycythemia and risk of paradoxical embolism. # 2 significant conditions end with it are: 1. Tetralogy of Fallot The most common cause of cyanotic congenital heart disease. Results from abnormal division into the pulmonary trunk and aortic root. Pulmonic stenosis results in right ventricular hypertrophy and a right-to-left shunt across a VSD, which also has an overriding aorta Composed of 4 features: 1) VSD-near the membranous portion of the septum. 2) Obstruction to the right ventricular outflow tract- The proximal aorta is larger than normal with diminished pulmonary trunk, pulmonary stenosis protects the lungs from overload and pulmonary hypertension. 3) An aorta that overrides the VSD. 4) Right ventricular hypertrophy- The heart is large and "boot shaped" due to right ventricular hypertrophy. 2. Transposition of Great Vessels # Due to abnormal formation of truncal and aortopulmonary septa => aorta arises from the right ventricle, and the pulmonary trunk originates from the left ventricle. The atrium-to-ventricle connections are normal. # The functional outcome is the separation of the systemic and pulmonary circulations, a condition inadequate with postnatal life. A VSD, or ASD with PDA, is needed for extra uterine survival. There is right-to-left shunting. # Clinical features – predominant manifestation is early cyanosis; the forecast of neonates with TGA depends on the degree of shunting, the magnitude of tissue hypoxia and the ability of the right ventricle to maintain systemic pressure. OBSTRUCTIVE LESION # Congenital obstruction to blood flow that occurs at the level of the heart valves, or within a great vessel. # Common congenital obstruction includes pulmonic valve stenosis, aortic valve stenosis, and coarctation of the aorta. Coarctation of the aorta # The narrowing of the aorta. Males are affected twice as much as females but It is common in girls who have Turner syndrome.. # There are 2 forms of aortic coarctation Infantile – » hypoplasia of the aortic arch narrowing of the aortic segment between the left subclavian artery and ductus arteriosus just before it Ductus arteriosus is usually patent and is the main source of blood delivered to distal aorta. The right side of the heart must supply the body (distal to the narrowing), resulting in hypertrophy of the right ventricle. Adult - ridge-like in folding of the aorta, just opposite to ligamentum arteriosum sharp constriction of the aorta - The constricted segment is made up of smooth muscle and elastic fibers that are continuous with the aortic media, lined by a thickened layer of intima -Ductus arteriosus is closed -Proximal to the contraction, the aortic arch and its branch vessels are dilated, and athersclrosed (in older patients). -Hypertrophy of the left ventricle Coarctation of the aorta may occur as a solitary defect, but in most cases (>50%) it is accompanied by a bicuspid aortic valve.

Answer 70

OBSTRUCTIVE VS. RESTRICTIVE # Pulmonary diseases can be classified as: » Obstructive disease – characterized by limitation of airflow, Expiratory obstruction may result from anatomic airway narrowing (asthma), or from loss of elastic recoil (emphysema) ,Includes 4 major diseases emphysema, chronic bronchitis, bronchiectasis, and asthma. Spirometry changes: Decreased expiratory flow rate and decreased forced vital capacity (FVC), with increased total lung capacity= tot. Amount of air in lung .  Most important FEV/FVC < 0.8 healthy (in COPD both decrease but FEV decrease a lot from 4L/5L to 2L/4L=0.5) » Restrictive disease – characterized by reduced expansion of lung parenchyma, accompanied by decreased total lung capacity FVC is reduced, and FEV is normal or proportionally reduced so FEV/FVC- near normal! The restrictive defect occurs in: # Chest wall disorders in the presence of normal lungs => severe obesity, diseases of pleura, and neuromuscular CHRONIC OBSTRUCTIVE PULMONARY DISEASES (COPD) # Group of chronic pulmonary diseases which impair the ability to empty the lung include chronic bronchitis and emphysema both link to smoking and manifest together usually. Unlike asthma also an obstructive diseas in COPD the damage lead to IRREVERSIBLE airflow obstruction in asthma there is REVERSIBLE airflow obstruction EMPHYSEMA # Characterized by permanent enlargement of the airspaces, result from destruction of alveoli walls so from multiple small spaces a large air filled space is formed . With the loss of elastic tissue in the surrounding alveolar septa, radial traction on the small airways is reduced. As a result, they tend to collapse during expiration—an important cause of chronic airflow obstruction in severe emphysema # Types of emphysema: (only the 1st 2 are clinically significant airway obstruction) » Centriacinar emphysema Most commonly seen as a consequence of smoking in people with no congenital deficiency of α1-antitrypsin The lesions are more common in the upper lobes The proximal parts of the acini, formed by respiratory bronchioles, are affected (distal part spared) => both emphysematous and normal airspaces exist in the same acinus In severe cases, the distal acinus also becomes involved » Panacinar (panlobular) Associated with deficiency of α1-antitrypsin, The acini are uniformly enlarged from the level of the terminal bronchiole to the alveoli Tends to occur in lower lung areas »Distal acinar (paraseptal) emphysema The proximal portion of the acinus is normal, but the distal part is affected The emphysema is adjacent to the pleura, near areas of fibrosis, scarring or atelectasis * Cause is unknown. Characterized by the presence of multiple enlarged airspaces (0.5mm-2cm) => may form cyst-like structures referred to as bullae »Irregular emphysema Clinically asymptomatic, and the most common form of emphysema. The acinus is irregularly involved, this condition is almost always associated with scarring, such as in healed inflammatory diseases. # Pathogenesis – Protease/antiprotease imbalance – always inhale some small particles (in-between 2-5 microns less than 2 filter to lymph more than 5 cough out ) which stimulate inflammation Exposure to toxic substances such as tobacco smoke and inhaled pollutants induce inflammation with accumulation of neutrophils, macrophage & lymphocytes. Neutrophils, the main source of cellular proteases, are found in peripheral capillaries (including those of the lungs), and gain access to the alveolar spaces.  Release Elastase. Exasseiv inflammation or lack of protease inhibitors result in emphysema: 1. Exposure to toxic substances such as tobacco smoke and inhaled pollutants induce inflammation with accumulation of neutrophils, macrophage & lymphocytes. Smoking promotes accumulation of leukocytes, such as neutrophils and macrophages, in the alveoli, and enhances the elastase activity of macrophages, which is NOT inhibited by α1-antitrypsin 2. deficiency of α1-antitrypsin a major inhibitor of proteases (mainly elastase) encoded by codominant genes The proteinase inhibitor allele (Pi) on chromosome 14- the most common healthy allele is PiM , mutation as PiZ allele result in misfolding of it ; patients homozygous to PiZ allele will present panacinar emphysema and may also manifest with liver cirrhosis cause of accumulation of misfolded alpha 1 antitrypsin in the ER of hepatocytes ; heterozygous patients are asymptomatic with lower levels of alpha 1 antitrypsin in blood , but upon smoking is a great risk for developing emphysema 3. Oxidant-antioxidant imbalance – the lung contains antioxidants that keep oxidative damage to a minimum => smoking increases the amount of free radicals, which deplete these mechanisms; activated neutrophils also add oxygen species to the alveoli. In general * In emphysema there is loss of not only epithelial and endothelial cells but also mesenchymal cells, leading to lack of extracellular matrix, the scaffolding upon which epithelial cells would have grown. Thus, emphysema can be thought of as resulting from insufficient wound repair. By contrast, patients with fibrosing lung diseases have excessive myofibroblastic or fibroblastic response to injury, leading to unchecked scarring. # Morphology – Macro -> paile air filled areas Panacinar emphysema – produces pale lungs with enhanced volume, which often obscure the heart.Cantriacinar emphysema – lungs appear in deeper pink, with less volume than in panacinar emphysema. Micro -> Histologic examination reveals destruction of alveolar walls without fibrosis, leading to enlarged air spaces. # Clinical features – dyspnea with cough (no sputum!!), prolonged expiration with pursed lips (duck lipes) weight loss, reduced FEV1, FEV1/FVC is reduced. # Barrel Chest (with no bronchitis) # Pink Puffer = Because of prominent dyspnea and adequate oxygenation of hemoglobin, these patients sometimes are called “pink puffers.” ASTHMA # Intermittent and reversible airway obstruction result from bronchoconstriction triggered by hyperactive respond following exposure to an allergen to which the person has been previously sensitized. # Chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough. The hallmarks of the disease are: Chronic bronchial inflammation with eosinophils, Bronchial smooth muscle cell hypertrophy and hyperreactivity, Increased mucus secretion. # There are 2 major types of asthma: 1) Atopic (extrinsic) asthma Constitute ~70% of cases  Patient has Genetic predisposition to type I hypersensitivity (atopy) show family history of asthmatic or related hypersensitivity 1 reactions, clinically showed with Associated with other allergic diseases such as allergic rhinitis and eczema. There is evidence for extrinsic allergen sensitization you can do skin test show wheal and fler reaction immediate after exposure to this specific allergen. 2) Non-atopic (intrinsic) asthma- triggers are less clear there is negative skin test to common inhalant allergens and normal serum concentrations of IgE. Caused by viral infections of the respiratory tract /inhaled air pollutants. Characterized by increased bronchoconstriction response due to increased airways reactivity Suspect that Viral inflammation of the respiratory mucosa lowers the threshold of the sub epithelial vagal receptors to irritants. 3) Drug Induced Asthma- Several pharmacologic agents provoke asthma, aspirin being the most striking example.Mechanism unknown. Maybe due to inhibition of COX pathway without harming the lipoxygenase pathway  shifting the balance toward leukotrines production that causes bronchial spasm. 4) Occupational Asthma- Asthma attacks usually develop after repeated exposure to the inciting antigen(s) # Pathogenesis- Humoral and cellular mediators of airway obstruction are common to both major variants of asthma.Caused by IgE (type I hypersensitivity) and TH2-mediated70 immune responses to environmental antigens (dust, pollens, animal hair, and food). First exposure to allergen => TH2 cells activation => release of IL-4 & IL-5 => eosinophils recruitment AND production of IgE (by plasma cells) => sensitization of mast cells (type I hypersensitivity) reexposure to allergen => immediate reaction is triggered by sensitized mast cells => early reaction see histamine realis increase primability of post capillary venoules and vasodilation of arteriole also realis leukotrienes induce bronchoconstriction and vascular primability so initial see constriction and edema late phase reaction initiated by recruited leukocytes that induce release of mediators from these cells, and lead to epithelial damage e.g. eosinophils realis major basic protein damage epithel and maintain bronchoconstriction Major basic protein induces mast cell and basophil degranulation, and is implicated in peripheral nerve remodellin # Morphology – # Macro # Lungs are overdistended because of over inflation. # Small area of atelectasis # Bronchi and bronchioles are occluded by thick mucous plugs # Micro # Shed epithelium = Curschmann spirals # Numerous eosinophils and Charcot- Leyden crystals (collections of crystalloids made up of eosinophil proteins) # Air way Remodeling1) Thickening of airway wall 2) Sub-basement membrane fibrosis 3) Increased vascularity in submucosa 4) An increase in size of the submucosal glands and goblet Cell metaplasia of the airway epithelium 5) Hypertrophy and/or hyperplasia of the bronchial muscle # An attack of asthma is characterized by severe dyspnea with wheezing; the chief difficulty lies in expiration. The victim labors to get air into the lungs and then cannot get it out, so that there is progressive hyperinflation of the lungs with air trapped distal to the bronchi, which are constricted and filled with mucus and debris. - Therapy, usually bronchodilators & corticosteroids. CHRONIC BRONCHITIS # Chronic inflammation of the mucous membranes of the bronchi that is defined as a persistent productive cough for at least 3 consecutive months in at least 2 consecutive years. # Usually occurs in smokers and urban/city residents, 40-65 age group. # There are 3 forms of chronic bronchitis: » Simple chronic bronchitis – most common type, cough raises mucoid sputum, but NO airway obstruction  In the early stages of the disease. » Chronic asthmatic bronchitis – hyper responsive airways with bronchospasms => asthma episodes. » Chronic obstructive bronchitis – heavy smokers that develop outflow obstruction, usually with associated emphysema. # Pathogenesis – » Distinctive feature is hypersecretion of mucous. Irritation (smoking, air pollutants) => hypertrophy & hyperplasia of bronchial mucous glands, resulting in hyper secretion of mucous => increase in mucin-secreting goblet cells of smaller bronchi and bronchioles » Irritants also cause inflammation (cytotoxic T cells, macrophages and neutrophils) *no Eosinophiles » Whereas the defining feature of chronic bronchitis (mucus hypersecretion) is primarily a reflection of large bronchial involvement, the morphologic basis of airflow obstruction in chronic bronchitis is more peripheral and results from (1) small airway disease, induced by goblet cell metaplasia with mucous plugging of the bronchiolar lumen, inflammation, and bronchiolar wall fibrosis, and (2) coexistent emphysema. » Microbial infection often is present but has a 2ndry role, chiefly by maintaining the inflammation and exacerbating symptoms. # Morphology – » Macro = Mucosal lining is hyperemic and swollen by edema, covered by mucinous or mucopurulent secretion. » Micro = Enlargement of mucous secreting glands in the trachea and large bronchi. » Inflammatory infiltration of mononuclear cells # Bronchiolitis = Small air way disease  inflammation of bronchioles, characterized by goblet cell metaplasia, fibrosis, inflammation, and mucous plugging. # In the most severe cases, there may be complete obliteration of the lumen as a consequence of fibrosis (bronchiolitis obliterans). It is the submucosal fibrosis that leads to luminal narrowing and airway obstruction. Changes of emphysema often co-exist. # Clinical Feature – # Early stage = No obstruction, only productive cough, no ventilation problems. # Some can develop significant COPD with outflow obstruction Cyanosis  “Blue Bloaters”. BRONCHIECTASIS # Bronchiectasis is defined as abnormal permanent dilatation of the bronchi caused by loss of muscle and elastic tissue due to chronic necrotizing infections. It can be congenital (children with cystic fibrosis, Kartagener syndrome, immunodeficiency states) or acquired (post-infectious, systemic autoimmune diseases, bronchial obstruction by foreign bodies or tumors), most commonly located in the lower lobes, uni- or bilateral. Why obstructive? Dilated airway impairs laminar air follow instead tubular flow and trapping of air more force needed for expiration. # Conditions that predispose to bronchiectasis are: 1. Tumors/foreign bodies/ plugs of mucous. With these conditions, the bronchiectasis is localized to the obstructed lung segment. 2. CF (causing wide spread bronchiectasis) due to secretion of abnormally viscid mucous which predisposes to infections of the bronchia tree. 3. Immunodeficiency states => due to repeated bacterial infections. 4. Kartagener syndrome => an autosomal recessive disorder causing immotile cilia (dynein protein) and impaired mucociliary clearance infections. (The syndrome also affects the mobility of the spermatozoa causing sterility in men, situs inversus and sinusitis)./ Young syndrome: infertility caused by azoospermia, but without ultrastructural ciliary abnormalities 5. Necrotizing or suppurative pneumonia (esp. staph. Aureus & spp. Klebsiella). May predispose patient to later bronchiectasis development e.g. post tuberculosis bronchiectasis # Pathogenesis – there are 2 processes that develop in bronchiectasis: Chronic persistent infection => direct demage to wall or Obstruction => impairs the clearance of the airways => secondary infection The tissue is also damaged in part by the host response of neutrophilic proteases, inflammatory cytokines, nitric oxide This results in damage to the muscular and elastic components of the bronchial wall. Additionally, peribronchial alveolar tissue may be damaged, resulting in diffuse peribronchial fibrosis. The result is abnormal bronchial dilatation with bronchial wall destruction and transmural inflammation. The most important functional finding of altered airway anatomy is severely impaired clearance of secretions from the bronchial tree. Impaired clearance of secretions causes colonization and infection with pathogenic organisms, The result is further bronchial damage and a vicious cycle of bronchial damage. # Morphology – Bronchiectasis most commonly presents as a focal process involving a lobe, segment of the lung. Far less commonly, it may be a diffuse process involving both lungs; these cases most often occur in association with systemic illnesses, such as cystic fibrosis (CF) bronchiectasis. Macroscopically, the lung has an irregular surface in the affected area. On cut surface, there are multiple cavities / cystic formations (dilated bronchi), round or oval, of varying sizes, with a thick, fibrous, gray-whitish wall and muco-purulent content, associated with changes of the adjacent lung parenchyma (areas of condensation or fibrosis). With progression, the lung parenchyma can be fully replaced by dysfunctional bronchial dilatation. MICRO: » Chronic inflammation, ulceration of bronchial wall, ossification of bronchial cartilage. » Intense inflammatory exudate within the walls of the bronchi and bronchioles and shedding of the lining epithelium cause extensive areas of ulceration. » Usually the injury is so severe that the epithelium lining the bronchial tree cannot regenerate and after healing abnormal dilation and scarring persists as Fibrosis of the bronchial and bronchiolar walls and peribronchial fibrosis develop in more chronic cases. # Clinical features – Consists of severe, persistant cough with mucopurulent sputum, which may contain blood.Hypoxemia, hypercapnia. Chronic complications => pulmonary hypertension or cor pulmonale (though rare).

Answer 71

ASTHMA # Intermittent and reversible airway obstruction result from bronchoconstriction triggered by hyperactive respond following exposure to an allergen to which the person has been previously sensitized. # Chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough. The hallmarks of the disease are: Chronic bronchial inflammation with eosinophils, Bronchial smooth muscle cell hypertrophy and hyperreactivity, Increased mucus secretion. # There are 2 major types of asthma: 1) Atopic (extrinsic) asthma Constitute ~70% of cases  Patient has Genetic predisposition to type I hypersensitivity (atopy) show family history of asthmatic or related hypersensitivity 1 reactions, clinically showed with Associated with other allergic diseases such as allergic rhinitis and eczema. There is evidence for extrinsic allergen sensitization you can do skin test show wheal and fler reaction immediate after exposure to this specific allergen. 2) Non-atopic (intrinsic) asthma- triggers are less clear there is negative skin test to common inhalant allergens and normal serum concentrations of IgE. Caused by viral infections of the respiratory tract /inhaled air pollutants. Characterized by increased bronchoconstriction response due to increased airways reactivity Suspect that Viral inflammation of the respiratory mucosa lowers the threshold of the sub epithelial vagal receptors to irritants. 3) Drug Induced Asthma- Several pharmacologic agents provoke asthma, aspirin being the most striking example.Mechanism unknown. Maybe due to inhibition of COX pathway without harming the lipoxygenase pathway  shifting the balance toward leukotrines production that causes bronchial spasm. 4) Occupational Asthma- Asthma attacks usually develop after repeated exposure to the inciting antigen(s). # Pathogenesis- Humoral and cellular mediators of airway obstruction are common to both major variants of asthma.Caused by IgE (type I hypersensitivity) and TH2-mediated70 immune responses to environmental antigens (dust, pollens, animal hair, and food). First exposure to allergen => TH2 cells activation => release of IL-4 & IL-5 => eosinophils recruitment AND production of IgE (by plasma cells) => sensitization of mast cells (type I hypersensitivity) reexposure to allergen => immediate reaction is triggered by sensitized mast cells => early reaction see histamine realis increase primability of post capillary venoules and vasodilation of arteriole also realis leukotrienes induce bronchoconstriction and vascular primability so initial see constriction and edema late phase reaction initiated by recruited leukocytes that induce release of mediators from these cells, and lead to epithelial damage e.g. eosinophils realis major basic protein damage epithel and maintain bronchoconstriction Major basic protein induces mast cell and basophil degranulation, and is implicated in peripheral nerve remodellin # Morphology – # Macro # Lungs are overdistended because of over inflation. # Small area of atelectasis # Bronchi and bronchioles are occluded by thick mucous plugs # Micro # Shed epithelium = Curschmann spirals # Numerous eosinophils and Charcot- Leyden crystals (collections of crystalloids made up of eosinophil proteins) # Air way Remodeling1) Thickening of airway wall 2) Sub-basement membrane fibrosis 3) Increased vascularity in submucosa 4) An increase in size of the submucosal glands and goblet Cell metaplasia of the airway epithelium 5) Hypertrophy and/or hyperplasia of the bronchial muscle # An attack of asthma is characterized by severe dyspnea with wheezing; the chief difficulty lies in expiration. The victim labors to get air into the lungs and then cannot get it out, so that there is progressive hyperinflation of the lungs with air trapped distal to the bronchi, which are constricted and filled with mucus and debris. - Therapy, usually bronchodilators & corticosteroids.

Answer 72

ACUTE RESPIRATORY DISTRESS SYNDROME # A clinical syndrome caused by diffuse alveolar capillaries and epithelium damage, resulting in Rapid onset of severe, life threatening respiratory insufficiency, cyanosis, severe arterial hypoxemia Deficient oxygenation of the blood , usually with severe pulmonary edema . # Most commonly caused by pneumonia and aspiration of gastric content (causing physical trauma).also : sepsis or shock e.g. Burns, diffuse pulmonary infections (viral, mycoplasma, Pneumocystis, tuberculosis), mechanical trauma, inhaled irritants chemical injury # Pathogenesis – » due to diffuse widespread damage to alveolar barrier73 Damage of the capillary endothelium and alveolar epithelium lead to Increased capillary permeability which result in accumulation of protein-rich fluid inside the alveoli alveolar odema, loss of diffusion capacity, and widespread surfactant abnormalities (due to damage to pneumovytes type II). » thereby producing diffuse alveolar damage, with release of pro-inflammatory cytokines, such as realis of IL-8, IL-1 and TNF by pulmonary macrophages => recruitment of neutrophils (IL-8), and activation of endothelium (IL-1, TNF) => neutrophils release toxic mediators, such as reactive oxygen species and proteases . Extensive free radical production overwhelms endogenous anti-oxidants and causes oxidative cell damage. => Damage to alveolar epithelium # Morphology – » In the acute phase The lungs are dark red, firm, airless and heavy Capillary congestion, necrosis of alveolar epithelium, interstitial and intra-alveolar edema Neutrophils in capillaries (especially in sepsis) Hyaline membranes line the distended alveolar ducts » In the organized phase Increased proliferation of type II pneumocytes => an attempt to regenerate alveolar lining Organization of fibrin exudates that result in intra-alveolar fibrosis ("honey comb lung") Thickening of alveolar septa # Clinical features – develops within 72 hours from insult, high mortality rates especially if related to sepsis and development of multiorgan failure. ATELECTASIS # The term atelectasis is derived from the Greek words ateles and ektasis, which mean incomplete expansion. The loss of lung volume caused by inadequate expansion of airspaces or collapse of previously inflated lung. # Results in shunting of inadequately oxygenated blood from pulmonary arteries into the pulmonary veins, leading to ventilation-perfusion imbalance and hypoxia. # Atelectasis is classified into 3 groups: » Resorption atelectasis – occurs when obstruction prevents air from reaching the distal airways, most commonly by mucous or mucopurulent plug => the level of obstruction determines the extent of the collapse (an entire lung, a complete lobe or some segments); the air already present is gradually absorbed and alveolar collapse follows. » Compression atelectasis – associated with accumulations of fluids, blood or air (pneumothorax) within the pleural cavity, which mechanically collapse the adjacent lung. » Contraction atelectasis – occurs when either local or generalized fibrotic changes in the lung or pleura prevents the expansion and caus increase elastic recoil during expiration.

Answer 73

RESPIRATORY DISTRESS SYNDROME OF THE NEWBORN # A syndrome of premature infants caused by developmental insufficiency of surfactant production and structural immaturity of the lungs. # Occurs in ~60% of infants born at less than 28 weeks of gestation; the incidence decreases with advancing gestational age. # Associated with prematurely born infants, maternal diabetes mellitus & cesarean section. # Pathogenesis – # The fundamental defect is the inability of the immature lung to synthesize surfactant => in a healthy baby, surfactant is synthesized by type II pneumocytes, and with first breath rapidly coats the surface of alveoli to reduce surface tension. # In a lung deficient in surfactant, alveoli tend to collapse, so inspiration requires greater effort to open alveoli => the infant rapidly tires, and atelectasis develops. # Hypoxia develops, eventually leading to epithelial and endothelial damage, and resulting in the formation of hyaline membranes. # Surfactant production is regulated by hormones => corticosteroids stimulate the formation of surfactant lipids, while high levels of insulin suppress synthesis by counteracting the effects of steroids. # Morphology – » The lungs are of normal size, but are heavy and relatively airless. » Have a mottled purple color. » The alveoli are poorly developed and collapsed. » If the infant dies within a few hours => only necrotic cellular debris are present in bronchioles. » If the infant dies after a few days => Neonatal Respiratory Distress Syndrome - NRDS (Hyaline membrane disease) is characterized by collapsed alveoli alternating with hyperaerated alveoli, vascular congestion and hyaline membranes (resulted from fibrin, cellular debris). Hyaline membranes appear like an eosinophilic, amorphous material, lining or filling the alveolar spaces and blocking the gases exchange. Hyaline membrane is NEVER seen in stillborns or infants who die within a few hours of birth. # Clinical features – prognosis of neonatal RDS depends on the maturity and birth weight of the infant; control of RDS focuses on prevention, either by delaying labor until the fetal lung matures, or by inducing maturation of the lung. # In affected infants, oxygen is required. Use of high concentrations of ventilatoradministered oxygen for prolonged periods, however, is associated with two wellknown complications: retrolental fibroplasia (also called retinopathy of prematurity) in the eyes and bronchopulmonary dysplasia. SUDDEN INFANT DEATH SYNDROME # Definition – Sudden unexpected infant deaths in infants younger than 12 months of age that occur suddenly, unexpectedly, and without obvious cause after a thorough investigation that includes complete autopsy, examination of the death scene, and review of clinical history. # In SIDS, infants usually die in their sleep. # Pathogenesis – SIDS is a multifactorial condition of overlapping variables: » A vulnerable infant – intrinsic developmental abnormalities in cardiorespiratory control. Regions of the brain stem, particularly the arcuate nucleus located in the ventral medullary surface, play a critical role in the body’s arousal response to noxious stimuli such as hypercarbia, hypoxia, and thermal stress encountered during sleep. In addition, these areas regulate breathing, heart rate, and body temperature. » A critical period in the development of homeostatic control mechanisms– these factors may be attributed to the parents (young mother, smoking during pregnancy, short intergestational intervals), or to the infant (brain stem abnormalities, prematurity). » An exogenous stressor – factors from the environment (prone sleep position decres responsiveness to noxius stimultion, sleeping on soft surface, hyperthermia). # Morphology – » Multiple petechiae present on the thymus, visceral and parietal pleura, and epicardium. » Lungs are congested Vascular engorgement (filled with blood), with or without pulmonary edema. » Hypoplasia of the arcuate nucleus. Summary Sudden Infant death syndrome SIDS is a disorder of unknown cause, defined as the sudden death of an infant younger than 1 year of age that remains unexplained after a thorough case investigation including performance of an autopsy. Most sids deaths occur between the ages of 2 anc 4 months. The most likely basis for sids is a delayed development in arousal reflexes and cardiorespiratory control. Numerous risk factors have been proposed, of which the prone sleeping position is best recognized, hence the success of the back to sleep program in reducing incidence of sids

Answer 74

Topic not enough CHRONIC RESTRICTIVE LUNG DISEASES (chronic interstitial) # A group of disorders characterized by involvement of the interstitium of the alveolar walls. Although may raise from chest wall abnormalities restrict breathing obesity ankylosing spongiusum –not a lung disease but obstructive… (Pulmonary interstitium  pulmonary interstitium is composed of the basement membrane of the endothelial and epithelial cells, collagen fibers, elastic tissue, fibroblasts, a few mast cells, and occasional mononuclear cells) # The main feature of these diseases is reduced compliance => more pressure is required to expand the lungs since they are stiff  more effort during breathing (dyspnea). See reduced forced vital capacity (FVC-air blow out after full inhaltion~5L)and normal ratio of FEV/FVC- as FEV is amount of air out in 1st min of forced expiration ~4,eventhow FVC is down to ~4 the FEV stays at ~3.5 hence ratio maintaind how come? 1st cuz no harm to airway problem in restrictive diseas is filling the lung not expiration as obstructive so FVC down and FEV normal 2nd interstitial fibrosis increase recoil so expiration more easly # Damage to alveolar epithelium and interstitial vasculature produce abnormalities in the ventilationperfusion ratio, leading to hypoxia. # With progression of the disease, individuals develop respiratory failure, pulmonary hypertension. # Pathogenesis – » Alveolitis – accumulation of inflammatory infiltrate within the alveolar walls and spaces. » Persistent injurious agent leads to cellular interactions (lymphocytes, macrophages, neutrophils) that result in parenchymal injury, causing proliferation of fibroblasts and interstitial fibrosis. » Macrophages are the main promoters of interstitial fibrosis: Activated macrophages => secretion of IL-8, and soluble mediators (proteases, oxidants) => recruitment and activation of neutrophils (IL-8) => epithelial injury and degradation of c. tissue ! Macrophages also secrete FGF, TGF-β, and PDGF => attract fibroblasts and stimulate their proliferation. IDIOPATHIC PULMONARY FIBROSIS (fibrosing disease) #A pulmonary disorder of unknown cause characterized by diffuse fibrosis of the lung interstitium, chronic progressive disease may results in severe hypoxemia and death. #Males are affected more than females.and ~2/3 of patient above 60 # Pathogenesis- The current concept is that IPF is caused by “repeated cycles” of epithelial activation/injury by some unidentified agent, TGF-β1 is released from injured type I pneumocytes and induces transformation of fibroblasts into myofibroblasts leading to excessive and continuing deposition of collagen and ECM. # Morphology – » MACRO = Pleural surface has the appearance of cobblestone.Cut surface shows fibrosis. (white rubbery area). Change affecting predominantly sub pleural regions peripheral region and lower lung zones the pleural surface shows a cobblestone appearance due to the retraction of interlobular septa-associated par septal scarring MICRO = histomorphology of Usual interstitial pneumonia (UPI) ,refers to a morphologic entity defined by a combination of (1) Patchy interstitial fibrosis- with alternating areas of normal lung, very in intensity more pronounced subpleural region (2) scattered fibroblastic foci - foci comprises mainly dense eosinophilic collagen deposition In the background fibroblasts and myofibroblasts are arranged in a linear fashion within matrix, over time become more collagenous & less cellular. (3) Architectural alteration due to chronic scarring or honeycomb change- dense fibrosis causes the collapse of alveoli and formation of cystic spaces lines with hyperplastic type II pneumocytes, or respiratory epithelium => HONEYCOMB FIBROSIS (Honeycomb change is defined by cystically dilated airspaces frequently lined by columnar respiratory type epithelium in scarred fibrotic lung tissue) # Clinical features – gradual onset of non-productive cough and progressive dyspnea; cyanosis, corpulmonale and peripheral edema may develop in later stages.

Answer 75

SARCOIDOSIS (granulomatous disease) # A multisystem disease of unknown cause characterized by non-caseating granulomas in many tissues and organs. Hilar nodes and lung involvement (leading to restrictive disease) are the most common locations. # Eye (uveitis) & skin (cutaneous nodules/erythema nodosum) involvement also common also may see salivary gland involvement and SS like manifest... # Sarcoidosis usually affects young adults (<40), with high incidence in Denmark and Sweden. And It is one of the few pulmonary diseases with higher prevalence in NON-SMOKERS. # Pathogenesis – as got unknown etiology but Several immunologic abnormalities in sarcoidosis suggest the development of a cell-mediated response to an unidentified antigen. The process is driven by CD4+ helper T cells. These abnormalities include: » Intra-alveolar and interstitial accumulation of TH1 cells. » Increase in TH1 derived cytokines => IL-2 resulting in T cell expansion, and IFN-γ resulting in macrophages activation. » Increase in the level of cytokines IL-8, TNF, macrophage inflammatory protein 1α => responsible for recruitment of additional T cells and monocytes => contribute to the formation of granulomas. » Polyclonal hypergammaglobulinemia. » The role of genetic factors is suggested by familial and racial clustering of cases and association with certain human leukocyte antigen (HLA) genotypes. # Morphology – » NON-CASEATING granulomas => a compact collection of epithelioid cells and giant cells no necrosis in granuloma center surrounded by an outer zone of T helper cells. granulomas are found mainly in interstitium of lung Peripheral to the granuloma => a thin layer of fibroblasts, which over time proliferates and deposits collagen that replaces the entire granuloma with scar tissue. The granulomas eventually are replaced by diffuse interstitial fibrosis, resulting in a so-called honeycomb lung. » The granulomas may also contain: 1) Schauman bodies – laminated concretions composed of calcium and proteins. 2) Asteroid bodies – stellate inclusions enclosed within giant cells » Enlargement of hilar and paratracheal lymph nodes.  unlike in tuberculosis, lymph nodes in sarcoidosis are “nonmatted” (no adherent) and do not ulcerate. » Skin lesions => erythema nodosum75. » Combined uveoparotid (uvea of eye + parotid) involvement is designated Mikulicz syndrome. » Involvement of the eye and lacrimal glands may occur, as well as spleen involvement (appearance of granulomas in the spleen & splenomegaly), and bone involvement (microscopic granulomatous lesions). » Granulomas in the liver are seen with no hepatomegaly or liver dysfunction. PNEUMOCONIOSIS (fibrosing restrictive disease) # A interstitial fibrosis of lung due to reaction to inhalation of small fibrogenic particles as mineral dusts, organic or inorganic particles. # Pathogenesis – » The reaction depends on the size and reactivity of the particles.For example: smaller particles can reach distal airways and precipitate there. Coal dust must be deposited in large amounts in order to cause lung disease; silica and asbestos are more reactive, resulting in fibrotic reactions in lower amounts. » Fibrosis is mediated by alveolar macrophages the particles are phagocytosed by alveolar macrophages (Key element in the initiation of the injury & fibrosis) and trigger the release of mediators of inflammation and fibroblast proliferation (TGF beta). # The most common minerals that induce pneumoconiosis are coal dust, silica and asbestos => nearly always due to exposure in the work place-pneumonioses is an chronic restrictive diseas need prolonged exposure to develop. COAL WORKER’S PNEUMOCONIOSIS Coal partical upon smoking /coal mind worker…. 1. Almost everyone has more mild exposure to coal dust in air pollution expressed as anthracosis and kinocyte = Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages, which then accumulate in the connective tissue along the lymphatics, including the pleural lymphatics, or in lymph nodes. 2. Simple coal worker’s pneumoconiosis (CWP) accumulations of macrophages occur with little to no pulmonary dysfunction. CWP shows as many centers of anthracosis and fibrosis scattered along lung dominantly in upper regions, may Progress into centrilobular emphysema impair normal functioning of lung. Characterized by coal macules and the larger coal nodule. - Coal macules = Consist of dust laden macrophage. - Dust Nodule = Macules + small amount of Collagen fibers. 3. Complicated CWP or progressive massive fibrosis (PMF)= in which fibrosis is extensive and lung function is compromised, requires many years and more massive exposure to develop, Extensive parts of lung tissue Appear as black scars . Once smoking-related risk has been taken into account, there is no increased frequency of lung carcinoma in coal miners, a feature that distinguishes CWP from both silica and asbestos exposures. SILICOSIS Inhalation of silica, mostly in occupational settings as sandblasters and silica miners -> After inhalation the particles interact with epithelial cells and macrophages -> Ingested silica particles cause activation and release of mediators by pulmonary macrophages(more silica impairs the phagolysosome formation and put individual susceptible to TB) Morphology: 1. Silicotic nodules -> (early stage). Tiny, discrete palt-to-blackened nodules in the upper zone of the lung. 2. Micro -> concentrically arranged hyalinized collagen fibers surrounding an amorphous center. 3. As the disease progresses, the individual nodules may coalesce into hard, collagenous scars, with eventual progression to PMF. 4. Honeycomb pattern may develop ASBESTOSIS AND ASBESTOS-RELATED DISEASES # asbestos is fibrogenic => asbestosis causes fibrosis by interacting with lung macrophages. See chronic exposure in plumbers construction workers and shipyard workers # Exposure to asbestos is linked to: 1) Diffused interstitial pulmonary fibrosis as UIP with asbestos bodies a long golden brown fibers with associated iron originated in macrophages tried to eat it.. 2) Localized fibrous Pleural plaques: well circumscribed plaques of dense collagen, do not contain asbestos bodies but rare if no asbestos history; may induce pleural effusions, or diffuse fibrosis in the pleura (rare). 3) Pleural effusions.- as Visceral pleura becomes fibrotic, may bind lung to chest wall 4) Lung carcinoma and mesotheliomas- Asbestos also is oncogenic 5) Bronchogenic or Laryngeal carcinoma. # Pathogenesis – Similar to other pneumoconiosis Initial injury is at bifurcations of small airways and ducts; macrophages ingest fibers, release chemotactic factors and fibrogenic mediators, causing interstitial fibrosis .Begins around respiratory bronchioles and alveolar ducts extends distally - in lower lobes and subpleurally (in contrast to coal workers' and silicosis) progresses to middle and upper lobes, eventually may causes honeycomb # Morphology – » Diffuse pulmonary interstitial fibrosis. » Asbestos bodies => golden-brown, beaded rods with translucent center, consist of asbestos fibers coated with iron-containing proteinaceous material; arise when macrophages attempt to phagocytose asbestos. » Begins in the lower lobes and subpleurally, unlike CWP and silicosis. » Contraction of fibrous tissue creates enlarged spaces enclosed within thick fibrous walls => HONEYCOMB LUNG. » Pleural plaques of collagen appear on the parietal pleura, and are the most common manifestation => they DO NOT contain asbestos bodies. # Clinical features – cannot be distinguished from other diffuse interstitial lung diseases BERYLLIOSIS » Berylliosis, or chronic beryllium disease (CBD), is a hypersensitivity granulomatous diseas caused by exposure to beryllium and its compounds. Such risk for air/space industry workers or beryllium miners or manufacturing of fluorescent light bulbs (which used to contain beryllium compounds in their internal phosphor coating). # Pathogenesis – » With single or prolonged exposure by inhalation, the lungs become hypersensitive to beryllium causing the development of Non-caseating granulomas. The key to the pathogenesis of chronic beryllium disease (CBD) is a delayed-type hypersensitivity reaction in which beryllium most likely functions as a hapten antigen, stimulating local proliferation and accumulation in the lung of beryllium-specific T cells. » Beryllosis is characterized by non caseating granulomas mainly in lung and hilar nodes but also in other organs It is distinguished from sarcoidosis by history of exposure and syntisition to brilium . » Link to incrased risk for lung cancer » Ultimately, this process leads to restrictive lung disease. # Clinical features » Patients experience cough and shortness of breath. Other symptoms include chest pain, joint aches, weight loss and fever. » Rarely, one can get granulomas in other organs including the liver. » The onset of symptoms can range from weeks up to tens of years from the initial exposure. In some individuals a single exposure can cause berylliosis.

Answer 76

PULMONARY THROMBOEMBOLISM # In the vast majority of cases the emboli is an thromboembolism that originate from the deep veins of lower limb (above the knee level) rear option is for paradoxical embolism from systemic circulation. # Risk factors for venous thrombosis are: » Prolonged bed rest. » Orthopedic surgery of the knee and hip./injury to endothelium » Primary disorders of hypercoagulability. # Most events are clinically silent~80% -The lung has a dual blood supply (pulmonary arteries AND the bronchial arteries), so if normal bronchial circulation and adequate perfusion are maintained, the decrease in blood flow will not result in necrosis. Second, mostly it’s an small emboli who is self-resolving (organization/fibrinolysis) and don’t have major impact on blood supply # a minority (5%) of cases causes acute cor pulmonale, shock or death, and the remaining cause pulmonary infarction. For clinical symptom patents is one who already suffer from cardiopulmonary diseas and occlusion of large to medium size vessel is involved: » Large Emboli = in main pulmonary artery, it’s major branches or in it’s bifurcation (= Saddle embolus) = Occlusion of a major vessel leads to increase in pulmonary artery pressure, diminished cardiac output, right-sided heart failure (cor pulmonale), and even sudden death upon acute increase in pulmo. Pressure sudden collapse of circulation. » Small Emboli + compromised cardiovascular status (no dual supply), as may occur with congestive left side heart failure, infarction results. # Hypoxemia occurs due to several mechanisms: » Perfusion of lung areas that have become atelectasis: - Ischemia = surfactant production decreases = alveolar collapse. Blood flow redirected to areas with more oxygen perfusion. More Decreased cardiac output results in widening of the difference in the arterialvenous oxygen saturation. » What is embolization? Intravascular solid, liquid or gaseous material that is carried by the blood stream away from sait of origin Causes obstruction of an b.v. clinically present with effected organ. HEMORRHAGIC PULMONARY INFARCTION » Hemorrhagic infarct of the lung- is an area of ischemic necrosis produced by b.v. obstruction on a background of passive congestion of lung from dual blood supply. » Infarction, when b.v. occlusion leading to ischemia to tissue ending in necrosis = in lung area wedge shape, with their base toward the pleura & Blocked vessel usually found in the apex. 1. The hallmark of fresh infarcts is coagulative necrosis of the lung parenchyma and hemorrhage 2. Lysis of RBC = infarct pales = Hemosiderin produced becoming red-brown. 3. Scarring -> fibrous replacement = grey-white. Histologically In infarct area, alveolar walls, vascular walls and bronchioles are necrotic. They appear eosinophilic (pink), homogenous, lacking the nuclei, but keep their shapes “- coagulative necrosis. Alveolar lumens from infarcted area are filled by red blood cells -hemorrhagic infarct (red)." # Diffuse alveolar hemorrhage syndromes are immune-mediated diseases that present as a triad of hemoptysis, anemia and diffuse pulmonary infiltration. GOODPASTURE SYNDROME # Characterized by a proliferative, and rapidly progressive, glomerulonephritis and hemorrhagic interstitial pneumonitis => both are caused by antibodies against part of collagen IV. # Morphology – » Diffuse alveolar hemorrhage. Micro: focal necrosis of alveolar walls associated with intra-alveolar hemorrhage, fibrous thickening of septa, and hypertrophy of septal lining cells. » IgG antibodies => present linear pattern of deposition in immunofluorescence. IDIOPATHIC PULMONARY HEMOSIDEROSIS # A disease of uncertain cause that has pulmonary manifestations and histological appearance similar to Goodpasture syndrome, but NO renal involvement or circulating anti-GBM antibodies. # The clinical course of the disease is mild, with periods of activity followed by prolonged, spontaneous remissions. # Most cases occur in children. PULMONARY ANGIITIS AND GRANULOMATOSIS (Wegner granulomatosis) # Necrotizing vasculitis characterized by acute necrotizing granulomas of the respiratory tract, necrotizing/granulomatous vasculitis (affecting small to medium blood vessels), and focal necrotizing glomerulonephritis. # The upper respiratory tract lesions range from inflammatory sinusitis with mucosal granulomas, to ulcerative lesions of the nose, palate and pharynx. # Late stage of the disease is characterized by necrotizing granulomatous involvement of the parenchyma and alveolar hemorrhage.

Answer 77

(Check topic in diff note again) # Pneumonia can be very broadly defined as any infection in the lung. Development of such as infection is due to impairment of normal defense mechanisms or lowered host resistance # Normal defense mechanisms are nasal clearance (sneezing, blowing, swallowing), tracheobronchial clearance (mucociliary action) and alveolar clearance (alveolar macrophages) Impairment is due to primary or acquired immunosuppression, suppression of cough reflex (drugs, virus, coma, anesthesia), injury to mucociliary apparatus (smoking, virus, Kartegeners syndrome), injury to macrophages (tobacco, alcohol, anoxia), pulmonary congestion / edema or accumulation of secretions (cystic fibrosis) Note: viral pneumonia predisposes to bacterial pneumonia # Acute bacterial typical pneumonias can present 2 patterns seen on chest x-ray: 1) Bronchopneumonia – (affects bronchioles and adjacent alveoli) patchy distribution of inflammation around bronchioles often raise multifocal and bilateral- more than one lobe => results from initial infection of bronchioles that extended into the alveoli. 2) Lobar pneumonia – the inflammation involve full segment are homogenously filled with exudates that can be visualized as segmental or lobar consolidation Consolidation: exudative solidification of lung=> main causative agent is Streptococcus pneumoniae Classic involve entire lobe with 4 gross phases of lobar pneumonia nowadays less seen thanks to AB treatment options Lobar pneumonia: Initially congestion edema heavy red lung with bacteria and few neutrophils; Then red hepatization (grossly resembles liver harder consistency) with massive congestion, neutrophils, fibrin in alveolar space; Then gray hepatization with fibrinopurulent exudate in alveoli RBC got lysed; Then resolution with resorption of exudate exudate enzyme digested debris cleaned by MQ /cough out/reorganize by fibroblasts 3) Atypical interstitial pattern BRONCHOPNEUMONIA # It is an acute inflammation of the walls of the bronchioles, associated with specific bacteria => Staphylococcus aureus, Klebsiella, E. coli and Pseudomonas. # Morphology – » Bronchopneumonia affects one or more lobes, being frequently bilateral and basal. Macroscopically, one can identify multiple foci of condensation (1 - 3 cm diameter), white-yellowish, imprecisely circumscribed, centered by bronchiole, separated by normal lung parenchyma Pleural involvement is less common than in lobar pneumonia. . in severe cases usually seen In children, it has a tendency to confluence, resulting in large condensation area (pseudo lobar pneumonia) » Microscopy: foci of inflammatory condensation centered by a bronchiole with acute bronchiolitis (suppurative exudate rich in neutrophils in the lumen, foci of ulceration of the epithelium and parietal inflammation). The alveolar lumens surrounding the bronchia are filled with neutrophils ("leukocytic alveolitis"). Capillaries in the alveolar walls show congestion. Inflammatory foci are separated by normal, aerated parenchyma. # Complications – » Tissue destruction and necrosis => abscess formation. » Accumulation of suppurative material in the pleural cavity => empyema. » Organization of the intra-alveolar exudates that may convert areas of the lung into solid fibrous tissue. » Bacterial distribution (dissemination) can lead to meningitis, arthritis or infective endocarditis Causes of lobar

Answer 78

Check diff note again COMMUNITY-ACQUIRED ATYPICAL PNEUMONIAS # "Primary atypical pneumonia" is called primary because it develops independently of other diseases ."Atypical pneumonia" is atypical in that it is presentation with only moderate amounts of sputum, absence of physical findings of consolidation, moderate elevation in WBC count, and lack of alveolar exudates. # Causative agents include Mycoplasma pneumoniae (most common cause) # Pathogenesis – Pneumonia is due to impairment of normal defense mechanisms or lowered host resistance Normal defense mechanisms are nasal clearance (sneezing, blowing, swallowing), tracheobronchial clearance (mucociliary action) and alveolar clearance (alveolar macrophages) Impairment is due to primary or acquired immunosuppression, suppression of cough reflex (drugs, virus, coma, anesthesia), injury to mucociliary apparatus (smoking, virus, Kartegeners syndrome), injury to macrophages (tobacco, alcohol, anoxia), pulmonary congestion / edema or accumulation of secretions (cystic fibrosis) Note: viral pneumonia predisposes to bacterial pneumonia # Morphology – » Macroscopically – the affected areas are red-blue and congested. » Histologically – inflammatory reaction is confined within the walls of the alveoli =interstitial (inflammation affects the interstitial tissue, mainly the alveolar walls), with widened and edematous septa; contain mononuclear infiltration of lymphocytes and histiocytes. # Clinical features – Non-productive cough. Respiratory distress without correlation with chest x-ray finding (interstitial inflammation just look a little clearer lung demarcations) mild to no fever

Answer 79

BRONCHIAL CARCINOMA # Lung cancer is 1st in cancer mortality in the us and 2nd in incidence in us 95% of lung cancer are carcinomas and remaining 5% include: sarcomas, lymphomas and benign tumors as hamartoma’s. # There are 4 major histologic types of lung carcinomas: squamous cell carcinoma, adenocarcinoma, large cell carcinoma and small cell carcinoma # Therapeutically, lung carcinomas are divided into small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) => SCLC metastasizes by the time of diagnosis surgery will not be helpful but it is better treated by chemotherapy, while NSCLC are better treated by surgery  Now therapies are available that target specific mutated gene products present in the various subtypes of NSCLC, mainly in adenocarcinomas. Thus, NSCLC must be sub- classified into histologic and molecular subtypes. # Pathogenesis – » Carcinomas of the lungs arise due to the transformation of normal bronchial epithelium or pneumocytes the alveolar epithelium into neoplastic cells. Exposure to carcinogens Dominantly Cigarette smoking’s 85% of cancers are related (polycyclic aromatic hydrocarbons and arsenic – squamous cell type especially associate) other environmental insults e.g. asbestos exposure (lung cancer and to lesser extent mesothelioma) or radon (raise from uranium decay in soil as gas) are the mainly responsible for the genetic changes that give rise to lung cancers. » In smoking exposure mutation accumulation has an predictable order Inactivation of known tumor suppressor genes ( short arm chromosome 3) occurs at an early stage and even found at”healthy” smokers respiratory epithel , while p53 mutations occur at a later stage. » There is a linear correlation between the intensity and duration of exposure to cigarette smoke and the appearance of epithelial changes that begin with cell hyperplasia and squamous metaplasia and progress to squamous dysplasia and carcinoma in situ, before culminating in invasive cancer. » Among the major histologic subtypes of lung cancer, squamous and small-cell carcinomas show the strongest association with tobacco exposure. (remember S for Smoking) # Morphology – » Carcinomas begin as firm, gray-white, small mucosal lesions. » They may form intra luminal masses, invade the bronchial mucosa, or form large masses that are pushed into adjacent lung parenchyma => some large masses might undergo cavitation due to central necrosis, or develop focal areas of hemorrhage. » Eventually, these tumors may invade the pleural cavity and chest wall. # Clinical features – » Carcinomas of the lung are silent lesions that extensively spread before any symptoms appear. » Can produce cough, sputum, weight loss, dyspnea, bronchiectasis or pneumonia. » NSCLCs have better prognosis than SCLC => if detected before metastasis occurs, cure is possible by lobectomy or pneumonectomy. » SCLCs are very sensitive to chemotherapy. » Paraneoplastic syndromes include: 1) Hypercalcemia due to secretion of PTH related peptide. 2) Cushing syndrome from increased production of ACTH. 3) Syndrome of inappropriate secretion of ADH (SIADH). 4) Neuromuscular syndromes. 5) Clubbing of the finge 6) Thrombophlebitis, non-bacterial endocarditis, and DIC. Squamous cell carcinoma Hypercalcemia most often is encountered Adenocarcinoma = hematologic syndromes Small cell carcinoma = The remaining syndromes SMALL CELL CARCINOMA # By the time of diagnosis, the carcinoma has already metastasized => it is not curable by surgery, and is treated by chemotherapy (with or without radiation). # Highly associated with male smokers. # Consists of poorly differentiated, relatively SMALL cells # It is thought to originate from neuroendocrine cells (APUD cells) in the bronchus called Feyrter cells. Hence, they express a variety of neuroendocrine markers, and may lead to ectopic production of hormones like ADH and ACTH that may result in paraneoplastic syndromes and Cushing's syndrome. # The tumor appears as centrally located pale-gray masses, with extension into the lung parenchyma and involvement of hilar lymph nodes at an early stage. Necrosis is present and may be extensive. # Tumor suppressor genes associated with this carcinoma are chromosome 3 deletions, RB gene mutations and p53 mutations. All the following Considered as non-small cell lung carcinoma (NSCLC); responds poorly to chemotherapy, thus it is treated by surgery. SQUAMOUS CELL CARCINOMA # Most common tumor in MALE SMOKERS (in general, it is more common in men than women). # Tend to arise centrally in major bronchi, and eventually spread to local hilar lymph nodes. # Larger lesions may undergo necrosis, giving rise to cavitation. # Squamous cell carcinoma is usually preceded by squamous metaplasia or dysplasia in the bronchial epithelium => carcinoma in situ => well defined tumor mass obstructs the lumen of the bronchus => production of distal atelectasis and infection. # The cells of this tumor range from well differentiated squamous cell neoplasms showing KERATIN PEARLS and/or INTERCELLULAR BRIDGES, to poorly differentiated neoplasms. # Produces PTH-related peptide so hypercalcemia may develop only in subset of patiants.ADENOCARCINOMA # Most common tumor in NON SMOKERS and FEMALE. Tumer cells form glands that produce mucin, usually forming smaller mass then other lung cancers growing slowly but metastise earlier then other tumors # Usually are located more peripherally (risk for involvement of the pleura). # Squamous metaplasia and dysplasia may be present in the epithelium proximal to adenocarcinomas, but these are not the precursor lesions for this tumor.The precursor of peripheral adenocarcinomas is thought to be atypical adenomatous hyperplasia (AAH) Can progress to: 1.Adenocarcinoma in situ = Bronchioalveolar carcinoma name in past ,the initial progression from hyperplasia less then 3 cm dimt.,grow alomg preexisting structures monolyer cuboidal tumor cells not invading stroma and maintain alveolar architecture-named also lepidic growth. 2.Minimal invasive adenocarcinoma although less then 3cm got invasive component 3.Invasive adenocarcinoma = more the 5 mm depth. # Histologically see usually mixed patterns and classify by predominant one e.g. predominant papillary… acinar pattern –gland formation/papillary pattern-fibromuscular cores lined by glandular tumor cells replacing normal alveolar lining(micropapillary no fibromuscular core but similar papillary pattern )/mucinous-grow along alveolar septa not invasive in situ /solid type-see mucin inside tumor cells may need special stain for recognizing, forming solid masses of cells. # Mainly associated with chromosome 3 short arm deletion, but also with p16 mutations The immuno histochemical profile can help differentiate between other various types of NSCLC. About 70% of the Adenocarcinomas are positive for the thyroid transcription factor-1 (TTF-1). BRONCHIOLOALVEOLAR CARCINOMA # Adenocarcinoma in situ (AIS), formerly called bronchioloalveolar carcinoma, often involves peripheral parts of the lung, as a single nodule. # The key features of AIS are diameter of 3 cm or less, growth along preexisting structures-not invade, and preservation of alveolar architecture. # The tumor cells, which may be nonmucinous, mucinous, or mixed, grow in a monolayer along the alveolar septa. # By definition, AIS does not demonstrate destruction of alveolar architecture or stromal invasion with desmoplasia-no growth of fibros tissue LARGE CELL CARCINOMA # Considered as non small cell lung carcinoma (NSCLC); responds poorly to chemotherapy, thus it is treated by surgery. # Commonly associated with SMOKING. # Composed of undifferentiated epithelial tumors that lack the cytologic features of small cell carcinoma, show no glandular differentiation or mucin, and no keratin pearls or intercellular bridges. # Can be central or peripheral. CARCINOIDS TUMORS- BRONCHIAL CARCINOIDS # Considered as part of carcinomas The neoplastic cells contain neurosecretory granules in their cytoplasm, and may secrete hormonally active peptides although not usually manifest with paraneoplastic syndrome. Tumor cells origin from the diffused neuroendocrine system of the lung (korchinski cell) solid tumor with rich capillary network with Fine delicate fibrovascularsepta inbt nests of cells Such as tumors morphology also seen in pancreas and adrenal glands … # They are classified into Typical and Atypical carcinoids: In both types distant metastasis is rare. Often resectable and curable Typical carcinoids (low grade) = These tumors are composed of nests of uniform cells that have regular round nuclei with "salt and pepper" chromatin & central nucleoli. Less than 5mitotic figures for HPF, no necrosis. Atypical Carcinoids (Intermediate grade)= > 5 mitotic figures for HPF (40x objective) with/without necrosis display a higher mitotic rate (but less than small or large cell carcinomas) and focal necrosis. # Most originate in the main bronchi & Can grow in one of two patterns: 1) Expanding growth-Obstructing polypoid, spherical, intraluminal mass. 2) Invasing-Mucosal plaque that penetrates the bronchial wall to spread in the peribronchial tissue. # Clinical symptoms: Cough, recurrent infections related to the intramural growth. Rare- carcinoid syndrome characterized by attacks of diarrhea flushing and vomiting

Answer 80

BENIGN PLEURAL LESIONS # Pathologic involvement of the pleura is almost always secondary complication of some underlying pulmonary disease. # Important primary disorders: » primary intrapleural bacterial infections » Primary neoplasm of the pleura known as malignant mesothelioma. PLEURAL EFFUSION AND PLEURITIS # Pleural effusion – the presence of fluid in the pleural space that can be either transudate (=hydrothorax) or exudate (Proteins & inflammatory cells) which suggest pleuritis. # CHF is the most common cause of hydrothorax. # There are 4 causes of pleural exudate formation: » Microbial invasion through either direct extension of a pulmonary infection, or blood borne seeding (empyema). » Cancer (lung carcinoma, metastasis, mesothelioma). » Pulmonary infarction. » Viral pleuritis. # These effusions are large frequently bloody => hemorrhagic pleuritis. # Transudates and serous exudates usually are resorbed without effects if the inciting cause is controlled. # Fibrinous, hemorrhagic, and suppurative exudates may lead to fibrous organization, yielding adhesions or fibrous pleural thickening, and sometimes minimal to massive calcifications. PNEUMOTHORAX # Refers to air or other gas in the pleural sac. # Primary/simple/spontaneous = Without any pulmonary disease. # Secondary = As a result of thoracic or lung disorder. Secondary pneumothorax is the consequence of rupture of any pulmonary lesion situated close to the pleural surface that allows inspired air to gain access to the pleural cavity. (Emphysema, lung abscess, tuberculosis, carcinoma) # Complications – 1. Pneumothorax may create a tension pneumothorax that shifts the mediastinum => compromise of pulmonary circulation => may be fatal. 2. If the leak seals but the lung is not re-expanded within a few weeks because of large amount of scarring so the lung cannot fully expand => serous fluid is collected in the pleural cavity => hydro pneumothorax 3. With prolonged collapse = the lung & the pleural cavity becomes vulnerable to infections = formation Empyema (pyopneumothorax). HEMOTHORAX # The collection of whole blood in the pleural cavity. # It is a complication of ruptured intra thoracic aortic aneurysm => almost always fatal!! # The blood clots within the pleural cavity. # Must be differentiated from bloody pleural effusion where the are no blood clots. # Wiki- a type of pleural effusion in which blood accumulates in the pleural cavity. Its cause is usually traumatic, from a blunt or penetrating injury to the thorax, resulting in a rupture of the serous membranes. This rupture allows blood to spill into the pleural space. CHYLOTHORAX # Pleural collection of lymphatic fluid that contains microglobules of lipids. # The total volume of fluid is not large. # The presence of chylothorax implies an obstruction of the major lymph ducts, usually by intra thoracic cancer. MALIGNANT MESOTHELIOMA # Rare cancer of mesothelial cells, usually arising in the pleura (either visceral or parietal). ! Less commonly occurs in the peritoneum and pericardium. # ~50% of cases related to exposure to asbestos in the air. # Morphology – » Preceded by extensive pleural fibrosis The tumors begin in a localized area and spread widely over time. The affected lung is enveloped by a yellow-white, firm, gelatinous layer of tumor . » There are 3 patterns of mesothelioma: 1) Epithelial – cuboidal cells line tubular and microcystic spaces with small papillary buds projecting into them = most common. 2) Sarcomatous – spindle shaped cells grow in non-distinctive sheets. 3) Biphasic – both patterns appear. # Clinical Presents with recurrent pleural effusions, dyspnea, and chest pain.

Answer 81

ACUTE INFECTIONS # the "common cold", characterized by nasal congestion accompanied by watery discharge, sneezing, sore throat and slight increase in temperature.common pathogens that elicit the common cold are rhinoviruses.Most infections are self-limited. # Pharyngitis – Acute pharyngitis is manifested as a sore throat.Mild pharyngitis frequently accompanies a cold, and is the most common form of pharyngitis. # Tonsillitis – Occurs with S.Pyogens and adenovirus infections in Streptococcal tonsillitis may develop peritonsillar abscesses. # Acute bacterial epiglottitis – Occurs in young children due to infection of the epiglottis by Heamophilus influenza.Pain and airway obstruction are common findings. # Acute laryngitis – Results from inhalation of irritants or by allergic reactions.It may also be caused by the agents that produce the common cold and usually involve the pharynx and nasal passages as well as the larynx. The less common forms of laryngitis are tuberculous laryngitis, due to active tuberculosis, and diphtheritic laryngitis. Corynebacterium diphtheriae implants on the mucosa of the upper airways, where it elaborates a powerful exotoxin that causes necrosis of the mucosal epithelium, accompanied by a dense fibrinopurulent exudate, to create the pseudomembrane of diphtheria. The major hazards of this infection are obstruction of major airways and absorption of bacterial exotoxins (producing myocarditis, peripheral neuropathy, or other tissue injury) NASOPHARYNGEAL CARCINOMA # Rare neoplasm if accrue closely related to EBV as it infects the host by first replicating in the nasopharyngeal epithelium and then infecting nearby tonsillar B lymphocytes # There are 3 histological variants: 1) Keratinizing squamous cell carcinoma. 2) Non keratinizing squamous cell carcinoma. 3) Undifferentiated carcinoma = most linked to EBV. most common, and is characterized by large epithelial cells with indistinct borders ("syncytial" growth) and eosinophilic nucleoli. # A massive influx of mature lymphocytes can be seen => the tumor is referred to as lymphoepithelioma. # Nasopharyngeal carcinomas invade locally, spread to cervical lymph nodes, and then metastasize to distant areas LARYNGEAL TUMORS # Non-neoplastic, benign and malignant neoplasms of squamous epithelial cells and mesenchymal origin. # Non malignant lesions: 1.Vocal cord nodules ("polyps") » Are smooth and hemispheric protrusions located on the true vocal cords. » The nodules are composed of fibrous tissue and covered by stratified squamous mucosa. » These lesions occur mainly in heavy smokers or singers. = chronic irritation or abuse. 2.Laryngeal papilloma or squamous papilloma of the larynx » A benign neoplasm, usually on the true vocal cords. » Forms a soft, raspberry-like lump. » Consists of multiple finger-like projections supported by central fibrovascular cores and covered by stratified squamous epithelium. » Caused by HPV6 and HPV11. » Do not become malignant, and often spontaneously regress at puberty. » Single lesion in adults, multiple lesions in children. # CARCINOMA OF THE LARYNX » Most commonly occurs after the age of 40, and is more common in men, » Occurrence is greatly influenced by environmental factors, such as smoking, alcohol and asbestos exposure. » Most laryngeal carcinomas (95%) are typical squamous cell carcinomas. » The tumor develops directly on the vocal cords in most cases, but may arise above the cords (supraglottic) or below it (subglottic). » The tumors begin as in situ lesions that later appear as gray, wrinkled plaques on the mucosal surface = cause ulceration & fungation. » The glottis tumors are usually keratinizing, well differentiated squamous cell carcinomas. » Clinically manifest itself as hoarseness » Glottis tumors are less likely to metastasize due to low lymphatic supply, while supraglottic tumors metastasize to cervical lymph nodes.

Answer 82

INFLAMMATORY LESIONS OF THE ORAL CAVITY # Aphthous ulcer-painful ulcer in oral mucosa has grayish (granulation tissue base ) and its rimes surrounded by erythema .self-resolving in few days but tend to reoccur exact etiology is unknown but may appear in link with inflammatory bowl disease or Bechet syndrome. (Recurrent aphthous ulcers, genital ulcers, and uveitis due to immune complex vasculitis involving small vessels) # Herpes simplex-Grouped vesicles on an erythematous base, later rapture and heal no scar seen along lips nostrils and oral mucosa. Caused by HSV1 most commonly also HSV2 may cause it, upon infection it sets in trigeminal ganglion following stress illness/mental/cold water it may reactivate sending viruses down axon reaching epithel cell and develop characteristic lesion as it cause lysis of these cells on the effected part of face innervate by this ganglia primary infection non symptomatic usually if do it in children with ulcers and fever enlarged lymph node or pharyngitis in older age. 2ndry infection characteristic appearance self-resolve few days # Oral candidiasis/thrust- caused by c.albicans in patient with damaged flora population e.g. after AB treatment or upon immune suppression characterly arise as early manifestation of AIDS. See pseudomembrane appearance of gray to white layer composed of fibrinosupporative exudate and fungi easily scraped off. PROLIFERATIVE & NEOPLASTIC LESIONFIBROUS PROLIFERATIVE LESIONS #Fibroma- Formed when chronic irritation results in reactive connective tissue hyperplasia as Submucosal nodular fibrous tissue masses9smooth pink nodule macro0 Occur most often on the buccal mucosa. #Pyogenic granulomas- erythematous hemorrhagic exophytic mass usually found on the gingiva of children, young adults. Richly vascular and typically are ulcerated, which gives them a red to purple color. PRECANCEROUS LESIONS Lesions that suggest dysplastic process and in risk to undergo malignant transformation, erythoplakia greater risk then leukoplakia… #Leukoplakia WHO = “a white plaque that cannot be scraped off and cannot be characterized clinically or pathologically as any other disease.” caused by hyperkeratosis of mucosal epithelium with (squamous) thickening= Hyperkeratosis overlying a thickened, acanthosis nonwipeable. it may represent dysplastic epithelial changes then it considered as precancerous lesion Strongly associated with use of tobacco. Up to 25% of cases transform to squamous cell carcinoma. Therefore, persistent or recurring white plaque must be biopsied for histopathology analysis,whether dysplastic or malignant! Erythroplakia – red, granular, circumscribed areas with marked epithelial dysplasia. The most severe dysplastic changes are associated with erythroplakia, and more than 50% of these cases undergo malignant transformation. SQUAMOUS CELL CARCINOMA () # 95% of oral cavity cancers are squamous cell carcinomas the reminder is mainly adenocarcinoma of salivary glands also lymphomas may arise… # Risk factors for oral cancers include: leukoplakia and erythroplakia, tobacco use, alcohol abuse chronic irritations chronic inflammation(HPV16 and HPV18, ) immune suppression # Morphology – » The predominant sites for oral cancer are ventral surface of the tongue, floor of the mouth, lower lip… » Early lesions are white to gray circumscribed thickening of the mucosa. » Squamous cell carcinoma develops from dysplastic precursor lesions. Histologic patterns range from well-differentiated keratinizing neoplasms to anaplastic, sometimes sarcomatoid tumors (= both carcinoma & sarcoma properties1= rare) # Clinical features – 50% mortality rate within 5 years! Cause local pain or difficulty in chewing, but many are asymptomatic (thus the lesion is ignored). Local infiltration follow by metastasis to cervical nodes and from there to mediastinal nodes lung and liver. SALIVARY GLAND DISEASES *Major SG = parotid, sub-mandivular, Sub-lingual Minor SG = Distributed throughout the mucosa. XEROSTOMIA #Defined as a dry mouth resulting from a decrease in the production of saliva. It is a major feature of the autoimmune disorder Sjögren syndrome, in which it usually is accompanied by dry eyes. #Complications of xerostomia include increased rates of dental caries and candidiasis, as well as difficulty in swallowing and speaking. SIALADENITIS #Inflammation of the major salivary glands due to trauma or infections (viral => mumps (predominant – parotid), bacterial => S. aureus, autoimmune => Sjogren syndrome). #Mumps = produces interstitial inflammation marked by a mononuclear inflammatory infiltrate. In adults it can cause pancreatitis or orchitis (inflammation of the testis). # Most common lesion is called mucocele resulting from blockage or rupture of the salivary gland duct => saliva leaks into the surrounding tissue. # Mucocele = cystlike space lined by inflammatory granulation tissue or fibrous connective tissue that is filled with mucin and inflammatory cells. # Bacterial sialadenitis occurs secondarily to ductal obstruction due to stone formation (sialolithiasis), or may arise after retrograde entry of oral cavity bacteria (S. aureus, S. viridians). # Autoimmune diseases =Sjogren syndrome. SALIVARY GLAND NEOPLASM- # Relatively uncommon and represent less than 2% of all human tumors. ~80% of tumors occur within the parotid glands usually at 60-70 years of age. # The likelihood that a salivary gland tumor is malignant is inversely proportional, roughly, to the size of the gland. (Parotid => submandibular => sublingual) # Most common tumor of the parotid gland is pleomorphic adenoma and the most malignant tumor of salivary glands is mucoepidermoid carcinoma (mainly in the parotid gland). # Pleomorphic adenoma - Arises at the superficial parotid, causes painless mobile swelling at the angle of the jaw. Consist of a mixture of ductal (epithelial) and myoepithelial cells, so they exhibit both epithelial and mesenchymal differentiation  Mixed tumor. Morphology – Rounded, well-demarcated masses rarely exceeding 6 cm in the greatest dimension. The capsule is not fully developed, and expansile growth produces protrusions into the surrounding tissues as Main cause for recurrence. The most striking histologic feature is their characteristic heterogeneity epithelial cells or myoepithelial cells dispersed within a mesenchyme- like background of loose myxoid tissue containing islands of chondroid and, rarely, foci of bone. # Mucoepidermoid Carcinoma- Most common form of primary malignant tumor of the salivary glands, composed of variable mixtures of squamous cells and mucus-secreting cells. Morphology = solid tumor well circumscribed uncapsuled gray tumor often contain inner small Cysts with mucin in it in micro see clusters of mucous, squamous and intermediate and cells may line cyst or just as cluster.

Answer 83

ANATOMICAL DISORDERS OF THE ESOPHAGUS # Mechanical Obstruction- caused by developmental abnormalities/fibrotic stricture/tumor… » Atresia = a thin, noncanalized cord which replaces a segment of the esophagus. Atresia occurs most commonly at or near the tracheal bifurcation and usually is associated with a fistula connecting the esophagus and the bronchus/trachea. » Esophageal stenosis = generally caused by Fibrous thickening of the submucosa (coming thogether with Atrophy of the muscularis propria and Secondary epithelial damage). Hence, Stenosis most often is due to inflammation and scarring, which may be caused by chronic gastroesophageal reflux, irradiation, or caustic injury. # Functional Obstruction – upon esophageal dysmotality characterized by discooardinated contraction or spasm of m. propria = functional obstruction, result in impaired forward movement of food to stomach. » Achalasia- Incomplete relaxation of the lower esophageal sphincter in response to swallowing => obstruction of esophagus => dilation of proximal esophagus Achalasia is characterized by the triad of: 1) Esophageal Aperistalsis. 2) Incomplete relaxation of the lower esophageal sphincter. 3) Increased tone of the lower esophageal sphincter. Primary achalasia –idiopathic failure of distal esophageal inhibitory neurons damage to myenteric ganglions. Secondary achalasia is caused by pathological processes that impair esophageal function Clinicaly-dysphagia Stasis of food may produce inflammation and ulceration, risk to develop squamus cell carcinoma ~5% of patiants # Ectopia - Usually asymptomatic ectopic gastric mucosaThe most frequent site is the upper third of the esophagus # Hiatal hernia = Separation of the diaphragmatic crura muscular crura and the esophageal wall => allows a segment of the stomach to protrude above the diaphragm. There are 2 patterns: 1) Sliding hernia – constitute 95% of cases; the protrusion of the stomach creates a bellshaped dilation. 2) Paraesophageal hernia – a separate portion of the stomach enters the thorax through the widened foramen. INFLAMMATION OF THE ESOPHAGUS # Esophagitis – injury to esophageal mucosa with subsequent inflammation. # Lacerations –Mallory- Longitudinal tears in the esophagus most common see at the esophagogastric junction as Mallory-Weiss tears. Pathogenesis-Occur upon severe vomiting in which see inadequate relaxation of the musculature of the lower sphincter so reflux result as injurus agent may see in alchol toxication ,Complications – hematemesis . *Boerhaave syndrome, char- acterized by transmural esophageal tears and mediastini- tis, occurs rarely and is a catastrophic event. # Reflux Esophagitis – most frequent cause of esophagitis,normally squamous esophageal epithel protect against mechanic injury from food mainly the lower esophageal sphincter but also submucosal mucus glands protect against acid of stomach come in contact with epithel. The clinical condition is termed gastro- esophageal reflux disease (GERD). Contributing factors are impaired anti-reflux mechanisms, sliding hiatal hernia, and increased gastric volume, obesity, pregnancy, alcohol, and Tabbaco users. Clinical features –Symptoms are heartburn with cheast pain and sour-tasting Complications, of reflux esophagitis include esophageal ulceration, stricture development, and Barrett esophagus. # Chemical Esophagitis- Esophagitis due to chemical injury generally causes only self-limited pain, particularly odynophagia (pain with swallowing), the esophagus may be damaged by a variety of irritants including alcohol, acids or alkalis, excessively hot fluids, and heavy smoking. # esophageal infection- usually seen in imm. Suppressed patients caused by herpes simplex viruses, cytomegalovirus (CMV), or fungal organism’s : » Candidiasis= is characterized by adherent, gray- white pseudomembranes composed of densely matted fungal hyphae and inflammatory cells covering the esophageal mucosa. » Herpes- viruses typically cause punched-out ulcers. » CMV (Cytomegalovirus) causes shallower ulcerations. # Eosinophilic Esophagitis -An allergic inflammatory condition of the esophagus , infiltration by large numbers of eosinophils, particularly superficially and at sites far from the gastro- esophageal junction. Linked to food allergy majority of patients are atopic may present additional atopic allergic rhianitis/dermatitis/asthma… VARICES # Abnormally dileted vains in submucosal venus plaxi of distal esophagus happened upon Diseases cause portal hypertension, important complication is the cause of esophageal bleeding. # Develop in 90% of cirrhotic patients, most commonly in association with alcoholic liver disease, other common reason worldwide is hepatic schistosomiasis. # Morphology – tortuous dilated veins lying within the submucosa of the distal esophagus and proximal stomach. # Rupture of varices produces a massive hemorrhage into the lumen, as well as spreading of the blood into the esophageal wall => varices produce NO symptoms until they are collapsed. # (~50% of patients with varices suffer from hepatocellular carcinoma) not in book.

Answer 84

BARRETT ESOPHAGUS # A common complication of long-standing gastroesophageal reflux. (GERD) ,Esophagus is normally lined by no keratinizing squamous epithelium (suited lo Handle friction of a food bolus). Chronic Acid reflux from the stomach causes metaplasia to nonciliated columnar epithelium with goblet cells (better able to handle the stress of acid). Metaplasia occurs via reprogramming of stem cells, which then produce the new cell Type. Metaplasia is reversible, in theory, with removal of the driving stressor. Hence treatment of gastroesophageal reflux may reverse Barrett Esophagus. # Affects males more than females and Barrett esophagus greatly increases the risk of developing esophageal ADENOCARCINOMA. # Morphology – Red mucosa appear in endoscopy extending from gastroesophageal junction and upward, in correlation with micro appearance of the metaplastic change of with esophageal squamous epithelium replaced by metaplastic columnar epithelium. ESOPHAGEAL CARCINOMA # Benign tumors may arise from squamous mucosa and underlying mesenchyme. # There are 2 variants of esophageal cancer account for majority of cases: » Adenocarcinoma –common in western countries influencing lower 1/3 of esophagus linked to Barret metaplasia –dysplasia-carcinoma sequence » Squamous cell carcinoma – most common variant worldwide, malignant proliferation of the squamous cells with increased risk with irritation to epithel lining as alcohol and Tabaco use. SQUAMOUS CELL CARCINOMA # Risk factors-key ward irritation! Hence, alcohol and Tabaco /obstructive esophageal diseas e.g. achalasia/sever injury by chemicals digestion etc./ Chronic esophagitis (epithelial squamous dysplasia => carcinoma in situ => invasive cancer). # Effect man 4 times more than woman and much highr prevalence in nonwestern countries like Iran central china South America and South Africa. # Associated with HPV, and with abnormalities of p16 tumor suppressor gene and p53 gene. # Morphology – » Macro: tend to appear at upper segments then the adenocarcinoma frequently seen in the middle third of the esophagus. Early lesions appear as small, gray-white plaque like thickening of the mucosa. Next The lesions grow to tumor masses, taking one of the following forms: 1) Polypoid exophytic masses that protrude into the lumen. 2) Ulcerating tumors. 3) Diffuse infiltrative neoplasms that cause thickening and rigidity of the wall, and narrowing of the lumen. » Micro: Squamous cell carcinomas are moderately to well differentiate. Other variants are less common. Squamous cell carcinoma composed of nests of malignant cells that partially recapitulate the stratified organization of squamous epithelium. # Clinically : First symptoms are weight loss upon difficulty in swallowing or hoarseness upon invasion to recurrent laryngeal nerve Symptomatic tumors are generally very large at diagnosis and have already invaded the esophageal wall. These tumors may extend into adjacent structures: respiratory tree, aorta, mediastinum & pericardium, cause damage. ADENOCARCINOMA # Most adenocarcinomas arise from Barrett metaplasia or from glandular metaplasia in the esophageal mucosa The development charcterly accrue by Progression of Barrett esophagus to adenocarcinoma # carcinoma sequence in Barrett mucosa with stepwise accumulation of genetic mutations, especially p53 gene; additional changes involve HER2/c-ERB-B2, cyclin D1, RB, p16 genes histologically seen as dysplasia with increased severity upon progression. # See 7 times more common in man and highr prevalence for western countries other risk factors include obesity and chronic gastric reflux. # Morphology – » Usually in the distal 1/3 of the esophagus, may invade the gastric cardia . » Usually moderate or well differentiated mucin producing (intestinal type mucosa) , Appear adjacent Barrett mucosa with high grade dysplasia (may be displaced by adenocarcinoma) # Clinical features – esophageal carcinoma produces dysphagia to solids, followed by dysphagia to all food as its gradually obstructs the lumen; weight loss, fatigue and weakness appear, followed by pain related to swallowing. Metastasis generally occurs early even in superficial tumors, due to extensive lymphatic network in esophagus that allows horizontal and longitudinal spread Adenocarcinoma occurs in lower esophagus and lymph node metastases involve gastric and celiac lymph nodes Recurrences are common

Answer 85

PYLORIC STENOSIS # A congenital disorder occurs secondary to hypertrophy and hyperplasia of the muscular layers of the pylorus, causing a functional gastric outlet obstruction. # The obstruction of gastric outlet => episodes of projectile vomiting that start in the first 2 weeks of life. # More common in boys. # Clinical features – clinicaly appear about 2 weeks after birth with » Non-bilious vominting => the gastric content did not reach the duodenum to meet bile acids. » Visible peristalsis (movment of stomach against obstruction) on abdominal surface. » Corrected by surgical incision of the hypertrophied muscle. CHRONIC GASTRITIS # Defined as the presence of chronic inflammatory changes in the mucosa, leading to mucosal atrophy and may lead to epithelial intestinal metaplasia to intestinal lining see goblet cells . (not in book => check) # There are 2 main causes out of The most common cause of chronic gastritis is infection with the bacillus Helicobacter pylori 2nd one much less common is the AI type. # Symptoms & signs = Less severe & more persistent then the acute gastritis 1. .H. pylori chronic infection »H. pylori organisms’ Small curved gram negative bacillus that colonizes the mucus layer of the stomach not invading cells they Are responsible to vast majority of chronic gastritis cases , characterly effecting the antrum . » Pathogenesis – fecal oral transmission upon situated in mucus lining above gastric epithel it got Urease enzyme- create ammonia from urea and secret it to protects the bacteria from the acidic environment but also increase stimulation for acid production hence, H. pylori infection most often manifests as a predominantly antral gastritis with high acid production, despite hypogastrinemia. » 3complications: 1) H.pylori realis different toxins and protease who exerts damage on the gastric epithelium In addition to the increased acid secretion that occurs in H. pylori gastritis together the infection result in peptic ulcer disease of the stomach or duodenum. 2) Lymphoid aggregates with germinal centers and abundant subepithelial plasma cells within the superficial lamina propria. Representing an induced form of mucosa-associated lymphoid tissue (MALT) that has the potential to trans- form into lymphoma 3) Intestinal metaplasia – columnar gastric epithelium with goblet cells the indicators of intestinal metaplasia increased risk for gastric adenocarcinoma. »Morphology – H. pylori are found within the superficial mucus overlying the epithelium, Neutrophils within the lamina propria and epithelium, Lymphoid aggregates with germinal centers and abundant subepithelial plasma cells within the superficial lamina propria, Intestinal metaplasia. Over time, chronic antral H. pylori gastritis may progress to pangastritis, resulting in multifo- cal atrophic gastritis, reduced acid secretion, intestinal metaplasia, and increased risk of gastric adenocarcinoma in a subset of patients (mechanism is yet clear). » Clinical features – Nausea and vomiting. Urea breath (due to ammonia production by urease) Hematemesis is uncommon. 2. Autoimmune gastritis » Seen in ~10% of cases as t cell mediated type 4 HS attack on parietal cells –more concentrate in body and fundus, a consequence of AI recognition of parietal cells Antibodies to parietal cells and intrinsic factor that can be detected in serum and gastric secretions helpful for diagnosis » In contrast with that caused by H. pylori, autoimmune gastritis typically spares the antrum and induces hypergastrinemia : Autoimmune gastritis is associated with loss of parietal cells and, which secrete acid and intrinsic factor= Defective gastric acid secretion (achlorhydria). Deficient acid production stimulates gastrin release hypergastrinemia, resulting in and hyperplasia of antral gastrin-producing G cells- Antral endocrine cell hyperplasia Parietal cell also secret intrinsic factor for vitamin B12 absorption, upon their destruction no intrinsic factor leading to B12 deficiency and megaloblastic anemia (pernicious anemia). » Morphology: - Diffuse atrophy (mucosa of body and fundus are thinned). - Inflammatory infiltrate more commonly is composed of lymphocytes, macrophages, and plasma cells. - The inflammatory reaction most often is deep and centered on the gastric glands. (Unlike in H.pylori). - Parietal and chief cell loss can be extensive, increased risk for intestinal metaplasia who lea to increase risk for adenocarcinoma to dvelop. ACUTE GASTRITIS # An acute mucosal inflammatory process, which may be accompanied by nausea, vomiting, & pain. In more severe cases there may be mucosal erosion, ulceration, hemorrhage, hematemesis % melena. # Caused by increased acidity of the stomach, or reduced protective mechanisms of the mucosa, results in acid damage to the mucosa. # Pathogenesis – acute gastritis is associated with (risk factors): »Heavy use of non-steroidal anti-inflammatory drugs (inhibit prostaglandins formation that increases acid production). »Excessive alcohol consumption. »Ingestion of harsh chemicals(strong acid/base) »Treatment with cancer chemotherapeutic drugs (reduces the ability of regeneration). »Increased ICP => increased vagal stimulation => increased acid production by parietal cells »Shock/sever burns => severe decrease in blood flow to organs. # Morphology – » Ranges from localized to diffuse. » Mild gastritis = The surface epithelium is intact, although scattered neutrophils may be present above BM . » More severe form = presence of erosion & hemorrhage = acute erosive hemorrhagic gastritis. # Acute peptic ulcer: lack of mucosa layer as depression see in it bottom necrotic debris and neutrophils, in chronic ulcer see under it upon healing granulation tissue and fibrosis not in acute! Caused from similar to above…: 1. NSAID stop prostaglandin production so less bicarbonate secretion and reduced blood perfusion. 2. curling ulcers upon hypoxia e.g. shock/burns come as multiple ulcers in stomach and proximal duodenum 3. chushing ulcers upon IICP. Clinically come with hematemesis –coffie ground vomit nausea treat underlying caus and give proton pumps inhibitor.

Answer 86

GASTRIC ULCERATION # Ulcer is a Focal lack of mucosa, peptic ulcer most common sites of ulcers are the stomach and duodenum. ACUTE PEPTIC ULCERATION # As result of Acute peptic injury/complication of therapy with NSAIDs as well as severe physiologic stress-shock. # 3 types of acute ulcers: » Stress ulcers =affecting patients with shock, sepsis, or severe trauma come as multiple ulceration lesions. » Curling ulcers =come as ulcers in stomach and proximal duodenum seen in sever burn victims » Cushing ulcers = arising in the stomach, duodenum, or esophagus of persons with IICP see increase vagal stimulation so more Ach to G cells more gastrin more HCL. # Pathogenesis: beside reasons above high connection to complication of NSAID administration - prevents prostaglandin synthesis = This eliminates the protective effects of prostaglandins, which include enhanced bicarbonate secretion and increased vascular perfusion. Also come as Acute gastritis can progress to acute gastric ulceration hence same reasons e.g. Excessive alcohol consumption/Ingestion of harsh chemicals(strong acid/base)/Treatment with cancer chemotherapeutic drugs (reduces the ability of regeneration). # Morphology: Lesions described as acute gastric ulcers range in depth from shallow erosions caused by superficial epithelial damage to deeper lesions that penetrate the mucosa. Rounded and small less than 1 cm in diameter acute stress ulcers are sharply demarcated, with essentially normal adjacent mucosa, the ulcer base frequently is stained brown to black by acid- digested extravasated red cells. No scarring no granulation or fibrosis under ulcer yes necrotic debris and neutrophils in depth of it… # Clinical feature- Symptoms of gastric ulcers include nausea, vomiting, and coffee-ground hematemesis. Complications: bleeding (may be massive; 1-4% of patients require transfusion), perforation, obstruction and loss of function scarring PEPTIC ULCER DISEASE – CHRONIC ULCER # Peptic ulcer disease (PUD) most often is associated with H. pylori infection or NSAID use. # Pathogenesis- The imbalances of mucosal defenses and damaging forces that cause chronic gastritis are also responsible for PUD  PUD generally develops on a background of chronic gastritis. Gastric hyperacidity is fundamental to the pathogenesis of PUD hence causes Associated most often with Helicobacter pylori-induced hyperclorhidric chronic gastritis and chronic NSAID use. Also caused by high chlorhydro-peptic gastric secretion, as a result of either parietal cell hyperplasia, excessive secretory response (i.e., psychological stress) or impaired inhibition of stimulatory mechanism such as gastrin release as in chronic renal failure or hyperparathyroidism bouth induce Hypercalcemia stimulates gastrin production => acid secretion. (Zollinger-Ellison syndrome, characterized by multiple peptic ulcerations in the stomach, duodenum, and even jejunum rear syndrome, is caused by uncontrolled release of gastrin by a tumor and the resulting massive acid production). # Morphology- appear in the Duodenum  near the pyloric valve and Stomach = small curvature in segment of antrum, more common in the proximal duodenum than in the stomach. Histo see base with necrotic debries under it granulation tissue rich in b.v. under it see fibrosis. # Clinical feature- Epigastric pain said to resolve after meal upon duodenal ulcer/get worse after meal upon gastric ulcer. # Complications of Chronic peptic ulcer: -Upper gastrointestinal bleeding - represents the most frequent complication of a chronic peptic ulcer, which occurs in the active phase of the ulcer, caused by the erosion of an arterial wall. -Perforation - represents a surgical emergency in which the loss of substance extends beyond the gastric serosa, resulting in the communication between the stomach and the peritoneal space. -Penetration - in the evolution of ulcers, inflammation of serosa leads to adhesions with adjacent organs (liver, pancreas, greater omentum) so that, when the loss of substance exceeds serosa, the ulcer base is represented by the parenchyma of that organ, with no communication with the peritoneal cavity. -Gastric stenosis - appears in chronic ulcers with extensive, abundant fibrosis. -Malignant transformation - represents a very rare complication (less than 1 % of the cases). In the malignant area, the ulcer's borders are irregular, anfractuous. This complication is controversial, as some believe that the ulcer represents in fact an ulcerated form of gastric carcinoma

Answer 87

GASTRIC ADENOCARCINOMA o The most common (~90% ( of gastric primary malignant tumors, Gastric adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the gastric mucosa. According to Lauren classification, gastric adenocarcinoma may be: intestinal type, diffuse type and mixed type. o Pathogenesiso Mutation – Diffuse type the loss of CDH1 gene who encodes E-cadherin (E-cadherin, a cell adhesion molecule that participates in normal cell differentiation and tissue architecture), seems to be a key step in the development of diffuse gastric cancer. Hereditary (Familial) Gastric Cancer see mutation of gene in one third. CDH1 is a tumor suppressor gene, since mutation of the second CDH1 allele, perhaps as the result of environmental influences such as H. pylori infection or diet, is required for full penetrance found also in sporadic type. Molecular Biology The development of gastric cancer is thought to occur through a multi-step process, in which the earliest lesion is atrophic gastritis, followed by the development of dysplasia, adenoma, and then adenocarcinoma. Progression from the preceding lesion to the next developmental stage is accompanied by molecular genetic events. Mutation to p53, a tumor suppressor gene, is found in 64% of gastric cancers. o Environmental Risk Factors- Environmental factors appear to be related to the intestinal type of gastric cancer and not to diffuse one. Diets high in fresh fruit, leafy vegetables, ascorbic acid, and beta-carotene are associated with reduced risk. Also increase consumption of nitrosamines in smoked food hence may be the increase prevalence in japan and Eastern Europe the relationship between alcohol consumption and gastric cancer is inconclusive. o Adenocarcinoma of the stomach arises in the setting of atrophic gastritis, a condition in which chronic inflammatory processes destroy stomach glands. related to the intestinal type of gastric cancer and not to diffuse one. In the most severe cases, histology of the gastric mucosa reveals features that characterize a pre-cancerous lesion known as intestinal metaplasia. Atrophic gastritis may arise in response to: 1) chronic infection with Helicobacter pylori, 2) autoimmune chronic gastritis Gastric carcinoma may develop in as many as 9% of patients with atrophic gastritis. o Gastric Polyps Gastric polyps may evolve into gastric cancer. Hyperplastic polyps are the most common and comprise about 80% of all gastric polyps. Their malignant potential significantly increases when their size is greater than 0.5 cm in diameter. Adenomatous polyps have a significant risk of cancer as well, and require endoscopic follow-up after removal. o EBV- 10% of gastric adenocarcinomas are associated with Epstein-Barr virus (EBV) infection. (unknown mechanism) - Morphologically, EBV-positive tumors tend to occur in the proximal stomach and most commonly have a diffuse morphology with a marked lymphocytic infiltrate. o Morphology – Lauren classification = separates gastric cancers into intestinal and diffuse types: 1) Intestinal: (Mass, glandular) Macro = elevated mass heaped up borders and central ulceration usually involve the lesser curvature of the antrum. Micro = Tumor cells describe irregular tubular structures, with stratification, multiple lumens surrounded by a reduced stroma ("back to back" aspect). On presentation The tumor invades the gastric wall, infiltrating the muscularis mucosae, the submucosa and may even invade the muscularis propria. Often it associates intestinal metaplasia in adjacent mucosa. Depending on glandular architecture, cellular pleomorphism and mucosecretion, adenocarcinoma may present 3 degrees of differentiation: well, moderate and poorly differentiate-alredy diffused type. 2) Diffuse: Macro = Linitis plastica. The gastric wall is markedly thickened upon desmoplasia, and rugal folds are partially lost. Micro = diffuse-Tumor cells are discohesive no gland structure - mucinous (colloid) adenocarcinoma, poorly differentiated (Lauren classification). Tumor cells secrete mucus= "signet-ring cell"( mucus remains inside the tumor cell, it pushes the nucleus against the cell membrane) also mucus may be delivered in the interstitium producing large pools of mucus/colloid (optically "empty" spaces) Infiltrative along layers of gastric wall induce reactivity of surrounding stroma desmoplasia buildup of fibrous c.t. o Clinical feature – Both types of carcinomas are generally asymptomatic, and can be discovered by repeated endoscopic examinations; advanced carcinoma involves abdominal discomfort or weight loss early satiety anemia. The most significant prognostic factor is depth of tumor invasion at the time of diagnosis. There are three classifications of gastric tumors. The Boorman classification is based on the macroscopic appearance of the tumor; the Lauren classification divides tumors into intestinal and diffuse types; and the TNM classification reflects the depth of tumor infiltration (T) at early stages, the lesion is confined to the mucosa and submucosa, while in advanced stages the neoplasm has extended into the muscularis propria and serosa or final T4 for invasion to other adjacent organs. Node involvement (N) , and the presence of distant metastases (M).All gastric carcinomas may eventually penetrate the wall and spread to regional and distal lymph nodes => Virchow node (earliest lymph node metastasis that involves the supraclavicular lymph nodes) commonly metastasize to liver also character for diffused type is the Krukenberg tumor (metastasis to ovary which effect both ovaries see signant ring cell and desmoplasia components of tumor but in ovaries Other stomach tumors 1. Extranodal lymphoma about 5% of gastric malignancies -although may appear everywhere it very common arise in GI especially at stomach ,most common as marginal zone b cell lymphoma also its most frequent sait for EBV derived B cell lymphoma to proliferate .arise undr stage of chronic inflamtion promoting the lymphatic proliferation… 2. Carcinoid tomor- malignant proliferation of neuroendocrine cells most common arise in GI mainly small intestine but also in stomach e.g. from G cells, 2nd common place is the bronchial three. GASTRIC POLYPS # Polyp – any nodule or mass that originates from the mucosa, and projects above its level. # Gastric polyps are uncommon. # Polyps may develop as a result of epithelial or stromal cell hyperplasia, inflammation, ectopia, or neoplasia. # Hyperplastic polyps (80%-85%) – arise in response to chronic gastritis, thus composed of hyperplastic mucosal epithelium and inflamed edematous stroma; they are NOT true neoplasms # Fundic gland polyps (~10%) – » Occur sporadically and in persons with familial adenomatous polyposis (FAP) but do not have neoplastic potential. » Their incidence has increased markedly as a result of the use of proton pump inhibitors reduced acidity increased gastrin secretion glandular hyperplasia. » These well-circumscribed polyps occur in the gastric body and fundus, often are multiple, and are composed of cystically dilated, irregular glands lined by flattened parietal and chief cells. # Gastric adenoma (10%)- » Adenomas almost always occur on a background of chronic gastritis with atrophy and intestinal metaplasia. » The risk for development of adenocarcinoma in gastric adenomas is related to the size of the lesion. » Commonly located in the antrum. » Gastrointestinal adenomas exhibit epithelial dysplasia

Answer 88

DEVELOPMENTAL ANOMALITIES # Atresia – the complete failure of development of the intestinal lumen, most commonly affects the duodenum (associated with down syndrome) , if there is narrowing of the intestinal lumen with incomplete obstruction its Stenosis. # Duplication – saccular to tubular cystic structures pinched off from the intestine, which may or may not communicate with the lumen of small intestine communicate as tubular duplication or non-communicating completely pinched off cystic duplication. # Meckel diverticulum –results from failure of involution of the omphalomesenteric duct, leaving a blind-ended tubular protrusion (5-6cm long), usually in the ileum (proximal to the ileocecal valve); prevalent as 2% of population generally asymptomatic unless bacterial overgrowth depletes vitamin B12 then you get a “syndrome” of pernicious anemia and Meckel’s diverticulum. Complications include: bleeding upon develop ectopic gastric mucosa there who realis HCL, volvulus(bowel twist along mesentery risk for obstruction of blood supply and segment twisted),infection, intussusception… Diverticulum am punching of hollow organ all layers its real if only part of mucosal layer its pseudo diverticulum. # Omphalocele – a congenital defect of the periumbilical abdominal musculature that creates a membranous sac into which the intestine can herniate. Upon gastrochisis see lack of formation of part of abdominal wall now, herniated part not enclosed in sack just free in ext. environment. # Malrotation – of the developing bowel, can prevent the intestine from assuming their normal intra-abdominal position This result in parts not in their normal anatomical position predisposition for volvulus or miss diagnosis of appendicitis because it comes with left upper quadrant pain # Hirschprung disease – leads to congenital megacolon involving the rectum and some cases also distal sigmoid colon also involve Pathogenesis- Results when the normal migration of neural crest cells to lower area of rectum is disrupted. This produces a distal intestinal segment that lacks both the Meissner submucosal plexus and the Auerbach myenteric plexus (“aganglionosis”).Coordinated peristaltic contractions are absent and the subsequent functional obstruction results in dilation proximal to the affected segment. Common mutation = mutations in the receptor tyrosine kinase RET. Morphology- The aganglionic region may have a grossly normal or contracted appearance, while the normally innervated proximal colon undergo progressive dilation as a result of the distal obstruction The affected segment is NOT distended => it is the upstream, properly innervated segment that is dilated. Critical lesion is the lack of ganglion cells and ganglia in both the muscle wall and submucosa. MEGACOLON # Megacolon is the distension of the colon to a diameter greater than 6-7cm, and occurs as both a congenital disorder and an acquired disorder. » Hirschprung disease (a congenital megacolon) occurs when segments of the colon lack both the Meissner (submucosal) plexus and Auerbach (myenteric) plexus => aganglionic segments. Clinical features – -Delay occurs in the initial passage of meconium (earliest stools of infants), followed by vomiting in 48-72 hours. -The principal threat is superimposed enterocolitis with fluid and electrolyte disturbances. » Acquired megacolon may result from: 1) Chagas disease in which Trypanosoma cursi invade the bowel wall and destroy the plexuses. 2) Organic obstruction of the bowel by neoplasm or inflammatory stricture. 3) Toxic megacolon complication of ulcerative colitis or Crohn disease. 4) Functional psychosomatic disorder stool retention psychologic/abuse for long time of laxative degenerate plexus ABDOMINAL HERNIA # Any weakness or defect in the wall of the peritoneal cavity may permit protrusion of a serosa-lined pouch of peritoneum called a hernia sac. # Acquired hernias most commonly occur anteriorly, through the inguinal and femoral canals or umbilicus, or at sites of surgical scars. # Visceral protrusion into the sac (usually in inguinal hernias) = external herniation = may become entrapped  Pressure at the neck of the pouch may impair venous drainage, leading to stasis and edema  These changes increase the bulk of the herniated loop, leading to permanent entrapment, or incarceration, and over time, arterial and venous compromise can result in infarction.

Answer 89

Vascular Disorders- - Main blood supply = Celiac, Sup. Mesenteric, Inf. Mesenteric. - Collaterals from the proximal celiac, distal pudendal & iliac circulations = make it possible to tolerate loss of BS from 1 artery. ISCHEMIC BOWEL DISEASE # Acute impaired blood supply by one of the major trunks (celiac, superior & inferior mesenteric) may lead to infarction of extensive segments of intestine. # Range from: Mucosal infarction = extending no deeper than the muscularis mucosa Mural infarction = of mucosa and submucosa Transmural infarction = involving all three layers of the wall Mucosal or mural infarctions often are secondary to acute or chronic hypo perfusion (Cardiac failure, shock, dehydration, or vasoconstrictive drugs.) Transmural infarction is generally caused by acute vascular obstruction (caused by thromboembolism lunch on artery upon AF/vasculitis as polyarthritis nodosa/thrombosis like in Venus drain upon lupus anticoagulant or polycythemia Vera…). # Pathogenesis Intestinal responses to ischemia occur in two phases: 1. Initial hypoxic injury Occurs at the onset of vascular compromise. Intestinal epithelial cells are relatively resistant to transient hypoxia not much damage. 2. Reperfusion injury- Initiated by restoration of the blood supply and associated with the greatest damage. (Involve free radical production, neutrophil infiltration, and release of inflammatory mediators, such as complement proteins and cytokines) - The severity of vascular compromise, time frame during which it develops, and vessels affected are the major variables that determine severity of ischemic bowel disease. -Intestinal segments at the end of their respective arterial supplies are particularly susceptible to ischemia = watershed zones. - Intestinal capillaries first supply the crypts and then empty at the surface. This configuration allows oxygenated blood to supply crypts but leaves the surface epithelium vulnerable to ischemic injury. This anatomy protects the crypts, which contain the epithelial stem cells that are necessary to repopulate the surface. Thus, surface epithelial atrophy, or even necrosis with consequent sloughing, with normal or hyperproliferative crypts constitutes a morphologic signature of ischemic intestinal disease. # Morphology- Mucosal and mural infarction May involve any level of the gut from stomach to anus Disease frequently is segmental and patchy in distribution The mucosa is hemorrhagic and often ulcerated. With severe disease, pathologic changes include extensive mucosal and submucosal hemorrhage and necrosis. Transmural infarction = Coagulative necrosis of the muscularis propria occurs within 1 to 4 days and may be associated with purulent serositis and perforation. Micro = Microscopic examination of ischemic intestine demonstrates atrophy or sloughing of surface epithelium. Crypts may be hyperproliferative, upon reperfusion later see acute inflammatory infiltrate and edema in LP or hemorrhage . - Chronic ischemia= Accompanied by fibrous scarring of the lamina propria. - Acute ischemia = superinfection and enterotoxin release may induce pseudomembrane formation . # Predisposing conditions for ischemia: » Arterial thrombosis – atherosclerosis of mesenteric vessels, hypercoagulable states, aortic reconstructive surgery etc. » Arterial embolism – cardiac vegetations, MI with mural thrombosis etc. » Venous thrombosis – hypercoagulable states induced by oral contraceptives or antithrombin III deficiency, cirrhosis, abdominal trauma Clinical feature – Ischemic bowel disease tends to occur in older persons with coexisting cardiac or vascular disease. - Acute transmural infarction typically manifests with sudden, severe abdominal pain and tenderness. - May progress to shock and vascular collapse within hours as a result of blood loss. -As the mucosal barrier breaks down, bacteria enter the circulation and sepsis can develop; the mortality rate may exceed 50%. - Mucosal and mural infarctions by themselves may not be fatal. However may progress to transmural. - Radiation enterocolitis- radiation-induced vascular injury may be significant and produce changes that are similar to ischemic disease. ANGIODYSPLASIA # Angiodysplasia is characterized by acquired structural abnormality of submucosal and mucosal blood vessels manifests as Entangled (tortuous) dilation of blood vessels, usually seen in the cecum and ascending colon –due to high wall tension and usually presents after the sixth decade of life. # Blood vessels of the mucosa and submucosa layers are dilated, which makes them prone to rupture and bleeding into the lumen of the GI tract. # Although the prevalence of angiodysplasia is less than 1% in the adult population, it accounts for 20% of major episodes of lower intestinal bleeding clinically present as Hematochezia which is the passage of fresh blood through the anus, usually in or with stools in an older adult. # Risk factors – Osler-Weber-Rendu syndrome => autosomal dominant hereditary hemorrhagic telangiectasia (dilation of small blood vessels near mucous membranes) or CREST syndrome of scleroderma. HEMORRHOIDS # Variceal dilations of the anal and peri-anal submucosal venous plexuses. # Hemorrhoids are dilated anal and perianal collateral vessels that connect the portal and caval venous systems to relieve elevated venous pressure within the hemorrhoid plexus. # Common after the age of 50. # Develop due to elevated venous pressure within the hemorrhoidal plexus. # Predisposing conditions: » Straining upon defecation /Chronic constipation. » Venous stasis (sitting for long time). » Pregnancy. » Hypertension due to liver cirrhosis. # Can be classified as: » External – varices of inferior hemorrhoidal plexus (drain inferior rectal area) that occur outside the anus and covered by anal mucosa; they are more prone to thrombosis, and present as very painful, swollen irritations. » Internal – varices of the superior and middle hemorrhoidal plexuses that occur inside the rectum; present as non-painful irritations, but may prolapsed outside the anus. Morphology- On histologic examination, hemorrhoids consist of thin-walled, dilated, submucosal vessels that protrude beneath the anal or rectal mucosa.

Answer 90

INFLAMMATORY BOWEL DISEASES # Inflammatory bowel disease (IBD) is a chronic inflammatory condition resulting from inappropriate mucosal immune activation. # IBD encompasses two major entities: 1. Ulcerative colitisinflammation is limited to the mucosa and submucosa and usually extends to the distal colon and rectum. 2. Crohn disease transmural inflammation and usually found in the ileum and proximal colon but has the potential to affect any part of the gastrointestinal tract from mouth to anus. # More common in young females usually present at teenage years till 30s, more common in western countries- North America Europe Ashkenazi Jews. . # Indeterminate colitis = Histopathologic and clinical overlap between ulcerative colitis and Crohn disease. # Pathogenesis – IBD may results from a combination of: » Genetic: There is a clear genetic predisposition for Crohn disease. First-degree relatives have a 13-18% increase in incidence, and there are concordance rates of 50% in monozygotic twins. Classic Mendelian inheritance is not seen, implying a polygenic basis of the disease . NOD2 is a susceptibility gene in Crohn disease. NOD2 encodes a protein that binds to intracellular bacterial peptidoglycans and subsequently activates NF-κB Nuclear factor kappa B (NF-κB) is an ubiquitous rapid response transcription factor in cells involved in immune and inflammatory reactions, and exerts its effect by expressing cytokines, chemokines, cell adhesion molecules… » Mucosal immune response: Mechanism still uncertain, some combination that activate mucosal immunity and suppress immunoregulation contribute to the development of both disease. Polarization of T cells to the T-helper cell type 1 (TH1) type is a well-recognized feature of CD. Type 1 T helper (Th1) cells produce interferon-gamma, interleukin (IL)-2, and tumor necrosis factor (TNF)-beta, which activate macrophages and are responsible for cell-mediated immunity and phagocyte-dependent protective responses. Emerging data indicate that TH17 cells also contribute to disease pathogenesis, whereas IL-23(an R involve in development and maintenance of Treg) receptor polymorphisms may confer protection from CD and UC. Only in ulcerative colitis = TH-2 is involved & polymorphism of IL-10 gene. » Epithelial Defect: Defects in intestinal epithelial tight junction barrier function are present in patients with Crohn disease such as defect result in more primableepithel so inflammation stimulating material e.g. bacteria can come in. Paneth cell granulesgot antimicrobial materials may alter microbe composition link to develop IBD. » Microbiota: The precise contribute to IBD pathogenesis remains to be defined. Possible mechanism: Transepithelial flux of luminal bacterial components activates innate and adaptive immune responses –in genetic susceptible individual, TNF other inflammatory cytokines stimulating the increase priamability of epithel more influx more cytokine- circle end as IBD. » Environmental factors - especially cigarette smoking and diet, are also clearly involved in CD Tobacco smoking doubles the risk of both initial and recurrent Crohn disease (CD), unlike the apparent protective effect of tobacco seen in ulcerative colitis CROHN DISEASE # transmural inflammation and usually found in the ileum and cecum (proximal colon) but has the potential to affect any part of the gastrointestinal tract from mouth to anus.may be accompanied by extra-intestinal complications of immune origin => uveitis (inflammation of uvea), sacroilitis, migratory polyarthritis, erythema nodosum, bile duct inflammatory disorders, and obstructive uropathy. # Morphology – » MACRO = the mucosal surface shows patchy lesional distribution with sharply delineated areas of disease surrounded by normal mucosa. » Transmural involvement of the bowel by an inflammatory process with thickening of mucosal wall The intestinal wall is rubbery and thick as a result of edema, inflammation, fibrosis, and hypertrophy of muscularis mucosae => causing the lumen to become narrow, Cobblestone appearance upon granular appearance of surface mucosa . » “Creeping fat" => formation of granulation tissue within the fissure involves the stricture of the fissure, which will pull up the fat of the mesentery. » Ulceration => focal in early stages (aphthous ulcers), elongated linear ulcers (due to fusion of ulcers) as disease progresses » MICRO = Microscopically, Crohn disease is characterized by transmural inflammation, inflammatory cells extend from mucosa through submucosa and muscularis and appear as infiltrates on the serosal surface anther characteristic future is the presence of non-caseating granulomas Clusters of neutrophils within a crypt are referred to as a crypt abscess and often are associated with crypt destruction destruction of normal epithelial mucosa. Epithelial metaplasia = Pseudo pyloric metaplasia /Paneth cell metaplasia also may occur in the left colon, where Paneth cells normally are absent. # Clinical features – recurrent episodes of diarrhea, cramps with abdominal pain, fever (days-weeks), malabsorption with nutritional deficiency. # Consequences – » Risk for Fistula formation to other segments of the bowel, urinary bladder, vagina or perianal skin. » Abdominal abscesses or peritonitis. » Intestinal stricture or obstruction. » Perforations and peritoneal abscesses are common. » Increased risk for colonic adenocarcinoma. ULCERATIVE COLITIS # Ulcero-inflammatory disease is limited to the colon & rectum and in these location limited to the mucosa and submucosa.Begins in the rectum and extends proximally (=in retrograde manner), and may involve the entire colon. (=Pancolitis) # Morphology – There are NO skip lesions => colonic involvement is continuous. The mucosal ulcers rarely extend beyond the submucosa. Unlike in Crohn disease, mural thickening is absent, the serosal surface is normal, and strictures do not occur. » Isolated islands of regenerating mucosa bulge upward => pseudopolyps. # Micro = » Inflammatory infiltrates, crypt abscesses, crypt distortion, and epithelial metaplasia = similar to Crohn. » Ulcer- extending to submucosa. » No granulomas. # Clinical features – Attacks of bloody mucoid diarrhea that may persist for days/weeks/months, and then subsides only to recur after an asymptomatic interval. » Toxic megacolon = caused by inflammation and damage to the muscularis propria = cause neuromuscular damage. » High risk of carcinoma development!! Depends on the extent of colonic involvement, and the duration of the disease.

Answer 91

INFECTIOUS ENTEROCOLITIS # Enterocolitis – an inflammation of the colon (colitis) and small intestine (enteritis). # Infectious enterocolitis – an intestinal inflammatory disease of microbial origin, presented by diarrhea and ulcero-inflammatory changes in the small or large intestine. # Infective enterocolitis responsible for ~1/2 of deaths before age of 5 worldwide the prevalence of disease and severity of symptoms linked to sanitary state and hosts defense e.g. immune system BACTERIAL INFECTION » Mechanisms of infection: 1) Ingestion of preformed toxin – present in food contaminated by S. aureus, vibrio, and Clostridium perfringens. 2) Infection by toxigenic organisms – adhere to the mucosa, proliferate within the gut lumen and elaborate enterotoxins. 3) Infection by enteroinvasive organisms – proliferate, invade and destroy the mucosal epithelial cells. » Bacterial virulence factors include: 1. Adherence to epithelial cells Via fimbriae or pili e.g. c. Jejuni /E.coli got fimbria 2. Enterotoxins e.g. cholera toxin/enterotoxic E.coli 3. Invasion factors-enteroinvasive E.coli 4. Cytotoxicity-shiga toxin/enterohemorrhagic E.coli » Morphology – Hyperemia, edema, erosion and ulceration of lamina propria. Lamina propria and intraepithelial neutrophil infiltrates. Cryptitis (neutrophil infiltration of the crypts) Crypt abscesses (crypts with accumulations of luminal neutrophils) note The preservation of crypt architecture is helpful in distinguishing these infections from inflammatory bowel disease! » Clinical features – Bacterial origin enterocolitis is more severe .Campylobacter, Shigella, Salmonella, Yersinia and E. coli, all induce a similar histopathology leading to acute self-limited colitis ASLC is defined as a transient, usually infectious colonic inflammation, which presents with the acute onset of diarrheal illness. The patients generally recover in 10 to 14 days without residual inflammation or recurrent symptoms. Specific Diagnosis of the pathogen is by stool culture (cannot be distinguished by biopsy) Diarrhea and abdominal distress. Complications like massive fluid loss or destruction of intestinal mucosa lead to dehydration and perforation. Cholera Comma-shaped,gram- negative bacteria that cause cholera. Transmitted primarily by contaminated drinking water, endemic for certain areas in India in general linked to poor water sanitation and wormer temperature. Pathogenesis: Vibrio organisms are noninvasive and remain within the intestinal lumen. It is the preformed enterotoxin, cholera toxin, which causes disease. Toxin = A & B subunit the a subunit act as ADP rybosylation of G protein who get active stimulating adenylate cyclase for increase cAMP lead to opening of CFTR chlorine channels = Cystic fibrosis transmembrane conductance regulator = cl out followed by Na + H2O = excretory diarrhea. Clinical Feature: Most cases are Asymptomatic in more severe cases = Massive watery diarrhea = hypovolemia risk. Campylobacter Entrocolitits Caused by Campylobacter Jejuni. Most common in developed countries an important pathogen of Traveler’s diarrhea it’s Transmission = under cooked chicken, unpasteurized milk or contaminated water. Pathogenesis: 4 main virulence properties: 1. Motility Flagella can swim along intestine next by 2. Adherence factor colonies the colon next appearance of watery diarrhea suggest 3. Toxin production may be cholera like toxin (although exact pathomechanisem of both systemic n enteric symptoms unclear) in rear cases may see bloody diarrhea suggesting cytotoxin production and 4. Invasion. May cause:  Dysentery (inflammation causing painful small volium bloody diarrhea)  associated with invasion and only occurs with a small minority of Campylobacter strains.  Enteric fever occurs when bacteria proliferate within the lamina propria and mesenteric lymph nodes. Typhoid fever is characterized by severe systemic illness with fever and abdominal pain the organism classically responsible for the enteric fever syndrome is Salmonella enterica (Salmonella typhi). The classic presentation includes fever, malaise, diffuse abdominal pain, and constipation. Untreated, typhoid fever is a grueling illness that may progress to delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within 1 month of onset.  Reactive arthritis, erythema nodosum and Guillain-Barrésyndrome (a descending flaccid paralysis) Clinical Feature: Watery diarrhea, either acute or with onset after an influenza-like symptoms, is the primary manifestation, and dysentery may develops in 15% to 50% of patients. Shigellosis Shigella organisms are gram-negative bacilli that are unencapsulated, nonmotile, facultative anaerobes. Only known Reservoir is human with fecal oral transmition and it is the most common causes of bloody diarrhea. Pathogenesis: its acid stable when reaching the distal ileum and colon the organism is taken up by M microfolde cells next exit to LP and can infect epithel cell with different virulence proteins infection of epithel view basolateral surface using type 3 secretion system ,usually disease is 1-4 days of diarrhea fever and abd. Crumps but some strains has toxins like shiga toxin who inhibit eukaryote prot. Synthesis result in dysenteric disease~50% of cases . Escherichia coli Escherichia coli are gram-negative bacilli that colonize the healthy GI tract; most are nonpathogenic, but a subset cause human disease. • Enterotoxigenic E. coli (ETEC) organisms are the principal cause of traveler’s diarrhea, and are spread by the fecal-oral route. They express a heat labile toxin (LT) that is similar to cholera toxin and a heat-stable toxin (ST) that increases intracellular cGMP with effects similar to the cAMP elevations caused by LT. • Enterohemorrhagic E. coli (EHEC) organisms are categorized as O157:H7 and non-O157:H7 serotypes. Outbreaks of E. coli O157:H7 in developed countries have been associated with the consumption of inadequately cooked ground beef, milk, and vegetables. Both O157:H7 and non-O157:H7 serotypes produce Shiga-like toxins and can cause dysentery. They can also give rise to hemolytic-uremic syndrome • Enteroinvasive E. coli (EIEC) organisms resemble Shigella bacteriologically but do not produce toxins. They invade the gut epithelial cells and produce a bloody diarrhea. • Enteroaggregative E. coli (EAEC) organisms attach to enterocytes by adherence fimbriae. Although they produce LT and Shiga-like toxins, histologic damage is minimal. VIRAL INFECTION » Viral infection of the superficial epithelium in the small intestine => destruction of enterocytes => reduced absorptive function. Repopulation of villi with immature enterocytes and relative preservation of crypt secretory cells lead to net secretion of water and electrolyte to the lumen accompaind by osmotic diarrhea from incompletely absorbed nutrients. » Most common viral agents are rotavirus, calicivirus and adenovirus. » Rotavirus- the most common cause of severe childhood diarrhea and diarrhea related deaths worldwide. Children between 6 and 24 months of age are most vulnerable. Protection in the first 6 months of life is probably due to the presence of antibodies to rotavirus in breast milk, while protection beyond 2 years is due to immunity that develops after the first infection. Rotavirus selectively infects and destroys mature (absorptive) enterocytes in the small intestine, and the villus surface is repopulated by immature secretory cells. This change in functional capacity results in loss of absorptive function And net secretion of water and electrolytes. Vaccines are now available, For unknown reasons, oral rotavirus vaccines have been less effective in developing countries where they are most needed. SIGMOID DIVERTICULITIS # Diverticulum – a blind outpouching in wall of gut in Colonic diverticulum is located in most cases (95%) in the sigmoid colon . # Usually come as acquired form with pseudodiverticuli of mucosa and submucosa into muscularis propria layer, congenital diverticula (Meckel diverticulum) includes all layers of the bowel wall (mucosa, submucosa, muscularis externa) => UNCOMMON. Acquired diverticula either lack muscularis mucosae or have thin (attenuated) muscularis mucosae. # Diverticula are most common in the colon due to its structure outer longitudinal layer of muscularis extrerna (teniae coli) => focal defects are created when nerves and blood vessels penetrate to reach the inner layer of circular muscles. # May result from constipation (low fiber diet, leading to reduced stool bulk with increased difficulty in passage of intestinal content) or other reasons increase intr. Luminal pressure. # Morphology – Small, spherical out pouching (0.5-1cm in diameter) Most diverticula penetrate between fibers of circular muscle. In a non-inflamed state diverticula in histology composed of atrophied flattened mucosa and submucosa pushed into circular layer. If diverticulum lumen obstruct inflammation may occur =diverticulitis and due to the thin wall of diveculi who composed only of atrophied mucosa and sub mucosa it may rapture lead to peridiverticulitis of surrounding segment more this rapture may create abscess formation or rarely spared to peritonitis. # Clinical features – Continuous left-sided lower quadrant discomfort Sensation of never being able to empty the rectum. In Diverticulitis produces left lower quadrant tenderness and fever. Less common complications => bleeding (hematochesia), perforation and fistula formation.

Answer 92

# Condition Characterized by defective absorption of fat, carbohydrates, proteins, vitamins electrolytes and water Manifests most commonly as result of chronic diarrhea. # A hallmark in such condition is steatorrhea (fatty feces). The 3 most common chronic malabsoptive disorders in the us: pancreatic insufficiency, celiac disease, and Crohn disease. # Diarrhea = Defined as an increase in stool mass, frequency, or fluidity, typically to volumes greater than 200 mL per day. severe case even become life threatening hypovolemia! Diarrhea may come as secretory/osmotic/malabsorptive or exudative. # Malabsorption occurs as a result of disturbance of at least one of these digestive functions usually involve combination of loss of functions: 1. Intraluminal digestion = nutrients are enzymatically digested in a process that begins in the mouth, and continues in the stomach and duodenum. 2. Terminal digestion = hydrolysis of carbo & peptides in the brush border of the s. intestine. 3. Transepithelial transport  nutrients, fluid, and electrolytes are transported across the epithel. 4. Lymphatic transport = of absorbed lipids. # Cystic Fibrosis = Intraluminal digestion defect Defect in the CFTR = Defect in intestinal & pancreatic Cl secretion = Result: 1. Exocrine pancreatic insufficiency fail in intraluminal phase no pancreatic enzymes see in ~80% of CF patient. 2. Meconium ileus = upon defective hydration in about 10% of CF newborns see Blockage of the first fetal feces. # Celiac disease = Terminal Dig. & Transepithelial Trans. An immune-mediated enteropathy triggered by the ingestion of gluten-containing cereals in genetically predisposed individuals. increased prevalence in European origins Pathogenesis = gluten is a protein found in wheat and other similar grins, gluten digested by intestinal brush border enzyme to gliadin peptide who transferred across epithel by tissue transglutaminase now it is may be recognized by antigen presenting cells in predisposed individual like one with class 2 HLA-DQ2 or HLA-DQ8 activating TH cells and B cells (with anti-gliadin and anti-tissue transglutaminase antibodies) for inflammatory respond. Upon inflammation see atrophy of villi and loss of brush borders with increased turnover cellular rate and occurrence of less differentiated less absorptive enterocytes together lead to malabsorption. Morphology = biopsy is taken from duodenum and proximal jejunum the histopathologic picture is characterized by increased numbers of intraepithelial CD8+ T lymphocytes, with intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy. Clinical feature = recognizing histo feature is actually common to other diseases e.g. viral infections the combination of biopsy and serum antigens lead to diagnosis treatment is gluten free diet, Patients with celiac disease exhibit a higher rate of malignancy. The most common celiac disease– associated cancer is enteropathy-associated T cell lymphoma, an aggressive tumor of intraepithelial T lymphocytes and small intestinal adenocarcinoma. # Enviroental (Tropical) Enteropathy- A syndrome of stunted growth and impaired intestinal function that is common in developing countries. Disorder believed to be due to frequent intestinal infections which may lead to chronic problems with absorbing nutrients which may result in malnutrition and growth stunting in children. Occurrence of Repeated bouts of diarrhea suffered within the first 2 or 3 years of life closely linked to this syndrome. Remembering that the first two years are critical for linear growth and maybe even more importantly brain development. Histologically intestine similar to one of celiac disease may explain that Supplementary diet and vita administration not capable of completely overcome syndrome- the chronic effects of environmental enteropathy are not recovered from easily. # Lactose intolerance - Occur due to Lactase (Disaccharides) Deficiency  Terminal Digestion of lactose impaired so osmotic diarrhea develop 2 types: Congenital lactase deficiency is an autosomal recessive disorder caused by a mutation in the gene encoding lactase. Acquired lactase deficiency is caused by downregulation of lactase gene expression. # Abetalipoproteinemia  Transepithelial transport Deficiency of apoprotein B => the mucosal cells are unable to export lipids since apoprotein B is required for the formation of chylomicrons => diarrhea and steatorrhea are common. micro: may see lipid vacuoles in enterocytes. # Irritable bowel syndrome (IBS) is characterized by chronic and relapsing abdominal pain, bloating, and changes in bowel habits including diarrhea and constipation. The pathogenesis is poorly defined but involves psychologic Stressors, diet, and abnormal gastrointestinal motility (no gross or microscopic Abnormalities are found in most IBS patients). IBS typically manifests between 20 and 40 years of age, and there is a significant female predominance. # Microscopic colitis -Microscopic colitis refers to two medical conditions both causing chronic watery diarrhea and macro appear normal only by histo appearance can recognize disease: 1. Collagenous colitis - Is characterized by the presence of a dense subepithelial collagen layer, increased numbers of intraepithelial lymphocytes, and a mixed inflammatory infiltrate within the lamina propria. 2. Lymphocytic colitis - is histologically similar, but the subepithelial collagen layer is of normal thickness and the increase in intraepithelial lymphocytes may be greater. # Clinical features of malabsorption– Symptoms and signs include diarrhea (from nutrient malabsorption and excessive intestinal secretion), flatus, abdominal pain, and weight loss. » Hematopoietic system – anemias result from deficiency in iron and/or vitamin B12, and bleeding disorders result from vitamin K deficiency. » Musculoskeletal system – defective absorption of calcium, magnesium, vitamin D and proteins result in osteopenia and tetany » Endocrine system – amenorrhea, impotence and infertility result from generalized malnutrition; hyperparathyroidism results from prolonged calcium and vitamin D deficiencies. » Skin – purpura and petechia from vitamin K deficiency, edema due to protein deficiency, hyperkeratosis because of vitamin A deficiency. » Nervous system – peripheral neuropathies due to lack of vitamin A and B12.

Answer 93

# small intestine is most commonly affected due to its small lumen, about 80% of BOWEL OBSTRUCTION obstructions occur view list blow other cases mostly come in connection with tumors. Types of obstruction (or tumors): » Hernia – weakness of the peritoneal wall permits protrusion of a pouch-like, serosa-lined sac of peritoneum  hernial sac. Most commonly occurs anteriorly through inguinal and femoral canals or umbilicus. External herniation – when segments of viscera intrude through the weakened wall. Incarceration – permanent trapping of the herniated viscera, caused by the pressure at the neck of the pouch impairs venous drainage, which leads to stasis and edema that increase the bulk of the herniated loop. » Intestinal adhesion – fibrous bridges that are created during healing, following a surgical procedure or infection. The intestine may slide and become trapped => internal herniation. » Intussusceptions –occurs when a segment of the intestine, constricted by a wave of peristalsis, telescopes into the immediately distal segment. Once trapped, the segment is propelled by peristalsis and pulls the mesentery along. May progress to intestinal obstruction, compression of mesenteric vessels, and infarction. Some cases are associated with viral infection and rotavirus vaccines, perhaps due to reactive hyperplasia of Peyer patches and other mucosa-associated lymphoid tissue In adults, it may point to an intraluminal mass, such as tumor, that becomes trapped by peristaltic movement and pulls its point of attachment. » Volvulus – twisting of the loop of bowel (or other structure, like ovary) about its base of attachment, constricting the venous outflow, and may damage arterial blood supply as well (causes obstruction and infraction). TUMORS OF THE SMALL AND LARGE INTESTINE The colon and rectum are the hosts to more primary neoplasms than any other organ, while the small intestine is an uncommon site for benign or malignant tumors. Tumors of the small and large intestine include:  Polyps -protrusions from epithelium come in 2 major types :Sessile polyps A polyp without a stalk /Pedunculated polyps Polyps with stalks » Non-neoplastic polyps Hyperplastic polyp – found in distal colon and rectum, usually have no malignant potential Hyperplastic polyps are the most common polyps of the colon and rectum; when single they are not considered malignant, but sessile serrated adenomas may have malignant potential. Hamartomata’s polyp – benign malformation that resembles a neoplasm Juvenile polyp – it is a hamartomata’s polyp that usually arises in children under the age of 5 Peutz-Jeghers polyp – hemartomatous, autosomal dominant inherited syndrome, characterized by polyps in the GI tract and hyperpigmented macules on the lips and oral mucosa Inflammatory polyp – occurs with acute/chronic inflammation that may be present with ulcerative colitis Lymphoid polyp – focal lymphoid hyperplasia » Neoplastic epithelial lesions Benign polyps => named adenomas neoplastic lesion benign with glandular origin Malignant lesions => adenocarcinoma, squamous cell carcinoma of the anus  Other tumors GI stromal tumors – can be classified as  Tumors that show smooth muscle cell differentiation.  Tumors with neural differentiation.  Tumors with smooth muscle/neural dual differentiation.  Tumors lacking differentiation towards these lineages. Carcinoid tumor – tumors that arise from endocrine cells of the GI tract Lymphoma – involvement of the GI tract due to secondary spreading of nonHodgkin lymphomas (extra-nodal location), or arising of tumors in gastric MALT Neoplasms of the small intestine are uncommon The most common neoplasm in small bowel is a metastasis which may cause local obstruction. Primary sites are often from nearby colon, ovary, pancreas, and stomach. Benign tumors can include leiomyomas, fibromas and lipomas most benign tumors are incidental submucosal lesions, though rarely they can be large enough to obstruct the lumen. Approximately 64% of all small-bowel tumors are malignant:  Adenocarcinoma are most common in this rear group - the majority of those that do occur arise in the region of the papilla of veter, where they may become symptomatic through biliary or pancreatic duct obstruction. Epidemiologically, small-bowel adenocarcinomas have a striking resemblance to large-bowel adenocarcinomas they share a similar geographic distribution, with predominance in Western countries. In addition, they tend to co-occur in the same individuals. Furthermore, similar to adenocarcinomas in the colon, those in the small bowel arise from premalignant adenomas. This occurs both sporadically and in the context of familial adenomatous polyposis. Through a stepwise accumulation of genetic mutations, these adenomas become dysplastic and progress to carcinomas in situ and then to invasive adenocarcinomas. They then metastasize via the lymphatics or portal circulation to the liver, lung, bone, brain, and other distant sites. In addition, genetic analyses of sporadic small-bowel adenocarcinomas suggest similarities and differences from the pathogenesis from colorectal carcinomas. Although Kras mutation and p53 overexpression appear to be as common in small-bowel adenocarcinoma as in colorectal carcinoma, mutation of the APC tumor suppressor gene, which is characteristic of colorectal carcinoma, does not commonly occur in small-bowel adenocarcinoma  Sarcomas account for approximately 15% of small-bowel malignancies in the United States. While some may exhibit clear histologic features of smooth muscle origin, many tumors display only partial differentiation with incomplete expression of muscle-associated antigens. Because they are mesenchymal neoplasms believed to be derived from the interstitial cells of Cajal in the GI tract, they have recently been named with the more general term GI stromal tumors (GISTs). GI stromal tumors – can be classified as  Tumors that show smooth muscle cell differentiation.  Tumors with neural differentiation.  Tumors with smooth muscle/neural dual differentiation.  Tumors lacking differentiation towards these lineages.  Lymphoma – involvement of the GI tract due to secondary spreading of nonHodgkin lymphomas (extra-nodal location), or arising of tumors in gastric MALT  Carcinoid tumor – tumors that arise from endocrine cells of the GI tract. Rarely, a malignant carcinoid tumor can occur as a large bulky mass. Metastatic carcinoid to the liver can rarely result in the carcinoid syndrome.

Answer 94

# Can be classified as: non- neoplastic or neoplastic POLYPS Polyp = mucosal outward raised protrusion, come at 2 morphology sessile without connecting stalk instead connected view broad base or pedunculated with connecting stalk. Most common in the colon NON-NEOPLASTIC POLYPS Inflammatory polyp - Chronic cycles of injury and healing produce a polypoid mass made up of inflamed and reactive mucosal tissue. The solitary rectal ulcer syndrome is an example of the purely inflammatory lesion. The underlying cause is impaired relaxation of the anorectal sphincter, creating a sharp angle at the anterior rectal shelf. Patients present with the clinical triad of rectal bleeding, mucus discharge, and an inflammatory lesion of the anterior rectal wall. Hamartomatous polyps- caused sporadic or by hamartomas polyposis syndromes which is rear.in syndrome it come with extra. GI involvement Hamartomas are disorganized, tumor-like growths composed of mature cell types normally present at the site at which they develops. Thought to be malformation but recent discovered to have neoplastic origin suggesting gene mutations in their genome me. » Juvenile polyps - type of hamartomatous polyp and they may be sporadic or syndromic. Sporadic  usually solitary + no malignant potential while Syndrome (juvenile polyposis)  multiple lesions increase risk for colonic adenocarcinoma. Also in syndrome see ext. GI risk for pulmonary arteriovenous malformation. The vast majority of juvenile polyps occur in children younger than 5 years of age, characteristically are located in the rectum and manifest with rectal bleeding, morphology they typically are Pedunculated, smooth- surfaced, small and reddish lesions. Peutz-Jeghers syndrome - A rare autosomal dominant disorder defined by the presence of multiple gastrointestinal hamartomatous polyps and ext. GI appearance of mucocutanus pigmented lesion around lips and in the mucosa oral and genitals. Connect to increased risk of several malignancies (e.g. colorectal breast and gynecological, lung, pancreatic …). The polyps are most common in the small intestine, although they may also occur in the stomach and colon. Morphology- in Macro  large and pedunculated with a lobulated contour and in Micro  Complex glandular architecture and bundles of smooth muscle helpto distinguish Peutz-Jeghers polyps from juvenile polyps. Hyperplastic polyps - Most common polyp (90%) appearing usually at the 6th-7th decade of life, have NO malignant potential. Can arise anywhere, but mostly in left colon rectum and sigmoid colon. Thought to result from delayed shedding of surface epithelial cells, leading to a crowding of cells and characteristic serrated –thoothsaw appearance with pilup of goblet cells. Note that mucosa Contains mature goblet cells & absorptive epithelial cells=no malignant potential. May be singular or multiple Small, nipple-like, smooth protrusion lesions ADENOMAS Adenoma = a benign tumor formed from glandular structures in epithelial tissue. Colonic adenomas arise due to neoplastic proliferation benign lesion carry potential to become malignant unlike hyperplastic polyp. Its 2nd most common type of polyp after hyperplastic estimated to be found in ~50% of older adults in western world. Most colon adenocarcinoma arise from it view adenoma carcinoma sequence but Most adenomas, however, do not progress to adenocarcinoma- if found should be removed regardless of its state. The risk of a polyp to develop malignancy depends on the size-most important! Larger then 2 cm is risk, sessile growth and villus histo architecture are related also the severity of epithelial dysplasia is important. Morphology – 0.3 to 10 cm in diameter and can be pedunculated or sessile the stalk usually is covered bynon- neoplastic epithelium, but dysplastic epithelium is sometimes present In histo: dysplasia see pseudo/stratification, increase nucleus size elongation and hyperchromatic of nucleus. Adenomas can be classified as tubular, tubulovillous, orvillous on the basis of their histologic architecture. Tubular adenomas: small pedunculated composed of tubular glands. Villus adenomas: larger and sessile covered by slender villi. Tubulo-villi adenomas: mixture of both elements. in case of Sessile serrated adenomas very similar to hyperplastic polyps but see serrate appearance involve also crypt (not in hyperplasia where only surface of gland) Clinical features – smaller adenomas are asymptomatic until they cause bleeding; tubular adenomas may secrete mucin rich in proteins and potassium (leads to hypoproteinemia and hypokalemia) FAMILIAL POLYPOSIS SYNDROMES- p.593 see table Familial adenomatous polyposis: Uncommon, autosomal dominant disorders in which you fined multiple adenomatous polyps that carpet the colon mucosal surface (most of which are tubular adenomas).The risk of colorectal adenocarcinoma is nearly 100% by midlife unless prophylactic colectomy is done. *At least 100 polyps is necessary for a diagnosis of classic FAP, # The genetic defect in FAP is mutation in APC (adenomatous polyposis coli) gene tumor suppressor located on chromosome 5. Variants of FAP: -Gardner syndrome – FAP with osteomas (benign bine tumor usually see in skull), dental abnormalities, thyroid tumor and fibromatosis(no neoplastic fivbrocyte proliferation usually in mediastinum destroys adjacent structures). -Turcot syndrome – FAP with CNS tumors (medulloblastoma and glial tumors). Peutz-Jeghers polyps are uncommon hemartomatous polyps that occur as part of peutz-Jeghers syndrome91, characterized in addition by melanin pigmentation of mucosal and cutaneous surfaces. Cowden syndrome92 is characterized by hemartomatous polyps in the GI tract and increased risk of neoplasms of the thyroid, breast, uterus, and skin. LYNCH SYNDROME= Hereditary nonpolyposis Colorectal Cancer An autosomal dominant disorder. Caused by mutation of DNA mismatch repair genes usually leading to microsatellite instability.(individual already inherited one mutation the 2nd he acquired together now he accumulate mutation much faster than normal individual) Has a high risk in developing into colon cancer, as well as other cancers => endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. # In such patient colon cancer tend to occur at younger ages and often are located in the right colon

Answer 95

Most common malignancy of GI as colorectal cancer is 3rd most common site of cancer and also 3rd in cancer related death Incidence increases with age, and reaches its peak at age 60-70. Both genetic and environmental factors contribute to the development of colorectal cancers: » In young individuals => pre-existing ulcerative colitis or one of the polyposis syndromes. » Individuals with hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome). » Dietary factors => low content of fibers with high content of carbohydrates, high fat content, and decreased intake of protective nutrients such as vitamins (A, C & E). » Genetic factors => COX-2 is over expressed in colorectal cancer patients; inhibition by aspirin and non-steroidal anti-inflammatory drugs may exert a protective effect against colon cancer. Colorectal carcinogenesis – there are 2 major pathways for the development of colorectal cancer both describe accumulation of mutations but involve different genes and different defected mechanism leading to such as accumulation: 1. APC/β-catenin pathway (adenoma-carcinoma sequence) - Characterized by chromosomal instability associated with stepwise accumulation of mutations in a number of oncogenes and tumor suppressor genes - Initially there is localized epithelial proliferation, followed by the formation of small adenomas that progressively enlarge, become more dysplastic and eventually develop into invasive cancer -Sequence of events: - Loss of APC tumor suppressor gene – both copies of the gene must be lost may be part of FAP syndrome one is already inherited or just acquired mutation in 2 copies; APC protein bind and promotes the degradation of β-catenin in cytosol => if absent APC accumulation of β-catenin, it translocate to nucleus bind TcF leads to transcription of growth promoting genes such as cyclin D1 and MYC that promote cell proliferation(usually such as thing happened upon WANT exposure hence path named WANT pathway), more! It cause gene expression of different repressors for E cadherin and suppress contact inhibition of growth. If APC is neutralized it related as mutation permissive for polyp development - Mutation of K-RAS – the gene encodes signal transduction GTPase in pathway of GF TKR receptors as PI3K/AKT or MEPK pathways. it alternates between activated GTP bound state and inactivated GDP bound state => when mutated, the molecule remains active constant growth signal to cell and lead to formation of adenomatous polyp. - loss of tumor suppressors allows the emergence of carcinoma. loss of tumor suppressor genes SMAD2 and SMAD4, encoding components of the TGFβ pathway TGF-β signaling normally inhibits the cell cycle by binding to TGFbeta receptor and inducing CDKI molec expression as SMAD are signal transducers in this pathway , loss of these genes may allow unrestrained cell proliferation . Also, loss of p53 – a tumor suppressor gene that inhibits neoplastic formation by inducing apoptosis if lost neoplastic cell now can evade death. 2. Mismatch repair pathway (microsatellite instability)  In patients with DNA mismatch repair deficiency (due to loss of mismatch repair genes) mutations accumulate in microsatellite repeats  a condition referred to as microsatellite instability.  These mutated microsatellite seq.may disrupt the coding sequence of TGF-b receptor (Leads to uncontrolled cell growth.) or of the pro-apoptotic protein BAX (enhances the survival of genetic abnormal clones).  Other common DNA mismatch repair defects are Mutation in the oncogene BRAF & hyper methylation of CpG islands. By contrast, KRAS and TP53 typically are not mutated. Thus, the combination of microsatellite instability, BRAF mutation, and methylation of specific targets, such as MLH1, is the signature of this pathway of carcinogenesis.

Answer 96

The vast majority of colorectal cancers are adenocarcinomas, tumors that arise from the mucosa cells of the colon. While most adenocarcinomas are well or moderately differentiated, approximately 15% are poorly or undifferentiated tumors. These tumors are associated with a poorer prognosis. Mucinous or colloid carcinomas, with moderate to prodigious mucin production, are also associated with less favorable fiveyear survival rates. THE MORPHOLOGY OF COLORECTAL CARCINOMA # Morphologic patterns: # Macro -> may occur anywhere along colon Both forms grow into the bowel wall over time and may be palpable as firm masses. » Proximal colon – tumors tend to grow as polypoid, exophytic mass that extend along one wall of the cecum and ascending colon. but rarely cause obstruction. » Distal colon – carcinomas tend to encircle the lumen producing a constrictive ring => narrowing of the lumen. Micro -> composed of Tall columnar epithel with elongated, hyperchromatic nuclei, increased size of nucleus. Depending on glandular architecture, cellular pleomorphism and mucosecretion of the predominant pattern, adenocarcinoma may present 3 degrees of differentiation: well, moderate and poorly differentiate. Well differentiated- The neoplastic glands are long and frond-like, similar to those seen in a villous adenoma. To more crowded gland appearance loss of goblet cells and normal gland architecture….other character histo finding include Necrotic debris in the gland lumen. And upon invasion of tumor cells they induce Strong stromal desmoplastic response responsible for their characteristic firm consistency even May be composed of signet ring cells that are similar to those in gastric cancer The vast majority of colon carcinomas are adenocarcinomas, many of which produce mucin. Cancers of the anus are most commonly squamous cell carcinomas CLINICAL FEATURES OF COLON CANCER May Remain asymptomatic for years as symptoms develop gradually and slowly, enhance the importance of screening from age 50/even younger at case of family past: » Cecal and right colonic cancers – appearance of fatigue, weakness and iron deficiency anemia. In general Iron deficiency anemia in older men is very suspicious for GI cancer until proven otherwise. » Left-sided lesions – changes in bowel habits, left lower quadrant discomfort, bleeding. STAGING OF COLON CANCER The two most important prognostic factors are depth of invasion and the presence or absence of lymph node metastases. For example tumors with muscularis propria involvement is carrying much poor prognosis already compered to lesser depth of invasion also the occurrence of lymph node involvement much reduce prognosis.. Colorectal tumors may spread by direct extension into adjacent structures, and by metastasis through the lymph and blood vessels. Sites of metastasis (in order of preference) => liver, regional lymph nodes, lungs, bones. Note that The rectum does not drain by way of the portal circulation -> usually doesn’t metastasize to the liver. Staging of colorectal cancer refers to how far a cancer has spread on a scale from 0 to IV, with 0 meaning a cancer that has not begun to invade the colon wall and IV describing cancer that has spread beyond the original site to other parts of the body. There is a close correlation between advancing stage and cancer mortality. Tumor size does not appear to be important in terms of outcome. The aggressiveness of colorectal cancer is based upon its ability to grow and invade the colonic wall, lymphatic systeM TNM Staging System -The TNM System, developed by the American Joint Committee on Cancer (AJCC) is the most widely used, and is considered the most precise and descriptive. T stands for tumor and the depth to which it has penetrated the colon wall, N stands for lymph node involvement, and M refers to metastases, or whether the cancer has spread to other body parts Colorectal cancer most commonly spreads to the liver or the lungs Detection and diagnosis is based on several test: » Digital rectal examination. » Fecal testing for presence of blood. » Barium enema – barium sulfate fills the colon to give an X-ray picture. » Sigmoidoscopy and colonoscopy. » Biopsy for final confirmation. » Radiographic studies (CT) to assess metastatic spread.

Answer 97

THE PATHOLOGY OF THE APPENDIX The appendix is a normal true diverticulum of the cecum. Like any diverticulum, it is prone to acute and chronic inflammation, more rear tumors may also appear. ACUTE APPENDICITIS # Usually seen in adulecent and young adult althoh accure at any age It’s the Most common abdominal complication that requires surgery. Males are affected more often than females (5:1 ratio). Pathogenesis – commonly Associated with obstruction in 50%-80% of cases this together with Continuous secretion of mucinous fluid (after obstruction) contributes to the buildup of intraluminal pressure that compromises venous out flow. The obstruction can be fecalith (mass made of feces), and less commonly by gallstone, tumor or ball of warms. Ischemic injury and stasis of luminal contents favor bacterial proliferation, trigger inflammatory responses including tissue edema and neutrophilic infiltration of the lumen. Morphology – Microscopically, acute appendicitis is marked by mucosal inflammation and necrosis Early acute appendicitis Neutrophilic infiltration into mucosa, submucosa and muscularis propria plus Congestion of sub-serosal blood vessels. if there is focal Abscess formation within the mucosal wall - Now named as Acute suppurative appendicitis ,as inflammation develop areas of hemorrhagic ulceration of the mucosa appear progress to gangrenous necrosis along appendix wall – now named as Acute gangrenous appendicitis. If extend transmurally reaching serosa may rapture appendix wall eliciting acute peritonitis. Macro see: Inflammatory reaction transforms the healthy serosa into dull, granular, red membrane. The cut surface at the right demonstrates yellowish-tan exudation with a hyperemic mucosa. # Clinical features – The classic case of appendicitis: Mild peri-umbilical discomfort Deep, constant pain in the right lower quadrant (Mcburney's point) Anorexia, nausea, and vomiting, Low grade fever Mild elevated peripheral white cell count » Disorders that may present similar clinical features: Mesenteric lymphadenitis often come secondary to Yersinia bacterial infection or viral enterocolitis. /Acute salpingitis, Ectopic pregnancy, Mittelschmerz (pain associated with ovulation) /Meckel diverticulitis. TUMORS OF THE APPENDIX Carcinoids Most common tumors in the appendix. Appendiceal carcinoids rarely metastasize. Tumors that arise from endocrine cells of the GI tract. May appear at any age, usually during the 6th decade. Mucinous neoplasms- Range from benign cystadenoma to mucinous cystadenocarcinoma. Mucinous cystadenocarcinoma invades the wall to form intra-peritoneal cancer => pseudomyxoma peritonei (clinical condition caused by cancerous cells that produce abundant mucin leading to gelatinous ascites may result from appendicle tumor or also ovarian cancer in female.). Adenomas or non–mucin-producing adenocarcinomas also occur in the appendix may cause obstruction and enlargement that mimics the changes of acute appendicitis. Mucocele -Cystic Dilation of the lumen of the appendix by mucinous secretion. May Caused by NON-neoplastic obstruction of the lumen e.g. Associated with fecalith in the lumen => allowing the accumulation of mucinous secretion => atrophy of mucin-secreting mucosal cells => asymptomatic unless ruptures (spilling into peritoneum). Also May be a consequence of mucinous cystadenoma or mucinous cystadenocarcinoma. CARCINOID TUMOR (called “carcinoid” because they are slower growing than carcinomas) Carcinoid tumors are malignant tumors arise from neuroendocrine secretory cells The majority occurs in the GI 40% in the S.intestine or stomach (from g cells), Lungs and the trachealbronchial tree are the next common place, also may see in pancreas May be associated with: Zollinger-Ellison syndrome, multiple endocrine neoplasia syndrom Morphology- Macro  Carcinoid tumors are intramural or submucosal masses that create small polypoid lesions. Yellow or tan in appearance and elicit an intense desmoplastic reaction that may cause kinking of the bowel and obstruction. Micro = see thin fibromuscular septa enclosing nests of tumor cells presenting typical salt and paper appearance of nucleus(chromatin and nucleoli in center)cell got neuroendocrine secretory granules. Divided into typical type with lower mitotic activity and no areas of narcosis and atypical with high mitotic activity and necrotic areas in tumor. Low- or intermediate grade neuroendocrine tumors = Carcinoids (WHO classification) * The grade is based on mitotic activity High grade neuroendocrine tumors= Neuroendocrine carcinoma. Frequently display necrosis and, in the GI tract, are most common in the jejunum. Clinical Feature-usually not elicit para neoplastic symptoms by their secretion symptoms depend on location obstructive to bronchiole and recurrent infections or hemopthasis in upper gi acute appendicitis etc. Also may occur secondary to carcinoid tumors secretion It is caused by endogenous secretion of mainly vasoactive substances. Vasoactive substances released are metabolized to inactive forms by the liver Thus, carcinoid syndrome occurs in less than 10% of patients. commonly classified according to their presumed derivation from the embryonic gut : Foregut: Lung, bronchial, and gastric and duodenal rarely metastasize, cured by resection. Gastrinomas = duodenal gastrin-producing carcinoid tumors. Have been associated with proton pump inhibitor therapy. Midgut: Small intestine and appendicle intestinal often are multiple and tend to be aggressive while Appendix occur at any age and are almost uniformly benign. Hindgut: Rectal carcinoid tumors tend to produce polypeptide hormones and may manifest with abdominal pain and weight loss; they only occasionally metastasize.

Answer 98

The Liver – The liver has the enormous task of maintaining the body’s metabolic homeostasis. A healthy liver does the following: 1.It regulates the composition of blood, including the amounts of sugar (glucose), protein, and fat that enters the bloodstream. 2.It removes bilirubin, ammonia, and other toxins from the blood. 3.It processes most of the nutrients absorbed by the intestines during digestion and converts those nutrients into forms that can be used by the body. The liver also stores some nutrients, such as vitamin A, iron, and other minerals. 4. It produces cholesterol and certain important proteins, such as albumin. 5. It produces clotting factors, chemicals needed to help blood clot. 6. It breaks down (metabolizes) alcohol and many drugs. CLINICAL SYNDROMES # The major clinical syndromes of liver disease are hepatic failure, cirrhosis, portal hypertension, and cholestasis. ACUTE AND CHRONIC HEPATIC FAILURE Most severe outcome of liver disease that may develops as the end point of progressive damage to the liver parenchyma or Less often, hepatic failure is the result of sudden and massive destruction of hepatic tissue. Note that Failure is almost certain when about 80%-90% of hepatic functioning tissue is lost In many cases balance “tipped” toward dysfunction when increased stress exarted on already injured liver such as systemic infections, electrolyte disturbances, surgery, heart failure and GI bleeding. There are 3 categories of patterns of injury resulting in liver failure: 1) Acute liver failure with massive hepatic necrosis- Characterized by massive hepatic necrosis, uncommon life threatening situation lead to necessitates liver transplanted. Most often Caused by drugs or viral hepatitis, in this type see Hepatic insufficiency that progresses into hepatic encephalopathy within 2-3 weeks.*subacute when ~3 month chain of events. 2) Chronic liver disease Most common route to hepatic failure represented as end point of process inflicting chronic liver damage often manifest a cirrhosis. The processes that initiate chronic damage to the liver can be classified as: 1. Primarily hepatocytic (or parenchymal) 2. Biliary 3. Vascular 3) Hepatic dysfunction without overt necrosis -The hepatocytes are viable, but cannot perform normal metabolic function Occurs in acute fatty liver of pregnancy, toxicity, and Reye syndrome Clinical features – # In chronic liver failure Jaundice a yellow discoloration of skin and sclerae (icterus), occurs when systemic retention of bilirubin produces serum levels above 2.0 mg/dL. Hypoalbuminemia => impaired synthesis of albumin; predisposes for peripheral edema. Hyperammonemia => defective urea cycle function (takes place only in the liver) Hyperestrogenemia => impaired estrogen metabolism; hypogonadism and gynecomastia (in males) Palmar erythema (a reflection of local vasodilatation) Spider angiomas of the skin (v a central, pulsating, dilated arteriole from which small vessels radiate) In acute liver failure May present as jaundice or encephalopathy, but without the clinical signs of chronic liver failure (gynecomstia, spider angiomas etc.) Complications – # Accumulation of toxic metabolites Multiple organ systems failure (respiratory/renal failure, pneumonia, sepsis, ). # Coagulopathies due to impaired synthesis of blood coagulation factors  Massive GI bleeding. CHOLESTASIS # Bile congestion in liver result from condition in which bile cannot flow from the liver to duodenum, decrease in bile flow may be due to impaired secretion by hepatocytes or to obstruction of bile flow through intra-or extrahepatic bile ducts. Can be classified as: # Obstruction – due to mechanical blockage in the duct system, such as gallstone or malignancy or malformation. # Metabolic/ intrahepatic cholestasis – due to disease of the intrahepatic biliary tree or hepatocellular secretory failure  cannot be treated surgically. # Morphology –may appear intracellular as bile brown pigment in cytoplasem, also ext. cell in canaliculi system congested distant canaliculi/filling space of disse etc.… Symptoms include: » Progressive fatigue » Malabsorption of fat – no bile » Jaundice- not always The presence of elevated serum concentration of conjugated bilirubin is a principal sign of cholestasis. It results in jaundice, which can be detected by scleral icterus at a concentration as low as 2 mg/dL, and by dark urine. Pale stool (in obstructive cholestasis) » Elevated serum alkaline phosphatase » Itchiness (pruritus)- unknown reason » Skin xanthomas (accumulation of cholesterol) HEPATIC ENCEPHALOPATHY # Hepatic encephalopathy is a clinical syndrome of impaired brain function occurring in patients with advanced liver failure=> manifests by the broad spectrum of neuropsychiatric disturbances such as: behavioral abnormality, confusion, deep coma and death Associated with neurologic signs such as rigidity, hyperreflexia, EEG changes, and seizures (rare). Main characteristic is asterixis (flapping tremor) => non-rhythmic, rapid extension-flexion movements of the head and extremities. hyperammonemia is the main factor responsible for the brain abnormalities in HE Two factors seem to be important in the genesis of this disorder: » Severe loss of hepatocellular function - Nitrogenous compounds are metabolized in liver urea cycle, resulting in the generation of urea which is subsequently excreted through the urine » Shunting of blood from portal to systemic circulation around the chronically disease liver. Exact patho mechanism is unclear but estimation: Ammonia bypasses the liver and accumulates in the systemic circulation; it then crosses the blood-brain barrier and is metabolized by astrocytes to synthesize glutamine Glutamine increases the osmotic pressure within the astrocyte and is thought to cause mitochondrial dysfunction the process of glutamine (Gln) synthesis from glutamate (Glu) and ammonia, glutamate and as result GABA depletion Ammonia influences also other mechanisms leading to development of hepatic encephalopathy such as: impaired blood-brain barrier, changes in neurotransmission, proinflammatory cytokines, and impaired cerebral blood flow Acute setting -> elevation in blood ammonia -> impairs neuronal function and promotes generalized brain edema. Chronic settings -> Deranged neurotransmitter production -> neuronal dysfunction. Hepatic bile formation serves two major functions: Primary pathway for the elimination of bilirubin, excess cholesterol and xenobiotics. Secreted bile salts and phospholipid molecules promote emulsification of dietary fat in the lumen of the gut. In prhepatic see unconjugated bilirubin elevated in serum in hepatic see both and in post hepatic see conjugated bilirubin elevated in serum.

Answer 99

Hepatitis = A descriptor for specific histopathologic patterns of hepatocyte injury associated with inflammation and, when chronic, with scarring. Hence, Acute & chronic hepatitis = Distinguished in part by duration and in part by the pattern of cell injury. Causes: Hepatitis viruses A-E, Autoimmune, Drug- toxin- induced hepatitides -> All share the same patterns of injury MORPHOLOGY » Mononuclear infiltrates predominate in all phases of most hepatitis diseases because they all invoke T cell–mediated immunity. » Distinction between acute and chronic hepatitis is based on the pattern of cell injury and severity of inflammation. » Acute hepatitis = less inflammation and more hepatocyte death than chronic hepatitis Macro: On gross inspection, liver involved by mild acute hepatitis appears normal or slightly enlarged red liver; greenish if there is cholestasis. At the other end of the spectrum, in massive hepatic necrosis the liver may shrink to 500to 700 g and become transformed into a limp, red organ covered by a wrinkled, baggy capsule. Micro: Lobular disarray-loss of normal architecture Hepatocyte injury-swelling (ballooning degeneration), in HCV: mild fatty change of hepatocytes Hepatocyte necrosis isolated cells or clusters or apoptosis (shrinkage) Inflammatory Influx- of mainly mononuclear cells into sinusoids inflammatory spillover into adjacent parenchyma When located in the parenchyma away from portal tracts, these features are called lobular hepatitis, Kupffer cells undergo hyperplasia and Hypertrophy. ACUTE VIRAL HEPATITIS Infection of the liver caused by a small group of viruses’ initial infection and following inflammation are the acute viral hepatitis in some cases it later may progress to chronic infection yelling chronic viral hepatitis. Acute hepatitis – less than 6 months of progression; initial features are nonspecific flu-like symptoms with malaise ("feeling bad"), muscle and joint pain, fever, nausea and vomiting => followed by jaundice and abdominal discomfort. Note that in viral hepatitis the Immune mediated mechanisms induce hepatocyte damage in response to viral antigens. Types of viruses: 1) Hepatitis A virus (HAV) and HEV: both causing only acute form not progress to chronic infection hence appearance of IgM noting acute infection while appearance of IgG signal for resolution(note HAV got vaccine so IgG may link to immunized individual). Both Transmission by contaminated water and food Present in stool, got short incubation periods. HEV infection associated with fuliment hepatitis (liver failure with massive liver necrosis) 2) Hepatitis B virus (HBV) Causing acute hepatitis and in some caseas~20% may progress into chronic case. HBV-induced chronic liver disease is a precursor for development of hepatocellular carcinoma HBV-X is required for viral infectivity and may have a role in the development of hepatocellular carcinoma by regulating p53 degradation and expression. Prolonged incubation (4-26 weeks) Transmission by blood and body fluids + vertical transmission from mother to child It is NOT present in stool Vaccine available= HBsAg Serology: o Hepatitis B core antigen (HBcAg) = retained in hepatocyte o Hepatitis Be antigen (HBeAg) = Secreted to blood -> essential for infection o Hepatitis B surface antigen (HBsAg) => produced & secreted to the blood in high amounts immunogenic. 1.acute infection – see HBsAg as initial serologic marker that rises denoting infection by virus, next in phase IgM against HBcAg raise (in window period only one to appear in serum) in resolution see IgG against both HBcAg and HBsAg providing protection against future infections. 2. Chronic infection- appearance of HBsAg longer than 6 months as the mark of enter chronic state more in such patient no IgG against HBsAg. HBeAg or viral DNA as indicators that patient is infective? there is IgG against HBcAg 3. Patient who got vaccine or resolved the disease will have IgG against HBsAg (vaccine itself composed of viral surface AG) 3) Hepatitis C virus (HCV) Transmission by blood and intravenous drug use More likely to progress into chronic liver disease and eventual cirrhosis Incubation time 2-26 weeks Acute hep. C is asymptomatic in 75% of cases Persistent infection is the hallmark of HCV infection, occurring in 80% to 85% of patients with sub- clinical or asymptomatic acute infection Hepatitis C confers a significantly increased risk for hepatocellular carcinoma. 4) Hepatitis D virus (HDV) Replication is dependent on HBV infection => replicates only when encapsulated by HBsAg. Coinfection = infection by both HBV & HDV  usually recover completely. Superinfection = First HBV then HDV = acceleration of hepatitis + more severe Chronic hepatitis. IgM anti-HDV antibody is the most reliable indicator of recent HDV exposure Clinical features & outcomes of viral hepatitis- - Asymptomatic acute infection: serologic evidence only - Acute hepatitis: anicteric or icteric - Fulminant hepatitis: submassive to massive hepatic necrosis with acute liver failure. - Chronic hepatitis: with or without progression to cirrhosis. - Chronic carrier state: asymptomatic without apparent disease. * HCV= development to chronic state is much more common then in HBV. HCV= chronic. PATHOMORPHOLOGY Acute viral hepatitis can be caused by any of the hepatitis viruses. # It is divided into 4 stages: » Incubation period. » Symptomatic pre-icteric phase – marked by nonspecific symptoms => fatigue, nausea, and loss of appetite. » Symptomatic icteric phase – with jaundice and scleric icterus (=jaundice) => characterized by conjugated hyperbilirubinemia (causing dark colored urine). Hepatocellular damage may occur (unconjugated hyperbilirubinemia) » Convalescence.

Answer 100

CHRONIC HEPATITIS Liver disease with persistent inflammatory injury to hepatocytes lasting longer than 6 months the chronic inflammation Associated with progressive fibrosis that ultimately leads to liver cirrhosis Etiology is the most important determinant of the probability to develop progressive chronic hepatitis. » Viral hepatitis – mainly HCV that causes chronic hepatitis, which will evolve to cirrhosis. Also, HBV. » Wilson's disease – autosomal recessive inherited, copper metabolism disorder, in which lack of copper transporter prohibit the excretion out of cells renders its accumulation in the tissues (mainly liver and brain). » α1-antitrypsin deficiency – causes defective A1AT => no protease inhibitor => tissue destruction. » Chronic alcoholism – leads to hepatic steatosis (fatty change) => liver cirrhosis. » Drugs – isoniazid (for treatment of TB), and methyldopa (selective for α2 receptors, used for treatment of high blood pressure). » Autoimmunity. Morphology – » Mononuclear infiltrates predominate in all phases of most hepatitic diseases because they all invoke T cell–mediated immunity. (chronic & acute) » Distinction between acute and chronic hepatitis is based on the pattern of cell injury and severity of inflammation. In chronic disease = more inflammation & less cellular death. » Macro: The gross appearance of the liver in chronic hepatitis may be normal or include grossly evident focal scarring or, as cirrhosis develops, may feature widespread nodularity surrounded by extensive scarring. » Micro: Dense mononuclear and lymphocyte portal infiltrates distended portal vains are the defining lesion of chronic hepatitis. Also, common interference hepatitis –inflammation infiltrate in interference border in btween hepatocellular parenchyma and portal stroma/scar. Other hallmark of severe chronic liver damage is scarring. Parenchymal changes are similar to acute viral hepatitis with reduced appearance of cell death but with regeneration attempts but no orientation so create nodular mass of hepatocytes with interfering scat tissue. -> Continued scarring and nodule formation leads to the development of cirrhosis. » HBV- Ground glass cell accumulation Of HBsAg in cytoplasm. (large pale pink cytoplasm) » HCV- Fatty change (altered lipid metabolism) Bile duct injury- infection of cholengiocytes by virus also in alcoholic disease. Clinical Features: » Mostly asymptomatic see some serum enzymes elevation as AST, ALT - Persistent elevations of serum aminotransferase levels (hepatocyte destruction) » Laboratory studies may reveal prolongation of the pro- thrombin time, Alkaline phosphatase and bilirubin levels are usually normal, except in stages of hepatic decompensation - hypergammaglobulinemia, hyperbilirubinemia, and mildly elevated alkaline phosphatase levels. AUTOIMMUNE HEPATITIS A syndrome of chronic hepatitis in people with immunologic abnormalities. Similar morphology to that of chronic hepatitis. # Main features: » Female predominance (70%). » No serologic markers for viral infection. » Elevated serum IgG (>2.5g/dL). » Presence of auto-antibodies => antinuclear, anti-smooth muscle cell etc. » Presence of other autoimmune diseases can be seen => rheumatoid arthritis, thyroiditis, Sjogren syndrome, and ulcerative colitis. The main effectors of cell damage in autoimmune hepatitis are believed to be CD4+ helper cells. Autoimmune hepatitis may manifest as mild to severe chronic hepatitis. Morphology- # Differentiation btw viral and autoimmunity us by the time course. # Autoimmunity = early onset. # necrosis

Answer 101

Liver is the major detoxifying organ => subjected to injury by drugs and toxins. Metabolism of ethanol: oxidation of ethanol to acetaldehyde by three different routes, and the generation of acetic acid. Note that oxidation by alcohol dehydrogenase (ADH) takes place in the cytosol; the cytochrome P-450 system and its CYP2E1 isoform are located in the ER and catalase is located in peroxisomes. Oxidation of acetaldehyde by aldehyde dehydrogenase (ALDH) occurs in mitochondria. The most common form of chronic liver diseas in the western world, manifest in 3 different forms (collectively referred to as alcoholic liver disease) » Hepatic steatosis (intra cellular fat accumulation) Due to intake of ethanol (>60g/day) => Causes: 1. Metabolism of ethanol by ADH produces NADH => signals the body it has enough energy (although it doesn’t) stop glycosis + production of lipids => accumulation of these lipids in hepatocytes => steatosis! Alcohol is oxidized by alcohol dehydrogenase which cause decrease in NAD+, and increase NADH. NAD+ required for fatty acid oxidation in the liver, and by that deficiency, fat accumulate in the liver of alcoholics 2. Impaired assembly & secretion of lipoproteins. 3. Increase peripheral catabolism of fat Liver is enlarged (4-6kg), soft, yellow, and greasy micro see Fatty liver disease. steatosis is most prominent around the central vein and extends outward to the portal tracts with increasing severity. The intracytoplasmic fat is seen as clear vacuoles smaller are microvasicles larger are macrovesicles may push nucleus aside.. Continued alcohol intake => fibrosis develops around the central veins and extends to adjacent sinusoids (center to periphery) Fatty change is a reversible state UNTIL fibrosis appears => by stopping alcohol consumption Clinical features – hepatomegaly with mild elevation of serum bilirubin and alkaline phosphatase Alcoholic hepatitis » Usually associated with acute episode of excessive drinking it may stem from one or more of the following toxic by products of ethanol and its metabolites: Acetaldehyde-disrupts cytoskeleton and lipid membranes induce lipid peroxidation. Alcohol-direct injury to cytoskeleton Mito and membrane fluidity ROS-from ER metabolism & cytokine mediated inflammation (major cytokine TNF)- stimulation for realis view ROS and alcohol stim. Microbe of gut for endotoxin realis so Kupffer cell realis cytokine Ballooning = Swelling and necrosis => scattered cells undergo swelling due to accumulation of fat, water and proteins, and then necrosis Mallory dank bodies => scattered hepatocytes accumulate damaged intermediate filaments, visible as eosinophilic cytoplasmic homogenous masses Neutrophil infiltration => accumulate around degenerating hepatocytes; lymphocytes and macrophages also enter the portal tracts and spill into the parenchyma Steatohepatitis with Fibrosis => Generation of acetaldehyde and free radicals is maximal in the centrilobular region this region is most susceptible to toxic injury Pericellular fibrosis and sinusoidal fibrosis develop in this area of the lobule. Upon repeated insult fibrosis become more prominent  cirrhosis. Clinical features – malaise, anorexia, presents with painful hepatomegaly and elevated liver enzymes (AST > ALT) and fever; laboratory findings include hyperbilirubinemia, elevated alkaline phosphate and neutrophilic leukocytosis » Alcoholic cirrhosis - Final and irreversible end stage organ form of alcoholic liver disease, ends as brown, shrunken, non-fatty organ (<1kg) - For unknown reasons, cirrhosis develops in only a small fraction of chronic alcoholics. - Concurrent viral hepatitis, particularly hepatitis C, is a major accelerator of liver disease in alcoholics. The prevalence of hepatitis C among alcoholic is about 30% on other hand, - With complete abstinence, some regression of scar can be seen in all cases, and the Micronodular liver transforms, with regeneration, into a macronodular - Cirrhotic organ; - Characteristic diffuse nodularity of the surface is induced by the underlying fibrous scarring. Small nodules with unorganized architecture are entrapped by fibrous tissue; fatty accumulation is no longer Seen in this “burned-out” stage. - Clinical features – Commonly, the first signs of cirrhosis relate to complications of Portal hypertension (e.g., an abdomen grossly distended with ascites, wasted extremities, and Caput medusa) alternatively, a patient may first present with lifethreatening variceal hemorrhage or hepatic encephalopathy. In other cases, cirrhosis may be clinically silent, discovered only at autopsy or when stress such as infection or trauma tips the balance toward hepatic insufficiency Laboratory findings reflect The developing hepatic disease, with elevated serum aminotransferase, Hyperbilirubinemia, variable elevation of alkaline phosphatase, hypoproteinemia (globulins, albumin, and clotting factors), and anemia. In chronic alcoholics, alcohol may become a major caloric source in the diet, displacing Other nutrients and leading to malnutrition and vitamin deficiencies (e.g., thiamine, vitamin B12). Among those with end-stage alcoholic liver disease, the immediate causes of death are: * Hepatic failure * Massive gastrointestinal hemorrhage * Intercurrent infection (to which affected persons are predisposed) * Hepatorenal syndrome * Hepatocellular carcinoma in 3% to 6% of cases NAFLD is condition in which fatty liver disease develops in persons who do not drink alcohol. The liver Can show any of the three types of changes described earlier (steatosis, steatohepatitis, and cirrhosis). NAFLD is associated with insulin resistance and Obesity. DRUG- AND TOXIN-INDUCED LIVER DISEASE # Liver is the major organ of detoxification; thus it is subjected to potential injury: » Direct toxic damage to hepatocytes. (conversion of xenobiotic  active toxin) » Immune-mediated hepatocytes destruction. (acting as hapten) Drug-induced liver disease is a common condition that may manifest as a mild reaction or, much more seriously, as acute liver failure or chronic liver disease. The most important agent that produces toxic liver injury is alcohol. Drug reactions may be classified as: » Predictable – occur in anyone who accumulates a sufficient dose of the drug. E.g. Acetaminophen toxicity = leading to acute failure & transplantation. The toxic agent is not acetaminophen itself, but rather toxic metabolite produced by the cytochrome P-450 system in acinus zone 3 hepatocytes. » Unpredictable – depends on the metabolic rate of the host and development of immune response to the antigenic stimulus. (Individual variation) e.g. Chlorpromazine (an agent that causes cholestasis in individuals who metabolize it slowly), halothane (which can cause a fatal immune-mediated hepatitis in some persons exposed to this anesthetic on several occasions) Morphology – » Massive necrosis => the entire liver may be involved, or only random areas are affected; necrotic areas have red, may be depressed appearance. Upon Massive loss of hepatic substance => liver may shrink to 500-700g. » Complete destruction of hepatocytes in continuous lobules leaves only reticulin framework and preserved Drug/Toxin-Mediated Injury Mimicking Hepatitis Clinically and histologically, drug-induced hepatitis cannot be distinguished from chronic viral hepatitis or autoimmune hepatitis => serologic markers are critical for making a diagnosis. » Acetaminophen toxicity = leading to acute failure & transplantation. » Isoniazid = chronic hepatitis. » Other drugs= induce autoimmune hepatitis. Drug/Toxin-Mediated Injury with Steatosis Fulminant liver failure and encephalopathy in children with viral illness who take aspirin Presents with hypoglycemia, elevated liver enzymes, and nausea with vomiting; may Progress to coma and death Morphology: hepatocellular microvesicular steatosis. Cerebral edema mitochondrial alternation in EM. Metathroxate and corticosteroids induce steatosis Amiodarone induce steattic hepatitis like alcohol

Answer 102

LIVER CIRRHOSIS Is the end stage process of repeated injury and attempts for regeneration with multiple underlying causes characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules. # Main characteristics: » Fibrous septa – fibrous bands and scars around multiple adjacent lobules. » Parenchymal nodules – lobule don’t have architecture instead contain non organized mixed cell population of hepatocytes in different stages as spherical lobule surrounded by fibrosis » Diffuse damage involve major part of liver Caused by 1. alcohol abuse Cirrhosis is a complication of long-term, chronic alcohol-induced liver damage; occurs in 10-20% of alcoholics, nonalcoholic steatosis 2. Hemochromatosis Excess body iron leading to deposition in tissues (hemosiderosis) and organ damage (hemochromatosis -Tissue damage is mediated by generation of free radicals. Due to autosomal recessive defect in iron absorption (primary) or chronic transfusions (secondary). 3. chronic infections HBV/HCV, autoimmune hepatitis 4. Biliary disease e.g. Primary ones -Autoimmune granulomatous destruction of intrahepatic bile ducts classically arises in women (average age is 40 years) Etiology is unknown; anti mitochondrial antibody is present. Presents with features of obstructive jaundice Cirrhosis is a late complication, Primary sclerosing cholangitis Inflammation and fibrosis of intrahepatic and extrahepatic bile ducts Etiology is unknown, but associated with ulcerative colitis; p-ANCA is often positive. Presents with obstructive jaundice; cirrhosis is a late complication. 5. Wilson diseas Autosomal recessive defect (ATP7B gene) in ATP-mediated hepatocyte copper transport Results in lack of copper transport into bile Copper builds up in hepatocytes, leaks into serum, and deposits in tissues. Copper-mediated production of hydroxyl Free radicals leads to tissue damage. Presents in childhood with Cirrhosis Pathogenesis – Three processes are central to the pathogenesis of cirrhosis: 1. Death of hepatocytes. replaced by Preexisting proliferating hepatocytes (regeneration) or newly formed hepatocytes (hepatobiliary stem cell niche) encircled by fibrotic bands. 2. ECM deposition = in cirrhosis, types I and III collagen and other ECM components are deposited in the space of Disse. *Source of collagen – Stellate cells (formally Ito cells) found in the space of Disse, which are transformed into myofibroblasts upon inflammation (cytokines, GFs e.g. TNF from injured hepatocytes and kupffer calls). 3. Vascular reorganization the major vascular lesions that contribute to defects in liver function are: loss of sinusoidal endothelial cell fenestrations = formation of high pressure, fast flowing vascular channels = no solute exchange = albumin, clotting f., lipoproteins remain in the liver. And 2nd one is Development of vascular shunts = abnormal vascular pressures in the liver and contributes to hepatic dysfunction and portal hypertension. Morphology-regenerative nodule surrounded by fibrous connective tissue extending between portal regions. Shrunk firm liver nodular surface appearance of Micronodule- less than 3mm. Macro- over 1 cm Clinical features – Early symptoms: nonspecific and include anorexia, weight loss, weakness. Fatal cirrhosis complications : » Progressive liver failure. » Complication associated with portal hypertension. » Development of hepatocellular carcinoma. PORTAL HYPERTENSION Increased resistance to portal blood flow. # Types of portal hypertension: » Pre-hepatic – blockage of portal vein due to occlusion, thrombosis, vascular invasion of primary or secondary cancer. » Intra-hepatic – cirrhosis (accounting for most portal hypertension), massive fatty change, diffuse granulomatous disease (sarcoidosis). » Portal hypertension in cirrhosis results from increased resistance to portal flow at the level of the sinusoids and compression of central veins by perivenular fibrosis and expanded parenchymal nodules. » Post-hepatic – right sided heart failure, Budd-Chiari syndrome => results from thrombosis of hepatic veins. » Another major cause: increase in portal venous blood flow. Bacteria absorbed from the gut bypasses the kupffer cells in the liver (due to intrahepatic shunting of blood from portal to systemic circulation)  Bacteria causes increase production of NO = causes arterial vasodilation in the splanchnic circulation  increase in blood flow. Clinical features – » Ascites – collection of excess fluid in the peritoneal cavity. Serous fluid with mainly albumin. » Pathogenesis:  Sinusoidal hypertension and hypoalbuminemia  Movement of intravascular fluid into the extravascular space of Disse.  Leakage of fluid from the hepatic interstitium into the peritoneal cavity. (With cirrhosis, hepatic lymphatic flow may approach 20 L/day, exceeding thoracic duct capacity) » Porto-caval anastomoses – portal venous pressure rises => development of bypasses where systemic and portal circulation anastomose => veins around the rectum (hemorrhoids), esophageal venous plexus cause esophageal varices (rupture causes hematemesis), periumbilical veins (caput medusa), and retroperitoneal venous plexus. » Hepatorenal syndrome- (rapidly developing renal failure secondary to cirrhosis without any predisposing renal damage in background) underlying cause unknown but Thoth to result from increase splanchnic blood flow plus peripheral resistance increased to mark decrease in renal blood flow mainly to cortex » Splenomegaly – long-lasting congestion with enlargement of the spleen (1kg) may come with hypersplanisem. » Hepatic encephalopathy. » Changes in pulmonary blood flow occurring secondary to hepatic failure may lead to portopulmonary hypertension or hepatopulmonary syndrome.

Answer 103

HEMOCHERATOSIS # disorders characterized by excessive accumulation of body iron, 2 Types of hemochromatosis: » Genetic – Hereditary hemochromatosis refers to genetic disorders characterized by excessive accumulation of body iron, most of which is deposited in the liver, pancreas, and heart. Most common form is An autosomal recessive disorder of adult onset, which results from mutation of HFE gene (chromosome 6), characterized by accelerated rate of iron absorption and progressive deposition. » Acquired (secondary) – results from multiple blood transfusions(each bag of blood bag of iron cuz transfused RBC after 120 day lysed and iron recycled), ineffective erythropoiesis (β-thalassemia ext. turnover plus treated by regular transfusion), and increased iron intake. # Pathogenesis – The total body content of iron is regulated by gastrointestinal absorption since there is no excretory pathway for excess absorbed iron. Hepcidin produced by the liver is a hormone responsible for reduce plasma iron levels it down regulate iron transporters on enterocytes and on other cells of body e.g. macrophages hence also reduce absorption of iron it regulated by HFE if missing it cannot stimulate hepcidin production such In hereditary Hemochromatosis = HFE mutated = no regulation of hepcidin # Manifestations appear when accumulated amount reaches 20g iron. Iron is directly toxic to tissues by:  Lipid peroxidation due to free radicals produced from iron (view Fenton reaction).  Stimulation of collagen formation.  Direct interaction of iron with DNA. # Morphology – The morphologic changes in hereditary hemochromatosis are all responses to the deposition of hemosiderin as golden-brown pigment and process of fibrosis in different organs. Fully developed cases show: (1) Cirrhosis seen in most patients- Deposition of hemosiderin – first appears as goldenyellow granules in the cytoplasm of hepatocytes, then spread to bile duct epithelium and Kupffer cells, making the liver brown. Fibrous septa slowly develop leading to micronodular cirrhosis in an intensely pigmented liver. Inflammation is absent. (2) Diabetes mellitus 1 - Intensely pigmented Hemosiderin can be found in acinar cells and islets of Langerhans. (3) Skin pigmentation –partially by hemosiderin in MQ and fibroblast of skin but mainly from increased melanin production. Other effected organs: » Heart Enlarged with hemosiderin granules within myocardial fibers Brown pigmentation of myocardium. Diffuse interstitial fibrosis. » Joints Deposition of hemosiderin in the synovial lining leading to development of acute synovitis. Clinical features – more common in men, late onset around age 50 take time for damage buildup…, hepatomegaly, diabetes mellitus 1 , cardiac dysfunctions (arrhythmias, cardiomyopathy), and arthritis. Blood test show- increase tot. Iron plasma, reduce iron binding capacity, increase transferrin saturation and increase ferritin production. The risk for hepatocellular carcinoma development in patients with hemochromatosis is 200 times higher than in normal populations. WILSON DISEASE # This autosomal recessive disorder is marked by the accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye. # Caused by mutation in ATP7B gene (chromosome 13), which encodes for an ATPase metal ion transporter localized in the Golgi of hepatocytes. # Pathogenesis – Normal copper physiology: Absorption of ingested copper (2 to 5 mg/day) in Plasma transport in complex with albumin Hepatocellular uptake, followed by binding to a α2-globulin (apoceruloplasmin) to form ceruloplasmin. Next again Secretion of ceruloplasmin bound copper into plasma ~95% of plasma copper is in this bound form Hepatic re uptake from the plasma and realis of copper follow by secretion of free copper into bile. » In Wilson disease, the initial steps of copper absorption and transport to the liver are normal. However, without ATP7B activity, copper cannot be passed on to apoceruloplasmin and therefore cannot be excreted into bile, the primary route for copper elimination from the body. » Copper progressively accumulates in the liver to cause toxic injury by formation of free radicals, binding to cellular proteins, and displacing metals from hepatic metalloproteins. » Copper begins to escape from the overloaded, damaged hepatocytes into the circulation => deposits in many other tissues => produces damage through the same mechanisms that injure hepatocytes. # Morphology – » May mimic fatty liver disease, acute/chronic hepatitis and may progress to cirrhosis. » In the brain, toxic injury affects basal ganglia => atrophy. » Eye lesions => Kayser-Fleischer rings (green brown rings upon deposition in BM of cornea) usually accompany neuro involvement. Note: copper may demonstrate with different stains such as orcein, its morphology cannot be distinguish from other copper overload cause diseases such as chronic obstructive cholestasis. ALPHA-1 ANTITRYPSIN DEFICIENCY # An inherited metabolic disorder characterized by abnormally low serum levels of α1-antitrypsin, a protease inhibitor. The major function of AAT is the inhibition of proteases, particularly neutrophil elastase released at sites of inflammation. # 2 character involve organs are In the lungs  AAT deficiency leads to pulmonary emphysema due to increase elastase activity and the liver => damage elicit by accumulation of mutated AAT # Pathogenesis - The AAT gene, located on human chromosome 14, is very polymorphic, most disease allelic variants produce normal or mildly reduced levels of serum AAT. Most severe form is as autosomal recessive disease that appears in patients who are homozygous to the Z allele of the AAT gene94 (chromosome 14) => PiZZ genotype. (Produce only 10% AAT) The PiZ polypeptide contains a single amino acid substitution that results in misfolding of the nascent polypeptide in the hepatocyte endoplasmic reticulum. The resultant mutant protein cannot be secreted by hepatocytes => accumulated in ER = unfolded protein response = apoptosis. # Morphology – Hepatocytes in AAT deficiency contain round to oval cytoplasmic globules composed of retained AAT, a glycoprotein that is strongly positive in a periodic acid–Schiff stain. Electron microscopy they lie within smooth endoplasmic reticulum. # Clinical features – Hepatic injury associated with PiZZ homozygosity may range from marked cholestasis with hepatocyte necrosis in newborns, to childhood cirrhosis, to a smoldering chronic hepatitis or cirrhosis that becomes apparent only late in life. » Cholestasis. » Pulmonary emphysema. » Chronic hepatitis. » Cirrhosis. » Hepatocellular carcinoma

Answer 104

BILIARY CIRRHOSIS The retention and accumulation of bile during cholestasis have long been implicated as a major cause of liver damage (could disrupt cell membranes through their detergent action on lipid components, promote the generation of reactive oxygen species (ROS) that eventually cause hepatocyte apoptosis) Injured hepatocytes may release molecules, including growth factors, cytokines, chemokines and lipid peroxide products, able to amplify the inflammatory response, stimulate fibrogenesis by hepatic stellate cells, or directly injure other nearby cells. Additionally, they can activate Kuepfer cells to generate ROS, which may further contribute to the liver cell insult. Upon chronic damage there is cellar death and inflammation eliciting continues damage and repair processes ending as liver cirrhosis. Primary biliary cirrhosis # An autoimmune chronic, progressive cholestatic diseas denoted by destruction of intrahepatic bile ducts The main feature of PBC is a nonsuppurative destruction of small and medium-sized intrahepatic bile ducts. # Occurs mainly in middle-aged women, come in relation with other autoimmune diseases as celiac disease. portal inflammation and scarring, and the development of cirrhosis and liver failure over years to decades. # Pathogenesis – not clear but in ~ 90% of patient found high levels of Anti-mitochondrial antibodies. Recently it had been suggested that Exposure to certain xenobiotics may contribute to modification of mitochondrial proteins => leads to decrease in immunologic tolerance. (this may be the trigger for the immune response) # Morphology – » Dense lymphocytic infiltrate in portal tracts with granulomatous/non granulomatous destruction and loss of interlobular bile ducts, focal and variable within the liver parenchyma. » Florid duct lesion: interlobular bile ducts are destroyed by poorly formed portal epithelioid granulomas, lymphocytes, plasma cells and macrophages » Portal tracts upstream from the damaged bile ducts show proliferation and inflammation + Necrosis of the adjacent periportal parenchyma  cause portal-portal septal fibrosis. » 2 path for End-stage liver disease: both taking years to evolve) 1. Portal hypertension leading to Nodular regenerative hyperplasia- widespread nodularity without the surrounding scar tissue seen in cirrhosis the nodular hyperplasia => hepatomegaly 2. Widespread duct loss leading to: Chronic Cholestasis (* The bile accumulation is not centrilobular, as in drug-induced or sepsis-associated cholestatic syndromes but is periportal/periseptal!) over years may lead to Cirrhosis  Mallory denk bodies (differ by their periportal rather than centrilobular location as in alcoholic hepatitis.)  Vivid green discoloration. Secondary biliary cirrhosis Occur when the accumulation of bile come secondary to identifiable reason for the Prolonged obstruction of the extrahepatic biliary tree which results in profound damage to the liver and cirrhosis . The most Common cause of obstruction is extrahepatic cholelithiasis. Other obstructive conditions include biliary atresia (discussed later on), malignancies of the biliary tree and head of the pancreas etc… The initial damage of cholestasis entirely reversible However, secondary inflammation resulting from biliary obstruction initiates periportal fibrogenesis, which eventually leads to scarring and nodule formation, generating secondary biliary cirrhosis. PRIMARY SCLEROSING CHOLANGITIS # A chronic cholestatic disorder, characterized by progressive fibrosis and destruction of extrahepatic and intrahepatic bile ducts of all sizes. # More common in middle-aged men. # Pathogenesis – Cause is unknown (idiopathic) but associated with inflammatory bowel disease, mainly ulcerative colitis. Often patient present with P-ANCA ABs …. # Morphology – » Changes in the ducts are patchy => shows "beading" of affected segments due to narrow strictures alternating with normal sized or dilated ducts. » Extrahepatic ducts + large intrahepatic ducts => chronic inflammation with superimposed acute inflammation => edema + scaring => narrowing. » Smaller ducts => Circumferential fibrosis= Onion skinning with little inflammation => lumen disappears leaving just scar tissue. » In response to duct loss, as in PBC, bile ductular proliferation, portal-portal septal fibrosis, and cirrhosis follow. # Symptoms – fatigue, pruritus (itching) and obstructive jaundice. Late complication –cirrhosis plus there is increased risk for cholangiocarcinoma.

Answer 105

CIRCULATORY DISORDERS # Grouped according to whether the blood flows into, though, or from the liver is impaired. IMPAIRED BLOOD FLOW INTO THE LIVER # Hepatic artery inflow » Occlusion of hepatic artery Does not usually produce ischemia due to dual blood supply(portal). » One exception => thrombosis of hepatic artery in transplanted liver => organ loss. » Localized parenchymal infarct may result from thrombosis/embolism/tumor/poly arthritis nodosa/sepsis leading to the occlusion of intrahepatic branch of the hepatic artery. # Portal vein obstruction and thrombosis » Occlusion of major branch/portal vain Produces abdominal pain, portal hypertension and its signs: ascites (fluid in peritoneal cavity), and esophageal varices (prone to rupture). » Acute obstruction also means => congestion of blood in the bowl => bowl infarction. » May arise from peritoneal sepsis, pancreatitis elicit splenic vein thrombosis that may propagates to the portal vein), and vascular invasion of cancer primary or secondary in the liver that occludes the vessel. » When acute intrahepatic obstruction of portal vein occur it does not cause ischemic infarction, but instead results in a demarcated area of red-blue discoloration (infarct of Zahn) => no necrosis, only hepatocellular atrophy and congested distended sinusoids. IMPAIRED BLOOD FLOW THROUGH THE LIVER # The most common intrahepatic cause of portal blood flow obstruction is cirrhosis. # Other causes for occlusion of the sinusoids - Sickle cell disease,DIC… # Passive congestion and centriolobular necrosis (note it caused by outflow obstruction!!!) » Right-sided cardiac dysfunction = congestion of the liver => if persistent centrilobular necrosis and uncommon complication of centrilobular fibrosis creating a kind of border mimic appearance of mini lobule around area of central vain (cardiac sclerosis). » Morphology –  Macro = enlarged and cyanotic liver, round edges. Nutmeg liver on cut surface see center mottalied red appearance of centrilobular hemorrhagic necrosis with pale periphery.  Micro = Nutmeg Liver centriolobular congested sinusoids, also necrotic hepatocytes # Peliosis hepatis - Primary sinusoidal dilation creating multiple blood filled cavities lesions. The exact mechanism is unknown but Associated with exposure to anabolic steroids, Lesions usually disappear after stopping the drug treatment. Risk to cause hemorrhage if rapture HEPATIC VEIN OUTFLOW OBSTRUCTION # Hepatic vein thrombosis (Budd-Chiari syndrome) » Budd Chiari syndrome relating to obstruction major by thrombosis of one or more major hepatic veins. Characterized by hepatomegaly, ascites and abdominal pain. » Associated with myeloproliferative disorders (polycythemia Vera especially), pregnancy and use of contraceptives, intra-abdominal cancers as hepatocellular carcinoma etc.(abscess/parasitic infection creating compressive mass in liver) » Other common reason for outflow obstruction is right sided heart failure ,more rear see IVC obstruction » Morphology – » Macro = liver is swollen congested, red-purple in color cyanotic? with tense capsule; » Micro = hepatic parenchyma shows centrilobular congestion and necrosis. # Sinusoidal obstruction syndrome » Caused by toxic injury to sinusoidal endothelium. Cells slough off and create emboli that block the blood flow. » Endothelial damage is accompanied by passage of blood cells into space of Disse, proliferation of Ito cells, and fibrosis of terminal branches of hepatic vein. » Seen mainly following 20-30 days after bone marrow transplantation, assumed to occur from chemotherapy injury to cell follow preparation for transplantation. » Clinically manifests as budd Chiari syndrome. TUMORS OF THE LIVER # The liver (as well as the lungs) are the visceral organs most often involved by metastatic cancers. # The most common hepatic neoplasms are metastatic carcinomas, (Most common- colon, lung & breast) # Primary hepatic malignancies are almost all hepatocellular carcinomas. BENIGN TUMORS 1. Cavernous Hemangioma- # Most common benign lesion # Lesions consist of endothelial-lined vascular channels and intervening stroma. # Red-blue, soft nodules, usually less than 2 cm in diameter, often directly beneath the capsule. 2. Von Meyenburg complexes # Also quite common Congenital bile duct hamartomas # Are usually isolated or present in small numbers.(if multiple may indicate polycystic liver disease and suspicion for occurrence of polycystic kidney disease is linked) # Containing bile ducts and collagenous stroma 3. Focal nodular hyperplasia # Localized, well demarcated lesion Poorly encapsulated lesion appearing in otherwise normal liver usually # Consists of hyperplastic hepatocyte nodules with a central fibrous scar. # No risk of malignancy. # It is not a true neoplasm but rather represents a response to abnormal vascular flow areas with/without blood supply. 4. Hepatic adenoma – # Benign Hepatocellular neoplasm that usually occurs in women using oral contraceptive pills (may regress upon stop pill use). # Well demarcated but un-encapsulated tumors up to 30 cm pale yellow to bile stained mass. # Composed of sheets and cords of cells that resemble hepatocytes in it no normal portal tracts and prominent neovascularization. # Significant neoplasm for 3 reasons: 1. When present as intrahepatic mass, may be mistaken for hepatocellular carcinoma. 2. Sub-capsular adenomas may rupture, causing life-threatening intra-abdominal hemorrhage. 3. Carry β-catenin mutations that increase the risk of developing cancer. Macro-regenerative nodules: Appear in cirrhotic liver. Larger than surrounding cirrhotic nodules, but no atypical features. Do not seem to be precursors for malignancy. PRECURSOR OF HEPATOCELLULAR CARCINOMA # The most common precursors are cellular changes and nodular lesions that are found in the setting of chronic liver disease, particularly chronic viral hepatitis, alcoholic liver disease, and metabolic disease. 1. Hepatocellular Dysplasia Two forms of hepatocellular dysplasia are recognized - most common in the setting of chronic viral hepatitis: # Large cell change = Very large hepatocytes with large pleomorphic nucleus, found scattered among normal hepatocytes = These cells are not believed to be on the pathway to malignant transformation ( serve as a marker for molecular change) # Small cell change = characterized by smaller-than-normal hepatocytes with normal-sized nuclei oval hyperchromatic nucleus. Situated in nodular clusters  considered to be directly premalignant. 2. Dysplastic nodules # Represent the major pathway to hepatocellular carcinoma in chronic liver disease. # Present In cirrhotic livers as larger size nodules 1-2 cm (instead of~ 0.5 cm) Encompass many adjacent hepatic lobules, without displacing all of the portal tracts. Hepatocytes in the nodules are highly proliferative with atypical features (pleomorphism, crowding). # High grade dysplastic lesions are considered precursors of hepatocellular cancers. HEPATOCELLULAR CARCINOMA # Most common type of primary liver cancer highly associated with liver viral chronic infections (HBV or HCV). # Pathogenesis – » Associated with viral infections (HBV or HCV), alcoholic cirrhosis and aflatoxin96 exposure. » Development of HCC is affected from many variables (age, gender, chemicals, viruses, hormones, alcohol and nutrition). » In most cases, HCC develops from small-cell, high-grade dysplastic nodules in cirrhotic liver => these are monoclonal and carry chromosomal aberrations. » Chronic inflammation may cause damage to DNA segments involved in tumor suppression (tp53), oncogene (beta catenin) and genes of DNA repair. These main contributors to the genetic instability leading to HCC- HCC usually presents with chromosomal abnormalities indicating for this instability. » HCC has a strong tendency for vascular invasion invade the portal vein and IVC. Extensive intrahepatic metastases are characteristic. # Morphology – » Macro = can appear as unifocal massive tumor or multifocal variable sized nodules, or diffusely infiltrative cancer. » Micro = range from well differentiated neoplastic cells to poorly differentiated lesions composed of multinucleated anaplastic giant cells. also, in more differentiated form intra cellular bile and pseudo canalicular structures recognized. » More soft tumor with minor stroma amount » Fibrolamellar carcinoma – a more rear variant of HCC that occurs in young adults without cirrhotic background/other risk factors in appearance resemble nodular hyperplasia including stromal fibrous bands- carry better prognosis. # Clinical features – rapid increase in liver size, sudden worsening of ascites, fever and pain (serology alpha fetoprotein in ~50% of patients). mainly radiologic screening of cirrhotic patients used to capture neoplastic lesions. TUMORS OF GALLBLADDER Keep in mind tumors of billery tract may extend to intra hepatic ducts and to liver parenchyma itself. CARCINOMA OF THE GALLBLADDER # Develops from the epithelial lining of the gallbladder, and is the most frequent tumor of the biliary tract. Vest majority are adenocarcinomas ~5% raise as SCC # Gallstones are present in 60%-90% of cases, causing recurrent trauma and chronic inflammation that may promote the development of cancer. # Morphology – may appear as Exophytic grows into the lumen as an irregular, cauliflower mass, while invading the underlying wall or Infiltrative (more common) – appears as poorly defined area of diffuse thickening of the gallbladder wall, which may evolve the entire gallbladder. # Clinical features – rarely detected in early stage by the time gallbladder carcinomas are detected, most have invaded the liver directly, or extended to the cystic duct => symptoms include abdominal pain, jaundice, anorexia, nausea and vomiting (similar to those of cholelithiasis – gallstones). CHOLANGIOCARCINOMA # Cholangiocarcinoma are adenocarcinomas that arise from the lining the intrahepatic and extrahepatic biliary ducts. # Extra hepatic (2/3) cholangiocarcinoma may develop at the hilum of the liver => Klatskin tumors, or more distally in the biliary tree. # Occurs mostly in individuals 50-70 years old. # Poor prognosis => cholangiocarcinoma is asymptomatic until late stages. # Morphology – » Well differentiated adenocarcinomas with abundant fibrous stroma => firm consistency. » Present clearly defined glandular and tubular structures lined by anaplastic cuboidal epithelial cells. » Because partial or complete obstruction of bile ducts rapidly leads to jaundice, extrahepatic biliary tumors tend to be relatively small at the time of diagnosis, whereas intrahepatic tumors may cause symptoms only when much of the liver is replaced by tumor. # Pathogenesis and clinical features – » All risk factors of cholangiocarcinoma cause chronic cholestasis and inflammation = promote mutation in cholengiocytes. » Intrahepatic cholangiocarcinoma may be manifested by the presence of a liver mass and nonspecific signs and symptoms. » Symptoms and signs arising from extrahepatic (jaundice, nausea and vomiting, and weight loss) result from biliary obstruction. » Several consistent genetic changes have been noted in these tumors, including activating mutations in the KRAS and BRAF oncogenes and loss-of-function mutations in the TP53 tumor suppressor gene.

Answer 106

CHOLANGITIS # Acute inflammation of the wall of the bile duct most commonly caused by bacterial infection of the normally sterile lumen. # It can result from any lesion that obstructs the bile flow, most commonly choldocholithiasis => presence of stones within the biliary tree. # Bacteria enter through the sphincter of Oddi rather than hematogenous route. # Ascending cholangitis – the tendency of bacteria, once within the biliary tree, to infect intrahepatic biliary ducts. # Pathogens – E. coli, Klebsiella, Clostridium, Bacteroides, or Enterobacter. # Symptoms – fever, chills, abdominal pain and jaundice. # Suppurative cholangitis- the most severe form in which purulent bile fills and distends bile ducts => risk of liver abscess formation. # Sepsis is the predominant risk. LIVER ABSCESSES # Result from parasitic infections (more common in developed countries), or from bacterial origin usually as complication of an infection elsewhere. # Organisms: 1. Amoebic parasites such as Entamoeba histolytica or echinococcos 2. Bacterial agents E.coli klebsiella pseudomonas # The organisms can reach the liver in one of the following pathways: » Ascending infections in the biliary tree (ascending cholangitis). » Vascular seeding (portal or arterial), mainly from the GI tract. » Direct invasion of the liver from a nearby source. » Penetrating injury. # Immune deficiency/old age is a common setting # Pyogenic hepatic abscesses can occur as solitary or multiple lesions, ranging from mm to cm. The abscess consists of liquefactive necrosis with abundant neutrophils. # Associated with fever, right upper quadrant pain and tender hepatomegaly. abscess may compress bile ducts /hepatic vains. CHOLECYSTITIS # Inflammation of the gallbladder, acute or chronic, almost always associated with gallstones. # Morphology – » Acute – gallbladder is enlarged serosa is covered by fibrin;in 90% cases stones obstruct the neck of the gallbladder or the cystic duct, with the lumen filled with bile containing fibrin, blood and pus (empyema of the gallbladder ). Mild cases the gallbladder wall is thickened and hyperemic. In more Severe cases the gallbladder is transformed into a green-black necrotic organ called gangrenous cholecystitis. Histo: inflammatory infiltrate-acute, congestion of b.v. , may see abscess formation or gangrenus necrosis of wall. » Chronic – changes are extremely variable, if no superimposed acute inflametion so micro only lymphocytes infiltration may be submucosa thickening from scarring but no rael change in gallbladder size. (ulcer is very rear) # Cholecystitis can be: » Acute calculous cholecystitis inflammation of the gallbladder that contains stones causing obstruction of the neck or cystic duct => the most common complication of gallstones => upon occumulation mucosal epithelium is exposed to direct detergent action of bile salts plus Distention and increased intraluminal pressure also may compromise blood flow to the mucosa. » These events occur in the absence of bacterial infection; only later may bacterial contamination develop in necrotized cells beckground » Clinical feature- severe pain in upper abdomen + right shoulder. Fever, nausea & leukocytosis. Conjugated hyperbilirubinemia . » Acute non-calculous cholecystitis = gallbladder inflammation WITHOUT stones, caused either by postoperative state, severe trauma, severe burns, or sepsis. » Chronic cholecystitis = almost always associated with gallstones, which DO NOT have a direct role in the initiation of inflammation, rather Supersaturation of bile predisposes the patient to both chronic inflammation and, in most instances, stone formation. » Unlike acute calculous cholecystitis, stone obstruction of gallbladder outflow in chronic cholecystitis is not a mast » Clinical feature- Recurrent attack of upper abdominal pain. With Nausea, vomiting, intolerance for fatty food. CHOLELITHIASIS # There are 2 main types of gallstones: » Cholesterol stones (80%) – contain crystalline cholesterol monohydrate. » Pigment stones – composed of bilirubin calcium salts. # Pathogenesis – Bile formation is the only significant pathway for elimination of excess cholesterol from the body, either as free cholesterol or as bile salts. Normal condition => cholesterol is aggregated with bile salts and lecithin to make it water soluble » When cholesterol exceeds the solubilization capacity of bile, and cannot remain dispersed and aggregates into solid crystals. » Gallstones formation is enhanced by:  Supersaturation of bile with cholesterol.  Hypomobility of the gallbladder (stasis)  Mucous hypersecretion to trap the crystals, and enhancing their aggregation into stones. » Pigment stones – unconjugated bilirubin increases the likelihood of pigment stone formation. (hemolytic anemia & infections of biliary tract) # Risk factors – » Age and gender – the chance of occurrence increases with age; more common in women. » Ethnic and geographic – more common in developed countries, and in Native Americans. » Heredity – family history of gallstones may increase the risk. » Environment – estrogen increases hepatic cholesterol uptake and synthesis. » Acquired disorders – any condition in which gallbladder motility is decreased => pregnancy, rapid weight loss and spinal cord injury # Morphology – » Cholesterol stones – arise only in the gallbladder, consist of 50%-100% cholesterol pale yellow with mostly cholesterol or gray till complete black upon calcium carbonate/ bilirubin in mix, and cannot be seen in radiography= radiolucent unless they consist sufficient calcium carbonate (20%). » Pigment stones – Can arise anywhere in the biliary tree Classified into brown/black in color, and mainly contain unconjugated bilirubin calcium salts .  Black stones = Sterlie gallbladder bile, small & numerous. (Radiopaque- due to high amount of calcium carbonate)  Brown stones = appear in intra/extra hepatic bile ducts, single/few in nomber.got more greasy sopelike consistency denoted from fatty acid salts -nonsterile (Radiolucent) # Clinical features – most individuals remain asymptomatic (70%-80%); symptoms include strong pain, constant or periodic, inflammation, empyema, perforation and fistula.

Answer 107

Note from topic 128 Maya TUMORS OF THE LIVER # The liver (as well as the lungs) are the visceral organs most often involved by metastatic cancers. # The most common hepatic neoplasms are metastatic carcinomas, (Most common- colon, lung & breast) # Primary hepatic malignancies are almost all hepatocellular carcinomas. BENIGN TUMORS 1. Cavernous Hemangioma- # Most common benign lesion # Lesions consist of endothelial-lined vascular channels and intervening stroma. # Red-blue, soft nodules, usually less than 2 cm in diameter, often directly beneath the capsule. 2. Von Meyenburg complexes # Also quite common Congenital bile duct hamartomas # Are usually isolated or present in small numbers.(if multiple may indicate polycystic liver disease and suspicion for occurrence of polycystic kidney disease is linked) # Containing bile ducts and collagenous stroma 3. Focal nodular hyperplasia # Localized, well demarcated lesion Poorly encapsulated lesion appearing in otherwise normal liver usually... # Consists of hyperplastic hepatocyte nodules with a central fibrous scar. # No risk of malignancy. # It is not a true neoplasm but rather represents a response to abnormal vascular flow areas with/without blood supply. 4. Hepatic adenoma – # Benign Hepatocellular neoplasm that usually occurs in women using oral contraceptive pills (may regress upon stop pill use). # Well demarcated but un-encapsulated tumors up to 30 cm pale yellow to bile stained mass. # Composed of sheets and cords of cells that resemble hepatocytes in it no normal portal tracts and prominent neovascularization. # Significant neoplasm for 3 reasons: 1. When present as intrahepatic mass, may be mistaken for hepatocellular carcinoma. 2. Sub-capsular adenomas may rupture, causing life-threatening intra-abdominal hemorrhage. 3. Carry β-catenin mutations that increase the risk of developing cancer. Macro-regenerative nodules: Appear in cirrhotic liver. Larger than surrounding cirrhotic nodules, but no atypical features. Do not seem to be precursors for malignancy. PRECURSOR OF HEPATOCELLULAR CARCINOMA # The most common precursors are cellular changes and nodular lesions that are found in the setting of chronic liver disease, particularly chronic viral hepatitis, alcoholic liver disease, and metabolic disease. 1. Hepatocellular Dysplasia Two forms of hepatocellular dysplasia are recognized - most common in the setting of chronic viral hepatitis: # Large cell change Very large hepatocytes with large pleomorphic nucleus, found scattered among normal hepatocytes  These cells are not believed to be on the pathway to malignant transformation ( serve as a marker for molecular change) # Small cell change characterized by smaller-than-normal hepatocytes with normal-sized nuclei oval hyperchromatic nucleus. Situated in nodular clusters  considered to be directly premalignant. 2. Dysplastic nodules # Represent the major pathway to hepatocellular carcinoma in chronic liver disease. # Present In cirrhotic livers as larger size nodules 1-2 cm (instead of~ 0.5 cm) Encompass many adjacent hepatic lobules, without displacing all of the portal tracts. Hepatocytes in the nodules are highly proliferative with atypical features (pleomorphism, crowding). # High grade dysplastic lesions are considered precursors of hepatocellular cancers. HEPATOCELLULAR CARCINOMA # Most common type of primary liver cancer highly associated with liver viral chronic infections (HBV or HCV). # Pathogenesis – » Associated with viral infections (HBV or HCV), alcoholic cirrhosis and aflatoxin exposure. » Development of HCC is affected from many variables (age, gender, chemicals, viruses, hormones, alcohol and nutrition). » In most cases, HCC develops from small-cell, high-grade dysplastic nodules in cirrhotic liver => these are monoclonal and carry chromosomal aberrations. » Chronic inflammation may cause damage to DNA segments involved in tumor suppression (tp53), oncogene (beta catenin) and genes of DNA repair. These main contributors to the genetic instability leading to HCC- HCC usually presents with chromosomal abnormalities indicating for this instability. » HCC has a strong tendency for vascular invasion invade the portal vein and IVC. Extensive intrahepatic metastases are characteristic. # Morphology – » Macro can appear as unifocal massive tumor or multifocal variable sized nodules, or diffusely infiltrative cancer. » Micro = range from well differentiated neoplastic cells to poorly differentiated lesions composed of multinucleated anaplastic giant cells. also, in more differentiated form intra cellular bile and pseudo canalicular structures recognized. » More soft tumor with minor stroma amount » Fibrolamellar carcinoma – a more rear variant of HCC that occurs in young adults without cirrhotic background/other risk factors in appearance resemble nodular hyperplasia including stromal fibrous bands- carry better prognosis. # Clinical features – rapid increase in liver size, sudden worsening of ascites, fever and pain (serology alpha fetoprotein in ~50% of patients). mainly radiologic screening of cirrhotic patients used to capture neoplastic lesions.

Answer 108

Pancreatitis- inflammation of pancreas range in severity from mild self-resolving to sever destructive event. Acute pancreatitis = function can return to normal if the underlying cause of inflammation is removed Chronic pancreatitis is defined by irreversible destruction of exocrine pancreatic parenchyma. ACUTE PANCREATITIS  Reversible relatively uncommon inflammatory disorder that varies in severity,  Etiology: Most of cases are attributable to either biliary tract disease or alcoholism. Genetic mutation = mutation in gene PRSS1 = no neg. feedback mechanism on trypsinogen = hyperactivation of trypsin + other enzymes that require trypsin cleavage for their activation. 20% idiopathic  Morphology o The basic alterations in acute pancreatitis are: (1) Microvascular leakage causing edema (2) Necrosis of fat by lipases (3) Acute inflammatory reaction (4) Proteolytic destruction of pancreatic parenchyma (5) Destruction of blood vessels leading to interstitial hemorrhage. o Mild form = Edema + Fat necrosis  Fat necrosis results from enzymatic destruction of fat cells; the released fatty acids combine with calcium to form insoluble salts that precipitate in situ. o Severe form (ex. acute necrotizing pancreatitis) necrosis of pancreatic parenchyma + vascular damage (cause hemorrhage).  Macro = red-black hemorrhagic areas interspersed with foci of yellow-white, chalky fat necrosis. o Most severe form= hemorrhagic pancreatitis = extensive parenchymal necrosis is accompanied by diffuse hemorrhage within the substance of the gland.  Pathogenesis o Autodigestion of the pancreatic substance by inappropriately activated pancreatic enzymes. Activation of trypsin is a critical triggering event in acute pancreatitis as it can activate itself as well as other proenzymes (lots of pancreatic enzymes need cleavage for activation) autodigestion. Trypsin activates the kinin system activation of the clotting and complement systems. 3 pathways can cause enzyme activation: 1. Pancreatic duct obstruction (gallstone, tumor)  blockage of ductal flow=> increase intraductal pressure => accumulation of enzyme rich interstitial fluid (containing active lipase) => fat necrosis => inflammation => interstitial edema => edema compromises local blood flow => ischemic injury to acinar cells. 2. Primary acinar cell injury => ischemia, viral infections (e.g., mumps), drugs, and direct trauma to the pancreas. 3. Defective transport of proenzymes within acinar cells in animal shown that metabolic derangements contribute to abnormal transport of enzymes together with lysosomal hydrolases result in activation. Role of alcohol in acute pancreatitis: 1. Increases pancreatic exocrine secretion Increases contraction of sphincter of oddi. 2. Direct toxic effect on acinar cells oxidative stress and membrane damage. 3. Chronic ingestion results in secretion of protein rich fluid that causes obstruction of small pancreatic ducts.  Clinical feature: o Abdominal pain is the major manifestation of acute pancreatitis. o Full-blown acute pancreatitis constitutes a medical emergency. o The manifestations of severe acute pancreatitis are attributable to systemic release of digestive enzymes and explosive activation of the inflammatory response: Leukocytosis, DIC, ARDS (acute res. Distress syndrome) & diffuse fat necrosis. o Can lead to shock  Pancreatic pseudocyst Liquefied areas of necrotic pancreatic tissue become walled off by fibrous tissue to form a cystic space, lacking an epithelial lining CHRONIC PANCREATITIS  Long-standing inflammation, fibrosis, and destruction of the exocrine pancreas. In late stages, the endocrine parenchyma also is lost.  The chief distinction between acute and chronic pancreatitis is the irreversible impairment in pancreatic function in the chronic state.  Etiology: o The most common cause of chronic pancreatitis is long-term alcohol abuse. o Less common:  Pancreatic duct obstruction (tumor/stone…)  Hereditary pancreatitis (PRRS1)  Associated with CFTR mutation => decreases bicarbonate secretion = > increase viscosity of secretion => plugging.  Morphology: o Parenchymal fibrosis, reduced number and size of acini, and variable dilation of the pancreatic ducts. The ductal epithelium may be atrophied / hyperplastic .Islets of Langerhans fused surrounded by sclerotic aggregates. o Macro= the gland is hard, sometimes with extremely dilated ducts and visible calcified concretions. o Autoimmune pancreatitis (AIP)- distinct form of chronic pancreatitis:  Lymphoplasmacytic sclerosing pancreatitis-striking lymphocytes and plasma cells infiltrate plus fibrosis  Idiopathic duct centric pancreatitis-mixed neutrophils and lymphcytic infiltrate obliterating the duct epithel.  Pathogenesis: Not well defined. Proposed hypotheses: o Ductal obstruction: Alcohol => inc. protein conc. of secretion => plugs. o Toxins: direct toxic effect injury to acinar cells and following inflammation /fibrosis. o Oxidative stress: Alcohol generates ROS => membrane damage and chemokines expression  recruit inflammatory cells. (more oxidative stress assume to cause lysosomal and proenzymes granules fusion subsequent enzyme activation and aggrevation of cell damage)  Clinical feature: o Severe pancreatic exocrine insufficiency and chronic malabsorption may develop, as can diabetes mellitus. o Severe chronic pain may dominate the clinical picture

Answer 109

Pancreatic exocrine neoplasm can be cystic or solid. They can be benign or malignant. 1. Cystic neoplasm-5% OF ALL PANCREATIC TUMORS a. Serous cystadenomas i. Composed of glycogen rich cuboidal cells surrounding small cysts containing clear' strew-colored fluid. ii. More common in females and in the seventh decade of life. Almost uniformly benign and curable by removed surgically. iii. Associated with somatic mutation of the von hipple-lindau tumor suppressor gene which its product binds to hypoxia induced factor alpha-1 and results in its degradation. b. Mucinous cystic neoplasm i. Vest majority raise in women In the body or tail of pancreas Present as painless, slow growing mass. ii. Cyst space is large and filled with steaky-viscose mucin walls are lined by columnar mucinous epithelium with an associated densely cellular stroma (similar to ovary). iii. Benign ones categorized by degree of dysplasia (cellular and architectural abnormalities) into “mucinous cystic neoplasm with low-grade dysplasia," "mucinous cystic neoplasm with moderate dysplasia," and "mucinous cystic neoplasm with high-grade dysplasia." These are all curable when completely removed surgically. iv. About a third of mucinous cystic neoplasms have progress to malignant invasive type these are designated as “mucinous cystic neoplasm with an associated invasive carcinoma." c. Intraductal papillary mucinous neoplasm i. Intraductal papillary mucinous neoplasms are tumors (neoplasms) that grow within the pancreatic ducts (intraductal) characterized by the production of thick fluid by the tumor cells (mucinous). ii. Arise in the main pancreatic duct or its major branches as papillary tumor distending the lumen histologically look as Cyst containing mucin lack the cellular stroma seen in mucinous cystic neoplasm iii. Again if benign categoriesed by severity of dysplasia and malignant said to be associated with adenocarcinoma component. iv. Unlike other cystic tumor they More frequent in males and more Frequently involved the head of pancreas(not tail as former 2. Pancreatic neoplasma. adenocarcinoma arising from pancreatic ducts: i. very high mortality rate ii. Most common seen in older age around 70 iii. Risk factor- smoking (double the risk), chronic pancreatitis and diabetes mellitus b. Pathogenesis i. As all cancers it’s a genetic disease arising as a consequence of inherited and acquired mutations in cancer associated genes. There is a progressive accumulation of genetic changes in pancreatic epithelium as it proceeds from non-neoplastic, to noninvasive lesion in small ducts and ductules to invasive carcinoma. ii. Three morphologic forms of non-invasive pancreatic neoplasia have been defined all may progress to carcinoma (pancreatic intraepithelial neoplasia (PanIN), mucinous cystic neoplasm (MCN) and intraductal papillary mucinous neoplasm (IPMN)). pancreatic intraepithelial neoplasia is the most potent of these to do this progress. Its an small papillary lesion ~1/2 cm raise in small pancreatic ducts, found next to carcinoma lesion and share similar genes mutations with it (all such lesions has dramatic telomerase shortening…) iii. Four genes are most commonly affected by somatic mutation of this neoplasm : K-RAS- GTPase found in vast majority of pancreatic cancers ,P16 , SMAD4 and P-53 also frequent involved genes. iv. The progression from normal ducts to pancreatic intraepithelial neoplasia is associated with both architectural and cytological changes. In PanIN-1 the nuclei are uniform and basally oriented the nuclei in PanIN-2 are slightly larger, more basophilic and there is some loss of nuclear polarity the nuclear pleomorphism in PanIN-3 can be significant. c. Presentation -signs and symptoms tend to appear only late in the course i. Abdominal pain epigastric plus weight loss. 1. Diabetics – mainly if tumor in the body/tail where islets are prominant ii. Obstructive jaundice – Most carcinoma of the head obstructs the distal common bile duct as it courses through the head of the pancreas. iii. Pancreatitis iv. ~10% may present with migratory thrombophlebitis (The Trousseau sign) medical sign rare variant of venous thromboembolism (VTE) that is characterized by recurrent, migratory thrombosis in superficial veins and in uncommon sites, such as the chest wall and arms. This syndrome is particularly associated with pancreatic and lung cancer. d. Morphology i. Site: pancreatic head (60%), body (15%), tail (5%), diffuse involves the entire organ (20%) as hard greyish white masses poorly definde ii. Pancreatic cancer highly invasive metastasize to nearby organs Distant metastases to lung and bone iii. Micro Seen as poorly formed glands surround by dens fibrotic stromadesmoplasia iv. Less common variant of pancreatic cancer Adensquamous carcinomas (with squamous cells) or Undifferentiated carcinoma with osteoclast-like giant cell ( with monocyte linage cells) e. Screening- endoscopic US and CT Treatment: surgical excision (whipple procedure) Prognosis: very poor 1 year survival rate Tumor markers: CEA and CA19-9 (not specific and not sensitive) Pancreatic neuroendocrine tumors1. Pancreatic neuroendocrine tumors (also known as islet cell tumors or islet cell carcinoma) are a type of neuroendocrine tumor found in the pancreas. Only 2 percent of pancreatic tumors arise in the islet cells. The vast majority of tumors found in the pancreas are adenocarcinoma. 2. All PanNET, except insulinoma, are regarded as having malignant potential. if they are malignant, the liver is the most common site of metastasis Proliferative rate is one of the best correlates to outcome 3. Genomic sequencing of sporadic PanNet has identified recurrent alteration genes a. MEN1-(multiple endocrine neoplasia type 1) b. Loss of function mutation in tumor suppressor genes such as PTEN which is a negative regulators of oncogenic TOR signaling pathway 4. Insulinoma (b-cell tumor) a. Most common type of islet cell tumor b. Tumor produces insulin - major symptom is Hypoglycemia (which occurs when plasma glucose level falls below 50 mg/dL) , sweating, hunger, confusion, insulin come Lab: elevated insulin and C-peptides c. As no malignant potential Most insulinomas are cured by surgical resection d. Morphology i. Majority are identified while they are small (less than 2 cm diameter) and localized to the pancreas Most are solitary lesions ii. Hitologically- Benign tumor looks like giant islets do not present much evidence of anaplasia and they may be deceptively encapsulated. 1. Deposition of amyloid (of amylin) in the EX tissue is a characteristic feature 2. Under EM, neoplastic b-cells, like their normal counterparts, display distinctive round granules. Gastrinoma (g-cell tumor) iii. Tumor produces gastrin and classicaly present as Zollinger-Ellison syndrome 1. Elevated serum gastrin 2. Gastric hyperacidity 3. Intractable peptic ulcer which may also occur in unusual locations such as the jejunum iv. May also arise outside the pancreas duodenum v. Gastrinomas can occur as isolated, sporadic neoplasms or as multiple, MEN-1 associated neoplasms vi. Morphology 1. Over half of gastrin-producing tumors are locally invasive or have already metastasized at the time of the diagnosis. 2. Gastin producing tumors are histologically bland and rarely exhibit marked anaplaisa Glucagonoma (alpha-cell tumor) vii. Glucagonomas are typically large and occur almost entirely within the pancreas. Glucagonomas secrete excessive amounts of glucagon, causing glucose intolerance, weight loss, and a pathognomonic rash known as necrolytic migratory erythema. Hyperglycemia (diabetes), anemia and skin rash Somatostatinoma viii. Tumor produces somatostatin Somatostatin inhibits 1. Insulin secretion = diabetes 2. Gastric secretion = hypochlorhydria 3. Cholecystokinin secretion = gallstone and steatorrhea VIPoma ix. Tumor produces vasoactive intestinal peoptide x. WDHA syndrome: watery diarrhea, hypokalemia and acholohydria With respect to the digestive system, VIP seems to induce smooth muscle relaxation (lower esophageal sphincter, stomach, and gallbladder), stimulate secretion of water into pancreatic juice and bile stimulating pancreatic bicarbonate secretion, and cause inhibiting gastrinstimulated gastric acid secretion also dilating peripheral blood vessels

Answer 110

damages of hyperglycemia 1. Non-enzymatic glycosylation Collagen glycosylation – advanced glycosylation end products (AGE) - vessels + interstitium - Extracellular matrix and cell surface proteins – polypeptide cross-links - Trapping of LDL and cholesterol – atherosclerosis - Glycosylated BM binds albumin – glomerular disease - diabetic nephropathy - Other plasma proteins with AGE residues bind to endothel, mesangium, macropahes – activation - Endothel: increase in permeability and coagulation - Fibroblast: proliferation - Macrophage: inflammation 2. Activation of protein kinase C (PKC) increase of VEGF – synthesis of matrix/BM 3. Intracellular hyperglycaemia Cell types not requiring insulin for glucose uptake affected (nerve, lens, kidney, endothel) Intracellular increase of osmolarity + oxydative stress Alternative glucose metabolism: sorbitol, polyol, fructose Important morphologic changes are related to late complications Pancreas » Reduction in the number and size of islets – mostly in type I DM » Leukocytic infiltration of the islets – mainly mononuclear cells (lymphocytes and macrophages). Appears in type I and II, early in the disease, by time of clinical evidence, inflammation is absent » Amyloid replacement of islets in long standing DM-II – deposition of pink, amorphous material in capillaries and between cells. At advanced stages, islets are obliterated; fibrosis may also be observed » An increase in the number and size of islets, especially in non-diabetic newborns of diabetic mothers – islets undergo hyperplasia. Vascular system » Diabetis macrovascular disease – accelerated atherosclerosis affecting aorta and medium-sized arteries. Most common cause of death – myocardial infarction. » gangrenes of the lower extremities 100x more frequent (diabetic foot) » narrowing of the renal artery although The Most damaging effect on kidney is at the level of the glomeruli and microcirculation » How its promote atherosclerosis? AGEs- advanced glycation end products, can induce crosslinking of collagen in b.v. BM which can cause vascular stiffening and entrapment of low-density lipoprotein particles (LDL) in the artery walls. AGEs can also cause glycation of LDL which can promote its oxidation . Oxidized LDL is one of the major factors in the development of atherosclerosis. Finally, AGEs can bind to RAGE (receptor for advanced glycation end products) and cause oxidative stress as well as activation of inflammatory pathways in vascular endothelial cells. Microangiopathy underlies the development of nephropathy, retinopathy and neuropathy. » Hyaline arteriosclerosis – vascular lesions associated with hypertension; amorphous hyaline thickening of the wall of arterioles = narrowing of the lumen ,appear more sever and with highr prevalence in diabetic patients » Diabetic microangiopathy – diffuse thickening of the BM97; most evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli and renal medulla; may also appear in renak tubules, peripheral nerves and placenta. despite the increase in thickness, capillaries are more leaky to plasma proteins. Diabetic nephropathy » Second cause of death, after MI is renal failure In diabetes, basement membranes of majority of capillaries in the body are thickened by deposits of nonenzymatic glycosilated proteins (diabetic microangiopathy): retinopathy, coronary arteries, and peripheral vessels. » In kidney, diabetic nephropathy includes : diabetic glomerulosclerosis, arteriolosclerosis and papillary necrosis, with an increased risk for pyelonephritis. » Diabetic nephropathy :  Recurrent pyelonephritis is an acute or chronic inflammation of the kidney, usually begins in the interstitial tissue and spreads to involve the tubules; special pattern of acute pyelonephritis is necrotizing papillitis (papillary necrosis).  Arterio/arteriolosclerosis hyaline arteriosclerosis affect afferent and efferent arterioles may elicit hypertension Involvement of renal arterioles leads to glomerulosclerosis, resulting in small, scarred kidneys with granular surface Preferential involvement of efferent arterioles leads to glomerular Hyper hit ration injury with microalbuminuria that eventually progresses to nephrotic syndrome; characterized by Kimmelstiel-Wilson nodules in glomeruli  Glomerulopathy – Diabetic glomerulosclerosis is characterized by thickening of glomerular basement membrane with increased permeability. With time, the mesangial space becomes larger by deposits of proteins (collagen IV) Diffuse BM thickening -(electron microscopy) –The deposits appear diffusely on the basement membranes of capillary loops of the glomeruli, as well as on basement membranes of tubules and arterioles. Nodular glomerulosclerosis (in 30% of DM)-In nodular diabetic glomerulosclerosis, PAS-positive nodular deposits ( hyaline-containing mucopolysaccharides, fibrils and collagen) may appear in the mesangial space, at the periphery of the glomerulus, pushing the capillaries. The lesion is focal to periphery. This pattern is also called Kimmelstiel-Wilson lesion. see in long standing diabetes may propgate to Diffuse diabetic glomerulosclerosis and chronic renal failure Ocular complications Retinopathy -potentially most blinding of these complications, however, is diabetic retinopathy which is, in fact, the leading cause of new blindness in persons aged 25-74 years in the United States o non-proliferative: microangiopathy, aneurysms, hemorrhage, exudate A persistent increase in blood glucose levels shunts excess glucose into the aldose reductase pathway in certain tissues, which converts sugars into alcohol (eg, glucose into sorbitol, galactose to dulcitol). Intramural pericytes of retinal capillaries seem to be affected by this increased level of sorbitol, eventually leading to the loss of their primary function (ie, autoregulation of retinal capillaries). This results in weakness and eventual saccular outpouching of capillary walls. These microaneurysms, are the earliest detectable signs of DM retinopathy. o proliferative: angiogenesis, fibrosis – retinal detachment More advanced retinal disease, including proliferative vascular changes and neovascularization in the setting of retinal ischemia retinal ischemia/hypoxia and subsequent release of an angiogenesis factor (eg, vascular endothelial growth factor [VEGF]), may be mediated by other mechanisms such as the action of vasoactive substances released during the inflammatory process. these new blood vessels can bleed, cloud vision, and destroy the retina. Fibrovascular proliferation can also cause tractional retinal detachment.. Cataract- It has been shown that the intracellular accumulation of sorbitol leads to osmotic changes resulting in hydropic lens fibers that degenerate and form sugar cataracts. The lens is composed of specialized proteins (called crystallins), whose optical properties are dependent on the fine arrangement of their three-dimensional structure and hydration * Glaucoma - Glaucoma is a group of eye diseases which Defined as optic neuropathy with distinct excavation of optic nerve head and incremental loss of visual field. Almost always due to increased intraocular pressure (due to impaired outflow of aqueous humor), which causes optic nerve damage and degenerative changes below in the proliferative retinopathies The new blood vessels can also grow into the angle of the anterior chamber of the eye and cause neovascular glaucoma . Aqueous humor is produced by pars plicata of ciliary body, discharged into posterior chamber, flows between lens and iris, through pupil, into anterior chamber, then through trabecular meshwork (in deep layers of peripheral cornea just in front of angle of anterior chamber), into Schlemm's canal, leaves eye via plexus of intrascleral and episcleral veins along limbus #Diabetic neuropathy » Peripheral nerve involvement, symmetric neuropathy of lower extremities affecting both motor and sensory function. Other form may be autonomic neuropathy – disturbance in bowel and bladder function, and sometimes sexual impotence » Diabetic Microangiopathy + direct toxic effects (sorbitol) Glucose freely enters into Schwann cells (which myelinate peripheral nerves), Aldose reductase converts glucose to sorbitol, resulting in osmotic damage. Diabetes mellitus a group of metabolic disorders all marked by hyperglycemia –normal Blood glucose 5.0-7.2mmol/l (90-130mg/dl). Insulin release and synthesis upon elevation of blood glucose by the beta cells in center of islets of Langerhans Glucagon is secreted by alpha cells; it opposes insulin in order to increase blood glucose levels (e.g., in states of fasting) and act via glycogenolysis and lipolysis Major anabolic hormone; upregulates insulin-dependent glucose transporter protein (G1.UT4) on skeletal muscle, liver cell and adipose tissue (glucose uptake by GLUT4 decreases serum glucose ,)Increased glucose uptake by tissues leads to increased glycogen synthesis, protein synthesis, and lipogenesis, Diagnosis: A .Random blood glucose concentration of 200 mg/dL or higher with classical signs and symptoms B. fasting glucose >126 mg/dL on at least two separate occasion C .a positive glucose tolerance test-give ~75g carbohydrate load and see after 2hr blood gluc. Level if 200mg\dL or more diabitis D. Measurement of glycosylated hemoglobin (HbA1c) is an excellent measurement of long term exposure (2-3 months/120 days) to hyperglycemia. It is relatively unaffected by day to day variation. IDDM (Type 1) 10% of all DM: childhood onset – progression with age, preexistence for many years without symptoms autoantibodies in 70-80% of patients against insulin or antiglutamate-dehydrogenase(b cell enzyme) are often present and may be seen years before clinical disease develops. considered to have an autoimmune aetiology in which the pancreatic β-cells are selectively destroyed by immune cells infiltrating islets (insulitis) Autoreactive T-lymphocytes against ßcell antigens, Th1 – macrophage activation, cytotoxic T-cells = insulitis Th1 cytokines, including IFN-γ, exerted their effects primarily at the level of macrophage and CD8+ T-cell activation, enhancing infiltration of these cells into the islets, thus accelerating β-cell destruction hence characteristic morphology of prominent reduction in number n size of islets together with sever inflammatory infiltrate of lymphocytes and macrophages. Associated with HLA-DR3 and HLA-DR4 Manifests in childhood /adolescences with clinical features of insulin deficiency High serum glucose-Weight loss, low muscle mass, Polyuria, polydipsia osmotic diuresis. Treatment involves lifelong insulin. Risk for diabetic ketoacidosis excessive serum ketosis Often arises with stress Liver converts FFAs to ketone bodies (|3-hydroxybutyric acid and acetoacetic acid). anion gap metabolic acidosis, and hyperkalemia Presents with Kussmaul respirations, dehydration, nausea, vomiting, mental status changes, and fruity smelling breath (due to acetone) Type 2 diabitis End-organ insulin resistance leading to a metabolic disorder characterized by Hyperglycemia Most common type of diabetes (90% of cases} Arises in middle-aged, obese adults 1. Obesity leads to decreased numbers of insulin receptors. measured by body mass index (BMI= weight/lenght2) - lifestyle: food intake ↑ - free fatty acids ↑ : inhibits insulin signaling in muscle and liver = lipotoxicity! - fat tissue – proteins with endocrine effect = adipokines (e.g. adiponectin pro insulin type ) PPARgamma: nuclear receptor and transcription factor – activation triggers the effect of insulin signaling in fat tissue 2. Strong genetic predisposition exists. Insulin levels are increased early in disease, but later, insulin deficiency develops due to beta cell exhaustion; histology reveals decrease in ß-cell mass: islet degeneration + amyloidosis (amylin is 90% detectable) Treatment involves weight loss (diet and exercise) initially High glucose (> 500 mg/dL) leads to life-threatening diuresiswith hypotension and coma. Ketones are absent due to small amounts of circulating insulin

Answer 111

1. scrotal enlargement a. Hydrocele: due to accumulation of serous fluid within tunica vaginalis (serous membrane that covers the testicle as well as the internal surface of the scrotum.) i. May arise in response to 1. neighboring infection 2. tumor/ blockage of lymphatic drainage- Chyloceles Elephantiasis (adults) 3. idiopathic 4. Associated with incomplete closure of the processes vaginalis leading to communication with the peritoneal! Cavity (infants) ii. may be distinguished from collection of blood, pus, lymph by allowing a beam of light to pass through b. Hematocele: accumulation of blood in tunica vaginalis 2. Inflammatory lesions : orchitic (inflammation of the testicle) a. More common in the epididymis than in testis proper. b. Nonspecific epididymitis and i. Usually begins as a primary UTI (e. coli, pseudomonas) that spread into testis through vas deference or the lymphatics of the spermatic cord. Involved testis swollen and tender and contains predominantly neutrophils infiltrate. ii. Chlamydia trachomatis (serotypes D-K) or Neisseria gonorrhoeae—seen in young adults. c. Mumps orchitis infection i. Infections are complicated by orchitis in roughly 20 % of infected adult males. Affected testis is edematous and congested and contains predominantly lymphoplasmacytic infiltrate. ii. Severe infection may lead to necrosis, loss of seminiferous epithelium, tubular atrophy, fibrosis and sterility. d. Testicular tuberculosis i. Begins as epididymitis with secondary involvement of testis histologicallygranulomatous inflammation and caseous necrosis. ii. Autoimmune orchitis also create granulomatous inflammation — characterized by granulomas involving the seminiferous tubules. 3. Testicular torsion a. Twisting of the spermatic cord; thin-walled veins become obstructed (while thick wall artery remain open)leading to congestion and hemorrhagic infarction b. Intense vascular engorgement and venous infarction follow unless torsion in relieved, Medical emergency-surgery. c. Two types of testicular torsion i. Neonatal torsion Occurs in utero or shortly after birth ii. Adult torsion Typically Seen in adolescence Manifest with sudden onset pain no related previous injury. Result from bilateral anatomic defect whereby testis lack of posterior adherence to inner wall of scrotum can turn around themselves twisting vas deference- increased mobility the abnormal anatomy named bell clapper anomality tunica vaginalis completely enclose testis. VARICOCELE A. Dilation of the spermatic vein due to impaired drainage Presents as scrotal swelling with a dilated veins appearance B. Usually left sided; left testicular vein drains into the left renal vein, while the right testicular vein drains directly into the IVC - Associated with left-sided renal cell carcinoma; RCC often invades the renal vein. c. Seen in a large percentage of infertile males 4. Cryptorchidism a. Failure of one or both testes to descend is known as cryptorchidism, normally testis descend from abdominal cavity into pelvis by the third month and then through the inguinal canal into scrotum during the last 2 month of intrauterine life. b. Diagnosis establish at age of 1 in ~ 1% of male babies most cases resolve spontaneously; otherwise, orchiopexy is performed before 2 years of age. i. Testes are most commonly found in inguinal canal ii. Undescended testes becomes atrophic with time. 1. Tubular atrophy is evident at age of 5-6 2. Hyalinization is present by time of puberty. 3. Foci of intratubular germ cell neoplasia may be present iii. Cause is unknown but there is Increased risk infertility and for developing testicular cancer effecting both testis even in unilateral condition.

Answer 112

1. Malformation- The most common malformation of the penis includes abnormalities of the distal urethral orifice. i.Hypospadias - Abnormal opening of urethra is on the ventral aspect of the penis anywhere along the shaft. Occur in 1 in 300 male birth 1. It results from incomplete closure of the urethral folds of urogenital sinus 2. Anomalous urethral orifice is sometimes constricted, resulting in urinary tract obstruction and increase risk of UTI 3. Associated with other congenital anomalies such as inguinal hernia and undescended testicles ii.Epispadiasis - Less common than hypospadias Abnormal urethral orifice is on the dorsal aspect of the penis 2. Phimosis- is a condition in which the foreskin of the penis cannot be pulled back past the glans. May result in pain during an erection, but otherwise not painful. Those affected are at greater risk of inflammation of the glans, known as balanitis, and other complications. May result from Congenital anomaly or Acquired- scaring of prepuce secondary to previous episode of balanoposthitis . 3. Inflammatory lesions a. Balanitis – local inflammation of the glans penis b. balanoposthitis – local inflammation of the overlying prepuce c. Most common agents – candida albicans, anaerobic bacteria, gardnerella, and pyogenic bacteria d. Consequences of poor hygiene in uncircumcised males, with accumulations of desquamated epithelial cells, sweat, and debris (termed smegma) acting as local irritants. 4. Neoplasmsa. Squamous cell carcinoma i.More than 95% of penile neoplasm arise on squamous epithelium Occur at the glance or shaft of the pines as ulcerated infiltrate lesion ii.More common in developing countries. Increased risk in uncircumcised males older than 40 iii.Risk factors: 1. Human papilloma virus (HPV) serotype 16 and 18 2. Poor hygiene 3. smoking v.Squamous cell carcinoma in situ of the penis (Bowen disease) occurs in older uncircumcised males and appears grossly as a solitary plaque on the shaft of the penis. Histologic The epithelium is above intact basement membrane and shows dysplasia, several mitotic figures, dyskeratosis and nuclear pleomorphism. v.Invasive squamous cell carcinoma of the penis appears as a gray, crusted, papular lesion, most commonly on the glans penis or prepuce. In many cases, infiltration of the underlying connective tissue produces an ulcerated lesion with irregular margins histologically, it is a typical keratinizing squamous cell carcinoma. The Prognosis is related to stage of tumor, may metastasize to inguinal lymph node. Verrucous carcinoma is a variant of squamous cell carcinoma characterized by a papillary architecture, virtually no cytologic atypia, and rounded, pushing deep margins. Verrucous carcinomas are locally invasive but do not metastasize.

Answer 113

1. Heterogeneous group of neoplasms may be divided into 2 major groups a. Germ cell tumor - ~95% of cases all malignant, usually occur between 15-40years of age b. Sex cord- stromal tumor (Sertoli or Leydig cells) - uncommon usually benign. 2. Cause of testicular neoplasm remains unknown. Risk Factor: a. Cryptorchidism (3-5 fold increase) b. Testicular dysgenesis (testicular feminization and Klinefelter syndrome) c. Caucasians > African Americans d. Family history e. An isochromosome of the short arm of chromosome 12 is found in all germ cell tumors. f. Most testicular tumors in post pubertal males arise from the in-site lesion intratubular germ cell neoplasm- Lesion can be found in grossly normal testicular tissue adjacent to germ cell tumors in all cases 3. Clinical presentation Firm, painless testicular mass Semonimas - Account for 50% of testicular neoplasm remain confined to the testis for a long time Spread mainly to paraarotic nodes- distant spread is rare. Non seminomatous – tumor Tend to spread earlier by both lymph and blood vessels Treatment: Radical orchiectomy and Chemotherapy 4. Germ cell tumors- although described separately As many as 60% of germ cell tumors are mixed and contain more than one component, tumors arising from pluripotent neoplastic germ cells. a. Seminoma- most common testicular cancer, good prognosis late metastasis react to treatment i. Gross: Soft, well-demarcated, gray-white tumor cut surface is homogenous no hemorrhage or necrosis ii. Micro Large polygonal, uniform cells with distinct border Clear, glycogen-rich cytoplasm Round nuclei and visible nucleoli (resembles ovarian dysgerminoma) Arranged in small lobules, which are separated by fibrous septae in it may see Lymphocytic infiltrate Variant; spermatocytic seminoma a. affect older men lack lymphocytic infiltrate and syncytiotrophoblasts b. Not associated with intralobular germ cell neoplasm Do not metastasize iii. In 10% of cases, syncytiotrophoblast are present that are the source of minimally elevated serum hCG concentration b. Embryonal carcinoma more rear 2-3% poor prognosis early metastasis poor reaction to treatment 1. Common appear at Age 20-30,malignant tumor comprised of immature, primitive cells. 2. Gross: mass with hemorrhage and necrosis Micro: large primitive appearing cells with basophilic cytoplasm Indistinct cell borders and large hyperchromatic nuclei with prominent nucleoli. Pleomorphic cells in cords, sheets or gland like arrangement. 3. Tumor markers: Negative (pure embryonal carcinoma) but in many cases tumor is mixed with choriocarcinoma or yolk sac tumor cells, so their markers may appear. c. Choriocarcinoma 1. Highly malignant with early hematogenous metastases most common in the liver and the lung. 2. Common appear at age of 20-30 in tumor see trophoblastic linageplacenta forming cells. 3. Gross: often small, non-palpable lesions with hemorrhage on cut surface, in compare to large metastatic centers it creates in different locations Micro: proliferation of syncytiotrophoblasts large eosinophilic multinucleated cells pleomorphic nucleus intermingle with small cuboidal cytotrophoblasts. 4. Tumor marker- hCG d. Yolk sac tumor (endodermal sinus tumor) 1. Most common germ cell tumor in children younger than 3. Good prognosis in children In adults, it is often mixed with embryonic carcinoma. 2. Marco: large and may be well demarcated 3. Micro: Low cuboidal to columnar epithelial cells forming microcyst, lacelike (reticular) patterns. schiller-Duval a developing glomerulus resembling structure character for tumor 4. Tumor marker- alpha fetoprotein AFP e. Teratoma 1. Neoplastic germ cells differentiate along somatic cell line Majority are malignant in male in female bening… 2. Gross: often cystic masses that may contain cartilage 3. Micro:tumor composed of mature fetal tissue derived from two or three embryonic layers(ectodermal, endodermal and mesodermal) in a haphazard arrangement. E.g. cartilage plus neuron plus glandular /squamous epithel. 4. They may occur at any age in young age more common and bening old age rear and malignant. Rarely, nongerm cell tumor may arise in Teratoma (teratoma with malignant transformation) 5. Tumor marker: 90% of patients have elevated hGC and AFP 5. Scrotal squamous cell carcinoma is associated with exposure to soot (chimney sweeps) SEXCORD-STROMALTUMORS A. Tumors that origin from stromal tissues of the testicle usually benign - Leydig cell tumor: are derived from normal Leydig cells that produce testosterone and are located in the interstitium of the testis. usually produces androgen, causing precocious puberty in Children or gynecomastia in adults Characteristic Reinke crystals (eosinophilic rod-shaped cytoplasmic structures that are the most definitive light microscopic marker of Leydig cell differentiation) may be seen on histology. - Sertoli cell tumor: tumor derived from Sertoli cells, located within seminiferous tubules, which help support spermatogenesis. Sertoli cell tumors are typically composed of solid tubules containing Sertoli cells and is usually clinically silent. IV. LYMPHOMA A. Most common cause of a testicular mass in males > 60 years old; often bilateral R. Usually of diffuse large B-cell type

Answer 114

Small, round organ that lies at the base of the bladder encircling the urethra-prostatic urethra, Sits anterior to the rectum; posterior aspect of prostate is palpable by digital recta! exam The prostate can be divided into peripheral and transition zones; the types of proliferative lesions are different in each region; hyperplastic lesions- common in inner transition zone; carcinoma – common in peripheral zone Normal prostate contains glands with two cell layers, a flat basal layer and an overlying columnar secretory cell layer; surrounding prostatic storma contains mixture of smooth muscle and fibrous tissue. secrete produce fluid for semen -alkaline, milky fluid that is added to sperm and seminalvesicle fluid to make semen.Glands and stroma are maintained by androgens It is dihydrotestosterone (DHT), a metabolite of testosterone, that predominantly regulates the prostate Prostatitis Inflammation of the prostate Includes 4 categories acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis / chronic pelvic pain syndrome and granulomatous prostatitis 1.Acute bacterial prostatitis – acute infiltrate are seen in prostatic acini and stroma 2-5% of cases Clinically associated with fever, chills, and dysuria, Rectal examination- prostate is tender in young its chlamydia n gonorrhea in old its E.coli 2. Chronic bacterial prostatitis - Associated with recurrent UTI Presents as dysuria with pelvic or low back pain culture may come negative although prostate show Infiltrate of lymphocytes, plasma cells and macrophages rule. 3. Chronic nonbacterial prostatitis or chronic pelvic pain syndrome (90-95% of cases)- Difficult to diagnose Clinically similar to chronic bacterial prostatitis, with persistent pain, especially after ejaculation but no bacteria are cultured from expressed prostatic secretions Histopathologic diagnosis less crucial or may not be required for diagnosis ,Excessive white blood cells (WBC) may be present or absent 4.Granulomatous prostatitis - an inflammatory condition of the prostate that histologically features the presence of granulomas; most common cause- instillation of bacilli Calmette-Guerin (BCG- attenuated tuberculosis strain.) within the bladder for treatment of superficial bladder cancer Histologically indistinguishable from tuberculosis. Fungal granulomatous prostatitis is typically seen in immunocompromised hosts, Nonspecific granulomatous prostatitis- common, a reaction to secretions99 from ruptured prostatic ducts and acini Nodular hyperplasia of the prostate Benign prostate hyperplasia – bening Proliferation of stromal and epithethlial elements not leading to cancer , very common start at 40 years age till 80 90 % got it = enlargement of inner transitional zone and sometimes causes urinary obstruction. Pathogenesis -Excessive androgen-dependent growth/trophic glandular hyperplasia. central role of Dihydrotestosterone (mediator of prostatic growth) as its synthesized in the prostate from circulating testosterone by enzymes 5Alpha-reductase = DHT binds to nuclear androgen receptor = regulates gene expression of growth and survival of prostatic epithelium and stromal cell. Morphology-Occurs in the inner, transitional zone of the prostate. Enlarged prostate with welldemarcated nodules; nodules may appear solid or contain cystic space; nodules compress the urethra. The adenomatous nodule composed of proliferating fibromuscular stroma surrounding a proliferated glandular epithet still maintaining its 2 distinct basal and tall columnar layers creating papillary in folding into cystic lumen which contains proteinaceous secretory material – Corpora Amylacea Clinical symptoms of lower urinary tract obstruction may be mediated by alpha 1 adregenic receptor on smooth muscle. occur in only 10% of men Lower urinary tract obstruction – difficulty in starting stream of urine and intermittent interruptions, Presence of residual urine in bladder increases risk of UTI.

Answer 115

Most prostate cancers (95%) are adenocarcinomas, approximately 4% of cases of prostate cancer have transitional cell morphology and are thought to arise from the urothelial lining of the prostatic urethra. Prostate adenocarcinoma is most common form of cancer in men usually seen in older age 99% with clinical disease are age 50+. Although the biological behavior may vary considerably from indolent lesion to clinical aggressive fetal tumor, it is the 2nd most common cancer-related death Pathogenesis » Androgens - cancer does not develop castrated before puberty, indicating androgens role in the development of cancer. Tumor resistant to anti-androgen therapy often acquires mutations that permit androgen receptors to activate the expression of their target genes even in the absence of the hormones. » Heredity Increased risk among first-degree relative. Otherwise increase prevalence in African origin while less likely to appear in Asian origin, When prostate cancer is related to inherited gene changes 2, the way that cancer risk is inherited depends on the gene involved. For example, mutations in the BRCA1, BRCA2, and HOXB13 genes are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase a person's chance of developing cancer. In other cases, the inheritance of prostate cancer risk is unclear. It is important to note that people inherit an increased risk of cancer, not the disease itself. Not all people who inherit mutations in these genes will develop cancer. Other Genetic variation associated with increased risk: A variant near MYC oncogene on chromosome 8 (African males) A susceptibility locus on chromosome 1 q24-q25 (American men) » Environment as aging diet see In Japanese immigrants to USA the incidence of the disease rises » Acquired somatic mutation-Gene rearrangement (fusion) that create fusion genes consisting of androgen-regulated promoter gene and the coding sequence of ETS family transcription factor. Mutations which lead to activation of oncogenic PI3K/AKT signaling pathwayInactivate the tumor suppressor gene PTEN, which acts as a brake on PI3K activity.  Loss of one or both copies of the tumor suppressor gene PTEN  TMPRSS2–ERG chromosome fusion (fusion of an androgen-responsive promoter with the ERG transcription factor)  P53 mutations  Overexpression of MYC Morphology: » Usually arises from peripheral zone (posterior and lateral) Most carcinomas detected clinically are not visible grossly. Advanced lesions are Ill-defined, firm, gray-white mass which infiltrate adjacent gland. » Histologically is characterized by Moderately differentiated adenocarcinoma that produce well-defined gland, smaller than benign glands in back-to-back pattern with scant to moderate intervening stroma. The single most important diagnostic morphologic feature is the complete absence of basal cell layer normally present around benign prostate glands. Thus, normal prostate glands have a double cell layer, the inner glandular cells and an outer basal layer whereas in prostate cancer the outer basal cell layer is absent Tumor cell: darker stain cytoplasm enlarged nuclei and prominent nucleoli helpful morphologic features are the presence of peri neural invasion in prostate cancer Abundant intraluminal mucin is a very helpful finding in prostate cancer (arrow). This finding is especially helpful in needle biopsies with very few malignant glands Clinical features » some arise in the peripheral glands  may be palpable in rectal examination as irregular hard nodules Can only identify tumors that are big enough to feel » Most localize cancer are clinically silent don’t press urethra so discovered by routine serum PSA level check in older males PSA is secreted by normal and cancerous prostatic cells, and the levels of circulating PSA often rise with prostate cancer. Thus, PSA levels can serve as a warning that the prostate gland has gone awry A serum level of 4 ng\mL is the cutoff between normal and abnormal note PSA not for diagnosis more for follow up treatment/recurrence detection. Prostate-specific antigen, or PSA, is a protein produced by cells of the prostate gland- serene protease whose function is to cleave and liquefy the seminal coagulum formed after ejaculation. The percentage of free PSA is lower in men with prostate cancer than in men with benign prostatic disease. » Histopathological analysis of prostate biopsy is needed to confirm the PCa and evaluate the Gleason grade!! Gleason system- grading system-the Gleason grading of prostatic carcinoma is based on the architectural growth pattern rather than nuclear features. Gleason grading scheme identifies five grading patterns from 1 to 5 with a predominant grade and the 2nd most predominant grade yielding a combined score after adding the two grades in any given cancer. Grade 1- most well differentiated tumors; grade 5- no glandular differentiation, Higher score suggests worse prognosis. Gleason grade 1 tumors, as shown here, consist of single and separate rather uniform acini with little intervening stroma and all acini are well demarcated from the surrounding stroma. In Gleason grade 2 the acini show moderate amounts of intervening stroma and the peripheral margin of tumor is not sharply delineated as opposed to grade 1 tumors. Note that tumor acini are lined by a single layer of columnar epithelial cells (arrowhead) and no basal cells can be found Gleason grade 3 is the most common pattern in prostate carcinoma and is characterized by small, separate, round to irregular glands with moderate to abundant intervening stroma. Gleason grade 4 pattern the tumor glands show gland fusion, and small to indistinct lumens This is the Tumor consists of complex, cribriform and confluent glands almost without any intervening stroma. Gleason grade 5 basically shows solid tumor with little gland formation. The tumor shows poorly differentiated single cells in an infiltrative or sheet-like pattern. » May present with lower back pain secondary to Bone metastases metastasis Spread to lumbar spine or pelvis is common  causes Osteoblastic – bone producing lesions

Answer 116

The vulva is the external female genitalia and includes the skin and mucosa in that region. disorders are frequently are inflammatory 1) Vulvitis (instance itching =puritis associated) 2) Lichen Sclerosus 3) Lichen Simplex Chronicus malignant tumors are rare 1) Condylomas 2) Carcinoma of the Vulva 3) Extramammary Paget Disease VULVITIS # One of the most common causes is reactive inflammation in response to exogenous stimulus- irritant/ allergen. Also may arise from infection. contact irritant dermatitis : Manifest as well defined erythematous weeping and crusting papules and plaques , May be a reaction to: 1) urine. 2)soaps,deordorant… 3) antiseptic, alcohol … # Contact allergic dermatitis 1) perfumes; creams, and soaps. 2) chemical treatments on clothing. caused by infections 1) human papillomavirus (HPV) ,herpes simplex virus (HSV-1 or -2) 2)N. Gonorrhoeae-suppurative infection of the glands. Treponema pallidum- syphilis, chancre at the site of inoculation 3)Candida # Trauma induced by the itching usually exacerbates primary condition An important complication of vulvitis is obstruction of the excretory ducts of Bartholin glands. This blockage may result in painful dilation of the glands (a Bartholin cyst) and abscess formation. NON-NEOPLASTIC EPITHELIAL DISORDERS 1) Lichen Sclerosus Atrophic thinning of vulvar skin(thinner epithel and dermal fibrosis) # May occur in all age groups most common in postmenopausal women. Pathogenesis uncertain suggest an autoimmune etiology (presence of T cells in subepithelial inflammatory infiltrate) minor increase in risk for squamous cell carcinoma of vulva. Macroscopy smooth white plaques (termed leukoplakia) or papules. upon spread influence see atrophic and constricted vaginal orifice . Microscopy 1) thinning of the epidermis, 2) disappearance of rete pegs- are the epithelial extensions that project into the underlying connective tissue 3) hydropic degeneration of the basal cells, 4) dermal fibrosis, 5) dermal inflammatory cell infiltrate. 2) Lichen Simplex Chronicus Characterize by hyperplastic thickening of epithelium. Consequence of chronic irritation, often caused by pruritus related to an underlying inflammation. No known increased predisposition to cancer. Lichen sclerosus and lichen simplex chronicus may coexist. Macroscopy 1) an area of leukoplakia Microscopy 1) epithelial thickening (acanthosis) hyperkeratosis and increased mitotic activity (basal layers) but note! no cellular atypia. 2) maybe inflammatory infiltration of the dermis TUMORS 1) Condylomas - warty lesion of the vulva, come in 2 major types a. Condylomata lata (seen in secondary syphilis) moist, minimally elevated lesion. Less common nowdays. b. Condylomata acuminata (HPV subtypes 6 and 11) - papillary elevated or flat and rugose Macroscopy - often seen as multiple lesions range from a few millimeters to many centimeters red-pink to pink-brown color. Microscopy – perinuclear cytoplasmic vacuolization (koilocytosis) = hallmark of HPV , hyperkeratosis and acanthosis. 2) Carcinoma of the Vulva 3% of all female genital tract cancers occur mostly in woman above 60. 90% are squamous cell carcinomas 10% adenocarcinomas or basal cell carcinomas . There appear to be two distinct forms of vulvar squamous cell carcinoma: 1) The less common form is preceded by Precancerous changes -vulvar intraepithelial neoplasia (VIN) early VIN or progressed form of it as CIS appear as leukoplakia later become ulcer/exophytic mass. associated with HPV subtypes 16 and 18 and cigarette smoking. HPV related carcinoma tends to occur multifocal and exhibit poor differentiated SC. 2) A second form of vulvar carcinoma occurs in older women. It is not associated with HPV but often is preceded by years of reactive epithelial changes (e.g. lichen sclerosus). Unifocal usually also Invasive tumors of this form tend to be well differentiated and highly keratinizing 3) Extramammary Paget Disease Paget disease is an intraepidermal proliferation of malignant epithelial cells, can occur in the skin of the vulva or (without demonstrable underlying tumor unlike case of nipple pagent disease) Macroscopy red scaly plaque Microscopy large epithelioid cells with abundant pale, finely granular cytoplasm(contain mucin) occasional cytoplasmic vacuoles infiltrate the epidermis, singly and in groups VAGINA  Rarely it’s the primary site of a lesion usually get secondary metastasis/infection from other organ nearby (e.g., cervix, vulva, bladder, rectum)  Congenital anomalies also very rear - absence of the vagina, septate or double vagina. - congenital lateral Gartner duct cysts arising from persistent Wolffian duct. VAGINITIS  Common condition that is usually transient and of no clinical consequence(complication abortion).  A large variety of organisms have been implicated, including bacteria Neisseria gonorrhea, fungi candida, and parasites trichomonas vaginalis.  Many are normal commensals that become pathogenic only in the setting of diabetes, systemic antibiotic therapy (which causes disruption of normal microbial flora), immunodeficiency, pregnancy, or  Candida albicans- characterized by a curdy white discharge (part of the normal vaginal flora)  Trichomonas vaginalis- produces a watery, copious gray-green discharge in which parasites can be identified by microscopy. MALIGNANT NEOPLASMS Squamous Cell Carcinoma - extremely uncommon if seen so in woman over 60 and nearly always in association with HPV. - Vaginal Intraepithelial Neoplasia is a precursor lesion (VIN) Clear Cell Adenocarcinoma - very rare tumor - precursor lesion is vaginal adenosis- small glandular or microcystic inclusion in the vaginal mucosa, red granular appearing foci lined by mucus secreting cells or ciliated columnar cells. - identified in a cluster of young women (in 1970) whose mothers took diethylstilbestrol during pregnancy to prevent threatened abortion the causative connection wasn't establish by research. Sarcoma Botryoides - embryonal rhabdomyosarcoma - manifests as soft polypoid masses - in infants and children younger than 5 years

Answer 117

CERVICITIS  inflammation of cervix really common are associated with a purulent vaginal discharge subclassified as infectious or noninfectious( Local trauma - e.g., cervical irritation caused by tampons, Chemical irritation or inflammation - eg, Behçet syndrome)  important are pathogens: STD - Chlamydia trachomatis (by far the most common), Neisseria gonorrhoeae - Trichomonas vaginalis - Candida albicans - HSV-2 (the agent of herpes genitalis) and certain types of HPV Macroscopy - hyperemia - leukorrhea - flow of a whitish, yellowish, or greenish vaginal discharge  Microscopy may be either acute (rear if appear so postpartum - staphylococci or streptococci parts of normal flora) or chronic much more common Chronic: inflammation and regeneration of epithel hence epithelium may show hyperplasia and even squamous metaplasia of the columnar epi NEOPLASIA OF THE CERVIX  Most tumors of the cervix are of epithelial origin and are caused by oncogenic strains of human papillomavirus (HPV), may come as SCC/ adenocarcinoma. Anatomically, comprises the "neck" of the uterus Divided into the exocervix (visible on vaginal exam) and lined by nonkeratinizing squamous epithelium and endocervix lined by a single layer of columnar cells. transition point between the exocervix and endocervix is called the transformation zone  pathogenesis:  Key risk factor is high-risk HPV infection(type 16,18-low risk are 6,11progress to condyloma- bening neoplastic lesion of epithel); secondary risk factors include smoking and immunodeficiency.  Most HPV infections are transient (eliminated immune sys ) but a subset of infections persists some of these progress to cervical intraepithelial neoplasia (CIN),a precursor lesion for invasive cervical carcinoma. (dysplasia=CIN continue into carcinoma in situ into invasive carcinoma)  HPV is Sexually transmitted DNA virus that infects the lower genital tract, especially the cervix in the transformation zone. persistent infection leads to an increased risk for cervical dysplasia. HPV genome encode two potent oncoproteins called E6 and E7 bind and inactivate two critical tumor suppressors, p53 and Rb respectively.  somatically acquired mutations in the tumor suppressor gene LKB1(20%) Cervical Intraepithelial Neoplasia (CIN) The precursor lesion for carcinoma development in background of HPV infection note it take years! Peak age incidence of CIN is about 30 years, carcinoma 45 years but it happens… Characterized by koiloeytic change, loss of cellular maturation- disruption of layering, nuclear atypia- cell pleomorphisem ,parakeratosis/dyskeratosis and increased mitotic activity within the cervical epithelium. Divided into grades based on the extent of epithelial involvement by immature Dysplastic cells 1. CIN I involves < 1/3 of the thickness of the epithelium basal layer. 2. CIN II involves < 2/3 of the thickness of the epithelium, 3. CIN III involves slightly less than the entire thickness of the epithelium 4. Carcinoma in situ (CIS) involves the entire thickness of the epithelium. Denoting that dysplasia is reversible but carcinoma in situ is not The higher the grade of dysplasia, the more likely it is to progress to carcinoma and the less likely it is to regress to normal.  LSIL - low-grade squamous intraepithelial lesion (includes HPV, mild dysplasia, CIN 1)  HSIL - high-grade squamous intraepithelial lesion (includes moderate and severe dysplasia, carcinoma in situ, CIN 2 and CIN 3) INVASIVE CARCINOMA OF THE CERVIX When neolastic cells cross BM The most common cervical carcinomas are 1) Squamous cell carcinomas (75%) 2) Adenocarcinomas and mixed adenosquamous carcinomas (20%) 3) Small cell neuroendocrine carcinomas (less than 5%) Morphology: - Invasive carcinomas of the cervix develop in the transformation zone and range from microscopic foci of stromal invasion to grossly conspicuous exophytic tumors Tumors encircling the cervix and penetrating into the underlying stroma produce a barrel cervix, (identified by direct palpation). - Advanced tumors often invade through the anterior uterine wall into the bladder, blocking the ureters. Hydronephrosis with postrenal failure is a common cause of death in advanced cervical carcinoma. - Micro same as above but add eoplastic cells in dermis may surround by inflammatory reaction. Pap smear is very effective screening tool Cells are scraped from the transformation zone using a brush and analyzed under microscope.

Answer 118

Body of uterus is composed of - endometrial mucosa and - the underlying smooth muscle myometrium ENDOMETRITIS Inflammation of the endometrium is classified as acute/chronic by inflammatory infiltrate. Acute:Bacterial infection (N. gonorrhoeae (neutrophils) ) of the endometrium Usually due to retained products of conception (part of placenta) retained products act as a nidus for infection. Presents as fever, abnormal uterine bleeding, and pelvic pain Chronic: Characterized by Plasma cells are necessary for the diagnosis of chronic endometritis given that lymphocytes are normally found in the endometrium. Causes include Retained products of conception/ intra uterine devises Chronic pelvic inflammatory disease (e.g., Chlamydia (prominent lymphoid follicles)) and TB (granulomatous endometritis). Presents as abnormal uterine bleeding, pain abdomen, and infertility ENDOMETRIOSIS  Endometriosis is defined by the abnormal presence of endometrial glands and stroma location outside the endomyometrium.  10% of women in their reproductive years and in nearly half of women with infertility  often involves pelvic structures 1) ovaries most common 2) pouch of Douglas, pain in defecation /rectovaginal septum. 3) uterine ligaments, pelvic pain/peritoneum 4) fallopian tube- may cause scarring =infertility, provide area for implantation of ectopic pregnancy. 5) Rearly in lung/skeletal muscle  Three hypotheses to explain the origin of the lesions: 1. regurgitation theory- menstrual backflow through the fallopian tubes leads to implantation of endometrial tissue 2. metaplastic theory- endometrial dysplastic differentiation of coelomic epithelium(of mullarian duct) 3. vascular or lymphatic dissemination theory  endometriosis externa almost always contains functioning endometrium  endometriotic tissue exhibits increased levels of inflammatory mediators, particularly prostaglandin E2, and increased estrogen production due to high aromatase activity of stromal cellsThese changes enhance the survival and persistence of the endometriotic tissue within a foreign location. Morphology:  In contrast with adenomyosis, endometriosis almost always contains functioning endometrium, which undergoes cyclic bleeding => blood collects in these aberrant foci  They usually appear grossly as red-brown nodules or Implants and they lie on or just under the affected serosal surface.  When the ovaries are involved, the lesions may form large, blood-filled cysts that turn brown (chocolate cysts)  The histologic diagnosis at all sites depends on finding two of the following three features within the lesions: endometrial glands, endometrial stroma, and hemosiderin pigment. Clinical features: depends on location  Almost all Produce dysmenorrhea, and pelvic pain as reslt frm intrapelvic bleeding and periuteraine adhesions.  Singes by location ADENOMYOSIS  the presence of endometriosis within the myometrium.  Adenomyosis (endometriosis interna) always contains nonfunctioning endometrium the glands in adenomyosis derive from the stratum basalis of the endometrium, they do not undergo cyclic bleeding.  The aberrant presence of endometrial tissue induces reactive hypertrophy of the myometrium, resulting in an enlarged, globular uterus with a thickened uterine wall. DYSFUNCTIONAL UTERINE BLEEDING  Abnormal bleeding from the uterus in the absence of rimary organic uterine lesion is called dysfunctional uterine bleeding.  In general abnormal bleeding Come as: - Menorrhagia - intense or prolonged bleeding at the time of the period - Metrorrhagia - irregular bleeding between the periods - Postmenopausal bleeding.  Common causes include endometrial polyps, leiomyomas, endometrial hyperplasia, endometrial carcinoma, and endometritis.  The probable primary cause of uterine bleeding in any given case depends somewhat on the age of the patient The various causes of abnormal uterine bleeding, both dysfunctional and that which is secondary to an organic lesion, can be segregated into four groups: 1) Failure of ovulation (results in excess of estrogen relative to progesterone) dominant cause for abnormal bleeding at both ends of reproductive life  The endometrium goes through a proliferative phase that is not followed by the normal secretory phase.  The endometrial glands may develop mild cystic changes or appear disorderly while the endometrial stroma, which requires progesterone for growth, may be scarce = this combination of abnormalities makes the endometrium prone to breakdown and abnormal bleeding. 1. hypothalamic-pituitary axis, adrenal, or thyroid dysfunction; 2. functional ovarian lesions producing excess estrogen; 3. malnutrition, obesity, or debilitating disease; and 4. severe physical or emotional stress 2) Inadequate luteal phase- The corpus luteum may fail to mature normally or may regress prematurely leading to a relative lack of progesterone. 3) Contraceptive-induced bleeding (older oral contraceptives) 4) Endomyometrial disorders -chronic endometritis, endometrial polyps, and submucosal leiomyomas This abnormalities makes the endometrium prone to breakdown and abnormal bleeding

Answer 119

ENDOMETRIAL HYPERPLASIA (>50% glands, ˂50%stroma)  Endometrial hyperplasia is a grow adaptation lesion produced by hyperestrinism which generates the glandular and stromal proliferation of endometrium. See thicker endometrium with marked increase in gland/stroma ratio- hence main gland proliferation.  Results with conditions of prolonged estrogen excess with unopposed estrogen (no progesterone secretion or lack of artificial progestin administration) and can lead to metrorrhagia (uterine bleeding at irregular intervals), menorrhagia (excessive bleeding with menstrual periods). - failure of ovulation perienapose period - prolonged administration of estrogenic steroids no contra balancing progestin. - estrogen-producing ovarian lesions polycystic ovary disease and granulosa-theca cell tumors - obesity = adipose tissue converts steroid precursors into estrogens  Classification :general morphology of strima increase in cell size and gland cystic lining of gland from simple ciliated columnar to pseudostrafide one A. based on: architectural crowding - simple (diffuse all around endometrium , gland may be cystic dilation give overall Swiss cheese morphology ) - complex (not diffuse but patchy lesion , crowded branching glands) B. the presence or absence of atypia(look a ncles) –see nucleus shape size chromatin nucleoli preset? … Endometrial hyperplasia may regress or may transform into adenocarcinoma EH is an important precursor of endometrial carcinoma!!! And the estimation of fait denote from level of atypia. - without atypia (complex without atypia less than 5% cancer risk) - with atypia (complex with atypia 20% to 50% cancer risk)  In a significant number of cases, the hyperplasia is associated with inactivating mutations in the PTEN tumor suppressor gene, Acquisition of PTEN mutations is believed to be one of several key steps in the transformation of hyperplasia to endometrial carcinomas.  Malignant proliferation of endometrial glands is the most frequent cancer occurring in the female genital tract in us (age 55-65)  two distinct kinds 1) endometrioid (80% of endometrial carcinomas) arise in association estrogen excess and endometrial hyperplasia in perimenopause women ( obesity, infertility and exposure to unopposed estrogen are risk factors) Mutations in mismatch repair genes and the tumor suppressor gene PTEN are early events in the stepwise development of endometrioid carcinoma. Histologically- similar to endometrium, Tumor cells are atypical (pleomorphic nucleus/squamous metaplasia may see…) and form irregular glands shape with multiple lumens. The stroma is reduced, producing the "back to back" aspect of the tumor glands. Graded I to III based on degree of differentiation Better prognostic features of moderate differentiation and superficial invasion. 2) serous carcinoma (less common about 15%) carcinoma arises in an atrophic endometrium with no evident precursor lesion in older postmenopausal women ~70.nearly all cases have mutations in the P53 tumor suppressor gene Serous microscopic pattern with papillary features high mitotic rate Form small tufts (cell clusters separated from papilla) and much greater cytological atypia and cellular pleomorphisem. Poor prognostic features of poor differentiation and greater invasiveness ENDOMETRIAL POLYP  a protruding outgrowth from endometrial lining range from 0.5 to 3 cm usually hemispheric sessile lesions  see at any age most frequent detected around time of menopause.  are composed of endometriumoften cysticaly dilated endometrial glands, Monoclonal stromal cells (rearrangement of chromosomal region 6p21, neoplastic component) frequently with small muscular arteries  clinical significance - abnormal uterine bleeding - Very low malignant potential. LEIOMYOMA  Benning smooth muscle cell neoplastic proliferation. the most common benign tumor in females (because of their firmness clinical practice also called fibroids).  30% to 50% of women of reproductive age estrogens stimulate the growth of leiomyomas shrink postmenopausally tumors are monoclonal (rearrangements of chromosomes 6 and 12)  Often are asymptomatic if not so abnormal bleeding, may be infertility if block opening of fallopian tube.  Morphology:  Macro = sharply circumscribed, firm gray-white masses with a characteristic whorled cut surface. often multiple tumors are scattered within the uterus, ranging from small nodules to large tumors  MICRO = On histologic examination, the tumors are characterized by bundles of smooth muscle cells mimicking the appearance of normal myometrium. LEIOMYOSARCOMAS  Malignant neoplastic tumor of smooth muscle, arise de novo from the mesenchymal cells of the myometrium (not from preexisting leiomyomas).  Usually as solitary lesion in postmenopausal women  macro = typically soft, hemorrhagic, necrotic masses histologic appearance varies widely from resembling leiomyoma to anaplastic neoplasms the diagnostic features of overt leiomyosarcoma include tumor necrosis, cytologic atypia, and high mitotic activity. It is much more cellular and the cells have much more pleomorphism and hyperchromatism than the benign leiomyoma.  recurrence after removal is common many metastasize, typically to the lungs 5-year survival rate of about 40%

Answer 120

THE PATHOLOGY OF THE FALLOPIAN TUBES  The most common disorder of the fallopian tubes is inflammation (salpingitis) usually as part of PID other Less common abnormalities include ectopic pregnancies, endometriosis and rear primary tumors.  Infections almost always microbial in origin: - gonorrhea, - Chlamydia, - Mycoplasma hominis, tuberculosis - Coliforms - streptococci and staphylococci (in the postpartum setting)  Non gonococcal infections can penetrate the wall of the tubes, giving rise to blood-borne infections, with seeding of the meninges, joint spaces, and sometimes even the heart valves  may produce fever, lower abdominal pain  may result - Adherence of the inflamed tube to the ovary and adjacent structures tuboovarian abscess complex. - tubal scarring increase risk for ectopic pregnancy n sever case permanent sterility  Primary tumors (serous or endometrioid) adenocarcinomas, show connection to BRCA1 mutation patients. Usually discovered at later stage when it already spreaded to peritoneum OVARIES FOLLICLE AND LUTEAL CYSTS  Degeneration of ovarian follicles (the oocyte theca and granulosa cells) results in follicular cysts. Small numbers of follicular cysts are very common in women and have no clinical significance. Originate from unruptured graafian follicles or from follicles that have ruptured and then become immediately sealed  Typically are small (1 to 1.5 cm in diameter) situated just under serosal covering of ovary , filled with clear serous fluid and lined by granulosa lining cells or luteal cells.  Occasionally become large (4 to 5 cm) produce palpable masses and pelvic pain these cysts rupture, producing intraperitoneal bleeding and peritoneal symptoms (acute abdomen) POLYCYSTIC OVARIAN DISEASE (Stein-Leventhal syndrome)  Multiple ovarian follicular cysts due to hormone imbalance (ovaries produce excess androgens and estrogens) Affects roughly 5% of women of reproductive age.  Characterized by increased LH and low FSH : 1. Increased LH induces excess androgen production (from theca cells) resulting in hirsutism (excess hair in a male distribution). 2. Androgen is converted to estrone in adipose tissue. i. Estrone feedback decreases FSH resulting in cystic degeneration of follicles (granulosa cell can’t produce estrogen from androgen realis by theca cells, no estrogen can’t maintain follicle instead see degeneration into cyst). ii. High levels of circulating estrone increase risk for endometrial carcinoma  Classic presentation is an young woman (teenage at first menstrual cycles) with oligomenorrhea, hirsutism later discover infertility and sometimes obesity. Some patients have insulin resistance and may develop type 2 diabetes mellitus 10-15 years later.

Answer 121

 Tumors of the ovary are amazingly varied. This diversity is attributable to the presence of three cell types hence 3 tumor groups plus metastasis, the multipotent surface (coelomic) epithelium, the totipotent germ cells, and the sex cord–stromal cells SURFACE EPITHELIAL TUMORS  Most common type of ovarian tumor (70% of cases) in woman above 40 age Surface Epithelial Tumors Serous Tumors and Mucinous Tumors, less common Endometrioid Tumors and Brenner Tumor.  Derived from coelomic epithelium that lines the ovary; coelomic epithelium embryologically produces the epithelial lining of the fallopian tube (serous cells), endometrium, and endocervix (mucinous cells). Two most common subtypes of surface epithelial tumors are serous -full of watery fluid and mucinous- full of mucus-like fluid both are usually cystic.  Benign lesions usually are cystic (cystadenoma) and may have an accompanying stromal component (cystadenofibroma) – benign more common in pre-menopause woman ~40. Malignant tumors may also be cystic (cystadenocarcinoma) or solid (carcinoma) – malignant more common to post menopause woman~70. Borderline tumors have features in between benign and malignant tumors.  risk factors 1) nulliparity- higher incidence in unmarried women 2) family history 3) and germline mutations in certain tumor suppressor genes- 10-15% familial associated with BRCA1,2  Prolonged use of oral contraceptives somewhat reduces the risk  Most common malignant ovarian tumor, Prognosis is generally poor for surface epithelial carcinoma (worst prognosis of female genital tract cancers).  Epithelial carcinomas tend to spread locally, especially to the peritoneum. CA-125 is a useful serum marker to monitor treatment response and screen for recurrence. 1) SEROUS TUMORS  The most common of the ovarian epithelial tumors most are benign but this category account for highest frequency malignant tumor of ovary  two types of serous carcinomas: - low-grade (KRAS, BRAF, or ERBB2 mutations) - high-grade (96% of tumors have mutations in TP53)  morphology: MACRO= - Most serous tumors are large, spherical to ovoid, cystic structures up to 30 to 40 cm in diameter, may have number of compartments. - In the benign form, the wall is smooth cystadenocarcinoma shows nodular irregularities as it infiltrates its surrounding Serosal penetration and solid areas of growth are suggestive of malignancy. - The cystic spaces usually are filled with a clear serous fluid. MICRO= - benign tumors contain a single layer of tall columnar epithelial cells that line the cystor cysts. The cells may be ciliated. - In carcinoma Papillary formations are complex and multilayered, nests or undifferentiated sheets of malignant cells invade the axial fibrous tissue. Metastasis along lymph node periartic and local. Psammoma bodies (concentrically laminated calcified concretions) - Tumors of low malignant potential-which exhibit less cytologic atypia and, typically, little or no stromal invasion. 2) MUCINOUS TUMOR Similar to serous tumors essential difference the neoplastic epithelium consists of mucin-secreting cells 80% are benign Morphology: MACRO produce cystic masses with mucinous nature of the cystic contents. They are more likely to be larger and multicystic the serous type. Micro= the cysts are lined by mucin-producing epithelial cells Compared with serous tumors, mucinous tumors are much less likely to be bilateral. This feature is sometimes useful in differentiating mucinous tumors of the ovary from Krukenberg tumor is a metastatic mucinous tumor that involves both ovaries; most Commonly due to metastatic gastric carcinoma (diffuse type) Implantation of mucinous tumor cells in the peritoneum with production of massive amounts of mucin is called pseudomyxoma peritonei in most cases, this disorder is caused by metastasis from the gastrointestinal tract, primarily the appendix to ovary 3) Endometrioid tumor Endometrioid rumors are composed of endometrial-like glands and are usually malignant. i. May arise from endometriosis ii. 15% of endometrioid carcinomas of the ovary are associated with an Independent endometrial carcinoma (endometrioid type). Have mutations in the PTEN tumor suppressor gene (similar to endometroid endometrial tumor)  They are bilateral in about 30% of cases they are distinguished by the formation of similar tubular glands to those of the endometrium within the lining of the cystic space. 4) Brenner Tumor  Brenner tumors are composed of bladder-like epithelium and are usually benign.  may arise from the surface epithelium or from urogenital epithelium trapped within the germinal ridge  macro=solid, usually unilateral ovarian tumor smoothly encapsulated and gray-white on cut section  Micro=abundant stroma containing nests of transitional-type epithelium resembling that of the urinary tract GERM CELL TUMORS  2nd most common type of ovarian tumor (15% of cases) usually occur in young women of reproductive age.  4 major groups: Tumor subtypes mimic tissues normally produced by germ cells. 1. Fetal tissue—cystic Teratoma and embryonal carcinoma 1) Benign (mature) cystic Teratoma (90% of germ tumor)  tumor composed of mature tissues derived from all three germ cell layers: ectoderm, endoderm and mesoderm Most common germ cell tumor in females;  bilateral in 10% of cases with Cystic cavity On cut section, they often are filled with sebaceous secretion and hair (ball) foci of bone and cartilage, nests of bronchial or gastrointestinal epithelium, and other tissues also are present  Struma ovarii is a Teratoma composed primarily of thyroid tissue.  incidentally are discovered in young women as ovarian masses or are found on abdominal radiographs or scans because they contain foci of calcification (tooth-like structures)  Benign, but presence of immature tissue (usually neural) or somatic malignancy (Usually squamous cell carcinoma of skin) indicates malignant potential.  Malignant(immature) teratomas (10%) are found early in life (18y) predominantly solid on cut section, and punctuated by areas of necrosis Uncommonly cystic foci are present that contain sebaceous secretion similar to those of mature teratomas On microscopic examination presence of immature elements or minimally differentiated 2. Oocytes—dysgerminoma  Tumor composed of cells with clear cytoplasm and central nuclei (resemble oocytes); Testicular counterpart is called seminoma (both result of gonadal dysgenesis)  Solid large to small gray masses Sheets or cords of large clear cells separated by scant fibrous strands Stroma may contain lymphocytes and occasional granulomas  All malignant but Good prognosis; responds to radiotherapy 3. Yolk sac—endodermal sinus tumor  Malignant tumor that mimics the yolk sac; most common germ cell tumor in Children Serum AFP is often elevated.  Schiller-Duval bodies (glomerulus-like structures) are classically seen on Histology 4. Placental tissue—choriocarcinoma  Malignant tumor composed of trophoblasts and syncytlotrophoblasts; mimics placental tissue, but villi are absent (unlike mole)  Small, hemorrhagic tumor with early hematogenous spread create larger metastatic masses than primary focus.  High beta-hCG is characteristic (produced by syncytiotrophoblasts)  poor respond to chemotherapy(unlike gestational related type) SEX CORD STROMAL TUMORS sex cord tumors are ones of stroma come from theca granulosa cells or from fibrocytes really Granulosa-theca cell tumor Neoplastic proliferation of granulosa and theca cells Often produces estrogen; presents with signs of estrogen excess i. Prior to puberty—precocious puberty ii. Reproductive age—menorrhagia or metrorrhagia iii. Postmenopausal (most common setting granulosa-theca cell tumors) Endometrial hyperplasia with postmenopausal uterine bleeding Malignant, but minimal risk for metastasis - Sertoli- leydig cell tumor Composed of Sertoli cells that form tubules and Leydig cells (between tubules) with characteristic Reinke crystals May produce androgen; associated with hirsutism and virilization - Fibroma Benign tumor of fibroblast, solid gray tumor. Associated with pleural effusions and ascites (Meigs syndrome); resolves with removal of tumor.

Answer 122

NORMAL HISTOLOGY REVIEW: 1) Membranes: The amnion lines the amniotic sac containing the fetus. The amnion consists of a single layer of cuboidal epithelium, its basement membrane, and a collagen layer. The fibrous chorion lies deep to the amnion, chorion are fetal in origin. Deep to it is the decidual layer (maternal in origin). This layer contains decasualized maternal cells, vessels, fibrin, and often some degree of hemorrhage. 2) Umbilical cord: The outer surface of the umbilical cord is covered by amniotic epithelium. Normally, 3 vessels (2 arteries and 1 vein) are embedded in (Wharton's jelly). 3) Placental disk: The chorionic plate (fetal surface) consists of a single layer of cuboidal amniotic epithelium overlying a paucicellular collagenous matrix (chorion) containing numerous large vessels of fetal origin. Below this are the villi (large stem villi to small terminal villi) separated by clear or blood containing spaces (the intervillous space) where the maternal blood circulates around the fetal villi. The villi consist of an outer layer of syncytiotrophoblasts deep to the syncytial trophoblast cells is a single, discontinuous layer of cytotrophoblasts cells (larger, cuboidal cells). The cellular matrix consists of macrophages and fibroblasts with numerous vessels the resulting smaller and more highly branched terminal villi increase the effective surface area in contact with the intervillous space thereby increasing gas and nutrient exchange without a significant increase in placental mass. The basal plate (maternal surface) consists of intermediate trophoblast cells, decasualized maternal cells and maternal vessels Normally, these vessels are invaded by extravillous trophoblast cells, remodeled with elimination of surrounding smooth muscle layers and enlarging the lumens leading into the sinusoidal intervillous spaces. PLACENTAL INFLAMMATIONS AND INFECTIONS Infections may reach the placenta by either of two paths: 1) ascension through the birth canal - more common in most instances, they are bacterial and are associated with premature rupture of the fetal membranes. - Major causative organism: Mycoplasma, Candida, and the numerous bacteria of the vaginal flora. - Micro = the chorioamnion shows neutrophilic infiltration associated with edema and congestion (acute chorioamnionitis). - the infection may involve the umbilical cord and placental villi, resulting in acute vasculitis of the cord (funisitis). 2) Hematogenous (transplacental) spread - Micro = on histologic examination, placental villi are the most frequently affected structures (villitis). - Causative agents: Syphilis, tuberculosis, listeriosis, toxoplasmosis, and various viruses (rubella, cytomegalovirus, herpes simplex virus) all can cause placental villitis. - Transplacental infections can affect the fetus and give rise to the socalled TORCH (toxoplasmosis, other infections, rubella,cytomegalovirus infection, herpes) complex . ECTOPIC PREGNANCY  Ectopic pregnancy is defined as implantation of a fertilized ovum in any site other than the uterus.  In more than 90% of these cases, implantation occurs in the fallopian tube (oviducts-tubal pregnancy);  other sites include the ovaries and the abdominal cavity Gestation within the abdominal cavity occurs when the fertilized egg drops out of the fimbriated end of the oviduct and implants on the peritoneum.  Any factor that retards passage of the ovum through the oviducts predisposes to ectopic pregnancy slowed passage is attributable to chronic inflammation and scarring, tumors and endometriosis etc.  MORPHOLOGY - In all sites, early development of ectopic pregnancies proceeds normally, with formation of placental tissue, the amniotic sac, and decidual changes. - With tubal pregnancies, the invading placenta eventually burrows through the wall of the oviduct, causing intratubal hematoma (hematosalpinx) The tube is usually distended by freshly clotted blood containing bits of gray placental tissue and fetal parts. - intraperitoneal hemorrhage major risk see sudden intense abdominal pain and blood loss. - Surgical emergency; - The histologic diagnosis depends on visualization of placental villi or, rarely, of the embryo. GESTATIONAL TROPHOBLASTIC DISEASE  Following conception instead of develop embryo develop trophoblastic tumor  have been divided on histopathologic grounds into three overlapping morphologic categories: hydatidiform mole, invasive mole, and choriocarcinoma. These demonstrate a range of aggressiveness from benign hydatidiform moles to highly malignant choriocarcinomas.  All elaborate human chorionic gonadotropin (hCG), which can be detected in the blood and urine at levels considerably higher than those found normally at that stage of pregnancy. 1) Hydatidiform Mole: Complete and Partial  The typical hydatidiform mole is edematous swollen chorionic villi, appearing grossly as grapelike structures. The swollen villi are covered by varying amounts of normal to highly atypical chorionic epithelium (proliferating trophoblasts).  There are two distinctive subtypes of hydatidiform moles: complete and partial. Invasive Mole  Invasive moles are complete moles that are more invasive locally but do not have the aggressive metastatic potential of a choriocarcinoma.  An invasive mole retains hydropic villi, which penetrate the uterine wall deeply, possibly causing rupture and sometimes life-threatening hemorrhage.  MICRO= the epithelium of the villi shows atypical changes, with proliferation of both trophoblastic and syncytial components.  Hydropic villi may embolize to distant organs, such as lungs or brain Bout invasive and hydatidform: - Uterus expands as if a normal pregnancy is present, but the uterus is much larger And hCG much higher than expected for date of gestation. - Classically presents in the second trimester as passage of grape-like masses through the vaginal canal with prenatal care, moles are diagnosed by routine ultrasound in the early first trimester. Fetal heart sounds are absent, and a 'snowstorm' appearance seen on ultrasound. - Treatment is curettage. Subsequent (3-hCG monitoring is important to ensure adequate mole removal and to screen for the development of choriocarcinoma. In invasive case sometime scraping not enough and see prolonged hCG elevation in some cases chemotherapy needed 3) Gestational Choriocarcinoma  Choriocarcinoma, a very aggressive malignant tumor, arises either from gestational chorionic epithelium or within the gonads as a germ cell tumor. Approximately 50% of choriocarcinomas arise from complete hydatidform moles; other arise after abortion/normal pregnancy and germ cell path…  MORPHOLOGY Choriocarcinomas usually appear as hemorrhagic, necrotic uterine massesprimary lesion “self-destruct,” and only the metastases tell the story. Very early invade myometrium and send metastasis.  In contrast with hydatidform moles and invasive moles, chorionic villi are not formed; instead, the tumor is composed of anaplastic cuboidal cytotrophoblasts and syncytiotrophoblasts  In most cases, choriocarcinoma manifests with a bloody, brownish discharge In general, the β-hCG titers are much higher than those associated with a mole.  widespread vascular spread usually has occurred to the lungs (50%), vagina (30% to 40%), brain, liver, or kidneys.  these tumors are remarkably sensitive to chemotherapy Nearly 100% of affected patients are cured. By contrast, response of ones that arise in the gonads (ovary or testis) is relatively poor. PREECLAMPSIAPregnancy-induced hypertension, proteinuria, and edema, usually arising in the third trimester; seen in approximately 5% of pregnancies Hypertension may be Due to abnormality of the maternal-fetal vascular interface in the placenta; resolves with delivery Eclampsia - is preeclampsia with seizures. HELLP is preeclampsia with thrombotic microangiopathy involving the liver; characterized by Hemolysis, Elevated Liver enzymes, and Low Platelets Both eclampsia and HELLP usually warrant immediate delivery.

Answer 123

The designation fibrocystic is applied to a miscellany of changes in the female breast that consist predominantly of cyst formation and fibrosis. (not neoplastic) Overall, fibrocystic changes are the most common breast abnormality seen in premenopausal women. The changes tend to arise during reproductive age and are most likely a consequence of the cyclic breast changes that occur normally in the menstrual cycle. NON PROLIFERATIVE CHANGES NON-PROLIFERATIVE FIBROCYSTIC CHANGE  Characterized by an increase in fibrous stroma associated with dilation of ducts and formation of variably sized cysts primarily affects the terminal duct lobular unit, not the large duct.  Macro: changes usually are multifocal and often bilateral. The cysts range from less than 1 cm and up to 5 cm in diameter. Unopened, they are brown to blue (blue dome cysts) and are filled with watery, turbid fluid. The secretions within the cysts may calcify, producing microcalcifications on mammograms.  Micro=epithelial lining that in larger cysts may be flattened or even totally atrophic  Apocrine metaplasia = a variant of non-proliferative fibrocystic change the lining cells are large and polygonal with abundant granular, eosinophilic cytoplasm (apical secretory granules) and small, round, deeply chromatic nuclei, do not increase risk for neoplastic change!  The stroma surrounding all types of cysts usually consists of compressed fibrous tissue that has lost the delicate, myxomatous appearance of normal breast stroma. EPITHELIAL HYPERPLASIA  a variant of proliferative fibrocystic change in which fined more than the 2 normal lining epithelial layers of the duct. Normal ducts and lobules of the breast are lined by two layers of cells—a layer of luminal cells overlying a second layer of myoepithelial cells.  MICRO= The ducts or lobules may be filled with orderly cuboidal cells within which small gland patterns (called fenestrations)  The proliferating epithelium projects as multiple small papillary excrescences into the ductal lumen ductal papillomatosis).  atypical ductal/lobular hyperplasia is used to describe hyperplasia’s that exhibit changes that start to resemble ones of carcinoma in situ(see description next pic)  Both atypical ductal and lobular hyperplasia are associated with an increased risk of invasive carcinoma. SCLEROSING ADENOSIS  hyperplastic process involving an increased number of glandular components (number of glands in one TDLU) =adenosis plus stromal proliferation that create hard palpable mass=sclerosis  Less common but worth mentioning cause Its clinical and morphologic features may mimic those of carcinoma.  MACRO= the lesion has a hard, rubbery consistency, similar to that of breast cancer.  MICRO= shows a characteristic: enlarged TDLU Preservation of luminal lining of epithelium and myopithel layer (Help to distinguish from invasive ductal carcinoma) with surrounding Dens Stromal fibrosis, which may compress and distort the proliferating glands. BENIGN BREAST TUMORS E. FIBROADENOMA  The most common benign neoplasm of the female breast. no increased risk of carcinoma  It is a biphasic slow growing tumor composed of fibroblastic stroma and epithelium-lined glands = only the stromal cells are clonal and truly neoplastic.  They seen as solitary mobile masses firm consistency number of cm size mass.  Estrogen sensitive grows during pregnancy and may be painful during the menstrual cycle also they peak in appearance in 3rd decade of life and after menopause, they may regress and calcify.  A cut section shows a uniform grayish white color, punctuated by softer yellow-pink specks representing the glandular areas.  MICRO: The epithelial proliferation appears as duct-like spaces of various shapes and sizes surrounded by a loose fibroblastic stroma. Depending on the proportion and the relationship between these two components, there are two main histological features: intracanalicular and pericanalicular. Often, both types are found in the same tumor. Intracanalicular fibroadenoma: stromal proliferation predominates and compresses the ducts, which are irregular, reduced to slits. Pericanalicular fibroadenoma: fibrous stroma proliferates around the ductal spaces, so that they remain round or oval, on cross section. The basement membrane is intact. PHYLLODES TUMOR  Fibroadenoma-like tumor However, the stromal element of these tumors is more cellular and abundant, often forming epithelium lined leaflike projections (phyllodes is Greek for “leaflike”).  Less common than fibroadenomas arise de novo, not from preexisting fibroadenomas.  changes suggesting malignancy include increased stromal cellularity, anaplasia, high mitotic activity, rapid increase in size, and infiltrative margins but most phyllodes tumors remain localized and are cured by excision INTRADUCTAL PAPILLOMA  Intraductal papilloma is a benign neoplastic papillary growth. Most often seen in premenopausal women.  These lesions typically are solitary and found within the principal lactiferous ducts or sinuses.  The clinical presentation may include * Serous or bloody nipple discharge * The presence of a small subareolar tumor a few millimeters in diameter * Nipple retraction  MICRO= they are composed of multiple papillae, each having a connective tissue core covered by epithelial cells that are double-layered, with an outer luminal layer overlying a myoepithelial layer. The presence of a double-layered epithelium helps to distinguish intraductal papilloma from intraductal papillary carcinoma.

Answer 124

 2nd to lung cancer in cancer related death among women The lifetime risk of developing breast cancer is 1 in 8 for women and 20-30% mortality rate in the United States.  risk factors for breast cancer: 1) Age. Risk increases after age of 30 , especially after menopause 2) Geographic Variations. The risk is significantly higher in North America and northern Europe than in Asia and Africa. These differences seem to be environmental rather than genetic in origin. 3) Family history 4) Age at menopause greater than 55 5) 1st Pregnancy after age of 35/nulliparous 6) Benning breast diseas as proliferative atypical hyperplasia 7) Other Risk Factors. - Prolonged exposure to exogenous estrogens postmenopausally, as occurs with hormone replacement therapy/Oral contraceptives- no effect. - Ionizing radiation its age-period of time depended before age of 30 during breast development and its dose depended also (therapy radiation increase risk but mammography not-smaller dose). - Less establish relation to: Obesity-alcohol consumption and a diet high in fat  pathogenesis: three sets of influences seem to be important: 1) Genetic changes  Is overexpression of the HER2/NEU proto-oncogene, which undergoes amplification in ~ 30% of invasive breast cancers. This gene is a member of the epidermal growth factor receptor family, and its overexpression is associated with a poor prognosis. Also Amplification of RAS and MYC genes also has been reported in some human breast cancers.  Gene expression profiling has demonstrated the presence of four molecular subtypes with distinct natural histories and clinical behavior. these generally align with the presence or absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2): (1) Luminal A (estrogen receptor–positive, HER2/NEU-negative);most common good prognosis associated with age (2) Luminal B (estrogen receptor–positive, HER2/NEU overexpressing); less good prognosis (3) HER2/ NEU positive (HER2/NEU over expressing, estrogen receptor– negative); less common more aggressive appear at younger ages (4) basal-like (estrogen receptor–negative and HER2/NEU-negative).also called triple negative appear more in African American woman carry poor prognosis and appear at younger age pre-menopausal. ~10% of cases are hereditary breast cancer specific related to one mutation, manifest as premenopausal appearance see also in first degree relative and bilateral tumor/other related tumor e.g. ovarian  Roughly one third of women with hereditary breast cancer have mutations in BRCA1 or BRCA2 ).both BRCA1 an BRCA2 are believed to function in a common DNA repair pathway BRCA1 and BRCA2 are classic tumor suppressor genes, in that cancer arises only when both alleles are inactivated or defective—the first caused by a germline inherited mutation and the second by a subsequent somatic mutation.  Less common genetic diseases associated with breast cancer are the Li-Fraumeni syndrome, Cowden syndrome (caused by germline mutations in PTEN—mentioned earlier under endometrial carcinoma) and the ataxia-telangiectasia gene carriers. 2) Hormonal Influences. Estrogen excess = hormonal imbalance Estrogens stimulate the production of growth factors (such as TGF-α, PDGF, and FGF) may promote tumor development through paracrine and autocrine mechanisms. 3) Environmental Variables. See above geography treatments alcohol obesity etc.…  Morphology:  The most common location of tumors within the breast is in the upper outer quadrant (50%), followed by the central portion (20%).  Breast cancers are classified according to whether they have or have not penetrated the limiting basement membrane: A. Noninvasive 1. Ductal carcinoma in situ (DCIS) 2. Lobular carcinoma in situ (LCIS) B. Invasive (infiltrating) 1. Invasive ductal carcinoma (“not otherwise specified”), the most common subtype of invasive carcinoma 2. Invasive lobular carcinoma 3. Medullary carcinoma 4. Colloid carcinoma (mucinous carcinoma) 5. Tubular carcinoma 6. Other types Noninvasive (in situ) Carcinoma  include: DCIS and LCIS. both types usually arise from ductal epithelium of the terminal duct lobular unit.  DCIS tends to fill and expand ductal lumen with proliferating ductal cells and necrosis, By contrast, LCIS usually expands but does not alter the acini of lobules PAGET DISEASE OF THE NIPPLE is caused by the extension of DCIS up the lactiferous ducts and into the contiguous skin of the nipple, producing a unilateral crusting exudate over the nipple and areolar skin. In almost all cases, an underlying carcinoma is present, and approximately 50% of the time this carcinoma is invasive. Prognosis is based on the underlying carcinoma and is not affected by the presence of Paget disease. Invasive (Infiltrating) Carcinoma 1) Invasive ductal carcinoma - A majority (70% to 80%) of cancers fall into this group. type of cancer usually is associated with DCIS and, rarely, LCIS. - Most ductal carcinomas produce a desmoplastic response = which replaces normal breast fat (resulting in a mammographic density) and forms a palpable mass - The microscopic appearance is quite heterogeneous, ranging from tumors with well-developed tubule formation and low-grade nuclei to tumors consisting of sheets of anaplastic cells The tumor margins typically are irregular - About two thirds express estrogen or progesterone receptors, and about one third overexpress HER2/NEU. 2) Invasive lobular carcinoma - Origen from lobule neoplastic cells morphologically identical to the cells of LCIS (monomorphic, mucin vacuoles). Two thirds of the cases are associated with adjacent LCIS. - The cells invade individually into stroma and are often aligned in “single-file/indian file” strands or chains. Associated with mutations in E cadherin - Most exhibit desmoplastic reaction so create palpable mass. - Lobular carcinomas have a unique pattern of metastases among breast cancers; they more frequently spread to cerebrospinal fluid, serosal surfaces, gastrointestinal tract, ovary, uterus, and bone marrow. - Almost all of these carcinomas express hormone receptors, whereas HER2/NEU overexpression is rare. 3) Inflammatory carcinoma 4) Medullary carcinoma - is a rare subtype of carcinoma, create cohesive sheets of high pleomorphic cells with well circumscribed, “pushing” borders, associated with prominent lymphocyte and plasma cells infiltration - Medullary carcinomas occur with increased frequency in women with BRCA1 mutations And its triplenegative tumor. 5) Colloid (mucinous) carcinoma - also is a rare subtype.The tumor cells produce abundant extracellular mucin into the surrounding stroma Like medullary carcinomas, they often present as well-circumscribed masses and can be mistaken for fibroadenomas.On gross evaluation, the tumors usually are soft and gelatinous. - Most express hormone receptors 6) Tubular carcinomas Common Features of Invasive Cancers - Invasive cancers tend to become adherent and fixed to the pectoral muscles or deep fascia of the chest wall and the overlying skin, with consequent retraction or dimpling of the skin or nipple.first indication of malignancy. - Involvement of the lymphatic pathways may result in localized lymphedemaIn such cases, the skin becomes thickened around exaggerated hair follicles, giving an appearance known as peau d’orange (“orange peel”). Clinical course:  At the time of clinical detection, the carcinoma typically is 2 to 3 cm in size, and involvement of the regional lymph nodes (most often axillary) is already present in about 50% of patients.  Breast cancer spread occurs through lymphatic and hematogenous channels. Favored locations are the lungs, skeleton, liver, adrenals, and (less commonly) brain, but no site is exempt.  Prognosis tumor-node-metastasis (TNM) staging classification: 1) Tumor invasion and size. In situ carcinomas carry an excellent prognosis (5-year survival rate greater than 90%), as do invasive carcinomas less than 2 cm in size (5-year survival rate of 87%). 2) Extent of lymph node involvement. With no axillary node involvement, the 5-year survival rate is close to 80%. Survival is inversely related to the number of involved lymph nodes and is less than 50% with 16 or more involved nodes. Sentinel node biopsy is currently the mainstay for staging the axila = This procedure identifies the primary lymph node(s) that drain the breast parenchyma using dye or a radioactive tracer (or sometimes both). Once identified, sentinel nodes are removed and examined microscopically. 3) Distant metastases. Patients who develop hematogenous spread are rarely curable 4) Histologic grade. The most common grading system for breast cancer evaluates tubule formation, nuclear grade, and mitotic rate. 5) The histologic type of carcinoma. All specialized types of breast carcinoma (tubular, medullary, and mucinous) are associated with a somewhat better prognosis than carcinomas of no special type (ductal carcinomas). A major exception is inflammatory carcinoma, which has a poor prognosis. 6) The presence or absence of estrogen or progesterone receptors. The presence of hormone receptors confers a slightly better prognosis. Overexpression of HER2/NEU. Overexpression is associated with a poorer prognosis. However, the clinical importance of evaluating HER2/NEU lies in predicting response to trastuzumab (Herceptin), a monoclonal antibody that binds and inhibits the function of HER2/NEU.

Answer 125

1. Pituitary gland a. Small, bean shaped structures located at the base of the brain, on the sella turcica. b. Connected to the hypothalamus by a stalk composed of axons and a rich venous plexuse. c. Central role in regulation of other endocrine glands d.Composed of two functionally and morphologically distinct components: 1.The anterior pituitary, or adenohypophysis, is composed of epithelial cells derived embryologically from the developing oral cavity. In routine histologic sections, see array of cells containing basophilic cytoplasm, eosinophilic cytoplasm, or poorly staining (chromophobic) cytoplasm the staining properties of these cells are related to the presence of various trophic polypeptide hormones within their cytoplasm . The pink acidophils secrete growth hormone (GH) and prolactin (PRL) The dark purple basophils secrete corticotrophin (ACTH), thyroid stimulating hormone (TSH), and gonadotrophins follicle stimulating hormone-luteinizing hormone (FSH and LH) The pale staining chromophobes have few cytoplasmic granules, but may have secretory activity. The release of trophic hormones is in turn under the control of factors produced in the hypothalamus; while most hypothalamic factors are stimulatory and promote pituitary hormone release, others (e.g., somatostatin and dopamine) are inhibitory in their effects Rarely, signs and symptoms of pituitary disease may be caused by excess or lack of the hypothalamic factors, rather than by a primary pituitary abnormality. 2.The neurohypophysis shown here resembles neural tissue, with glial cells, nerve fibers, nerve endings, and intra-axonal neurosecretory granules. The hormones vasopressin (antidiuretic hormone, or ADH) and oxytocin made in the hypothalamus (supraoptic and paraventricular nuclei) are transported into the intra-axonal neurosecretory granules where they are released. Diseases of the pituitary, accordingly, can be divided into those that primarily affect the anterior lobe and those that primarily affect the posterior lobe. Hyperpituitarism and pituitary adenoma  Hyperpituitarism arises from excessive secretion of trophic hormones. It most often results from an anterior pituitary adenoma but also may be caused by other pituitary and extrapituitary lesions .Causes of hyperpituitarism: a. Adenoma arising in anterior lobe (most common) b. Hyperplasia and carcinoma of anterior lobe c. Secretion of hormones by extrapituitary tumors d. Hypothalamic disorders Pituitary adenomas  Benign tumor of anterior lobe Found in adult 30-50 years old.  pituitary adenomas are usually composed of a single type of cell type and produce a single predominant hormone. Some adenomas secrete two hormones Most common combination- GH and prolactin Plurihormonal adenomas- rare  May be functional (hormone producing and clinical sings), nonfunctional ( clinical silent) or hormone negative i. Nonfunctional and hormone negative (null cell) Likely to come to clinical attenation at a later stage May cause hypopituitarism due to compression of the normal pituitary tissue ii. Functional tumors represent with features based on the type of hormone produced.  Most adenomas occur as isolated lesion Microadenomas- less than 1 cm Macroadenoma- exceeds 1 cm in diameter.  Most cases are sperodic but ~3% of adenomas are associated with multiple endocrine neoplasia.  Pathogenesis  One of most common mutations is Constitutive activation of a stimulatory G protein. A mutation in the alpha-subunit that interferes with its intrinsic GTPase activity Results in persistent generation of cAMP and unchecked cellular proliferation Alpha subunit is encoded by GNAS1 gene  Pituitary adenomas that arise in the context of familial MEN-1 syndrome harbor mutation from MEN-1 gene (interfer with check point regulation on p27) appear at younger age  Other abnormality is P53 mutation aggressive tumor.  Morphology  Usually well circumscribed, soft small lesion. Small tumors are confined by sella turcica, while larger lesions typically extend into supracellar region, where they compress optic chiasm and adjacent structures.  Invasive adenomas- In 30% of cases, adenomas are grossly nonencapsulated and infiltrate adjacent bone, dura and (uncommonly) bone.  Microscopically- mark by cellular monomorphism and absence of reticulin network. Composed of relatively uniform, polygonal cells arrayed in sheets, cords or papillae Very little mitotic activity Cytoplasm may be acidophilic, basophilic or chromophobic depending on type of secretory product. Supportive CT-reticulin, is relatively absent accounting for soft consistency Different adenomas subtypes 1. Prolactinoma  Most common type of pituitary adenoma Hyperprolactinemia due to Lactotroph cells secrete prolactin.  Hyperprolacinemia may be caused by other conditions than adenoma pregnancy, high dose estrogen therapy/dopamine inhibiting drugs, renal failure, hypothalamic lesions or Stalk effect- any mass in the suprasellar compartment that may disturb the normal inhibitory influence of hypothalamus on prolactin secretion.  Clinical features 1. Galactorrhea, amenorrhea and infertility 2. Decreased libido and impotence 3. Manifestation of hyperprolactinemia is more obvious in postmenopausal women. 2. Growth hormone producing adenoma  GH producing , somatotroph cells, neoplasms are the second most common type of functional pituitary adenoma Clinical manifestation may be subtle, so spmatotroph cell adenoma may be quite big by the time they come to clinical attention  Microscopically Densely or sparsely granulated cells and GH within cytoplsm  Lab Elevated GH Elevated somatomedin C (IGF-1)  Giantism Occurs in children and adolescents prior to fusion of the growth plates Tall structure and long extremities Acromegaly Occurs in adults after the growth plates have fused Prominent jaw Flat, broad forehead Enlarged hands and feet The internal organs are typically enlarged  GH excess is also associated with a number of other disturbances Abnormal glucose and diabetes mellitus Generalized muscle weakness Hypertension Arthritis Osteoporosis Congestive heart failure 3. Corticotroph cell adenomas  Usually small at the time of diagnosis Usually stained positive with PAS as a result of the accumulation of glycosylated ACTH proteins ACTH is synthesized as part of a larger prohormone that includes melanocyte stimulating hormone, there may be hyperpigmentation.  May be clinically silent or may cause hypercortisolism (Cushing syndrome) because of stimulatory effect on adrenal cortex.  Cushing disease- when hypercorticolism is caused by excessive production by pituitary gland Nelson syndrome- aggressive corticotroph adeomona may develop after surgical removal of adrenal glands for treatment of cushing syndrome. Due to loss of the inhibitory effect of adrenal chorticoids on a preexisting corticotroph microadenoma 4. Other anterior pituitary neoplasm  Gonadotroph (LH and FST-producing hormones) adenoma  Difficult to recognize a. Secrete hormones inefficiently and variably b. Secretory product do not cuase a recognizable clinical syndrome  Most frequent in middle age when tumor becomes large enough to cause neurological symptoms Impaired vision Headaches Diplopia  FSH is usually the predominant secreted hormone.  Thyrotroph (TSH-produsing hormone) adenoma Rare cause of hyperthyroidism  Pituitary carcinoma Rare Local extension beyond the sella turcica Always distant metastases

Answer 126

Hypopitutarism 1. Insufficient production of hormones by anterior pituitary gland. Symptoms arise when >75% of pituitary parenchyma is lost 2. Causes in general may be congenital=very rear or acquired in which lesion intrinsic to pituatry more common than hypothalamus lesion( in case of neurohypophysis hypothalamic lesion is usually the causing problem) include: a. Non functioning pituitary adenomas (adults) or craniopharyngioma (children)- due to mass effect or pituitary apoplexy (bleeding into adenoma) b. Destruction of tissue following radiation/surgary/trauma-elevated ICP etc… c. Sheehan syndrome- pregnancy related infarction of the pituitary gland,the most common cause of ischemic pituatry necrosis) i. Anterior part get blood from portal circulation posterior part from artery in pragnent woman pituatry size increase duble (more prolactin cells) but the portal blood supply remain the same so pituatry is suseptable to ischemic injury if extansive bleeding occure may lead to ischemic necrosis(e.g. bleeding in labor/event of hypotantion) ii. Present as poor lactation, loss of pubic hair and fatigue. d. Empty sella syndrome- congenital defect of the sella - Herniation of the arachnoid and csf into the sella compresses and destroys the pituitary glan Pituitary gland is absent on imaging- congenital very rear e. Disorder that interfere with the delivery of pituitary releasing factors from hypothalamus (eg. Hypothalamic tumor) f. Other less common causes :Inflammatory lesios- sarcoidoisis, tuberculosis/metastatic neoplasem/trauma /congenital 3. Clinical manifestation depends on specific hormones that are lacking a. GH deficiency- pituitary dwarfism(in children) b. GnRH deficiency - decreased libido, impotence and loss of pubic hair for male for female also amenorrhea. c. TSH deficiency- hypothyroidism d. ACTH deficiency- hypoadrenalism e. Prolactin deficiency- failure of postpartum and lactation f. Anterior lobe is a rich source of MSH, synthesized from the same source of ACTH. Therefore one of the manifestations of hypopituitarism is paleness from loss of stimulatory effects of MSH on melanocytes. Posterior pituitary gland (neurohypophysis) syndromes 1. Basic principles Posterior pituitary is composed of modified glial cells (pituicytes) and axonal processes extending from nerve cell bodies in the hypothalamus. Antidiuretic hormone and oxytocin are made in the hypothalamus and then transported via the axon to the posterior pituitary for release i. ADH acts on the distal tubules and collecting ducts of the kidney to promote free water retention 1. Nonpeptide hormone 2. Released in response to different stimuli including increase in plasma oncotic pressure, stress and increase sympathetic action.. ii. Oxytocin mediates uterine contraction during labor and release of breast milk in lactating mother 2. Upon ADH defficency you get Central Diabetes inspidus a. Inability of water reuptake from urin leading to polyuria b. Due to hypothalamic or posterior pituitary pathology (eg. Tumor, trauma infection or inflammation) c. Clinical features are based on loss of free water i. Polyuria and polydipsia with risk of life threatening dehydration (Hypernatremia and high serum osmolality) ii. Low urin osmolality and specific gravity- not able to concentrate urin… in Water deprevation test fails to increase urine osmolality iii. Treatment is desmopressin (ADH analogue) d. Nephrogenic Diabetes insipidus -Impaired renal response to ADH Due to inherited mutation or drugs Clinical features are similar to central diabetes insipidus, but there is no response to desmopressin 3. Syndrome of inappropriate ADH (SIADH) secretion a. Excess ADH secretion which causes excessive amount of free water , with resultant hyponatermia. b. Most often due to ectopic production (eg. Small cell carcinoma of the lung). Other causes include CNS trauma (injury to hypothalamus or neurohypophysis), pulmonary infection and drugs (cyclophosphamide) c. Clinical features based on retention of free water i. Hyponatermia and low serum osmolality ii. Mental status chanhes and seizures- hyponatermia leads to neuronal swelling and cerebral edema iii. Water retention without odema d. Treatment is free water restriction

Answer 127

Grave disease 1. Autoimmune disease characterized by producing IgG autoantibodies to the TSH receptor 2. Most common cuase of endogeanous hyperthyroidism Females>males; age 20-40 3. Characterized by triad of manifestation: a. Hyperthyroidesem (Thyrotoxicosis) and goiter b. Opthalmopathy: exophthalamus (40% of patients) or proptosis only one eye seen only in graves. c. Localized infiltrate dermopathy: peritibial myxedema (in a minority of cases) Characterized by thickening of the dermis, as a result of deposition of glycosaminoglycans and lymphocyte infiltration 4. Pathogenesis a. Characterized by a breakdown in self tolerance to thyroid autoantigens, of which the most important is the TSH receptor. The result is the production of multiple autoantibodies i. Thyroid stimulating immunoglobulin- bindsto TSH receptor and mimics the action of TSH, stimulating adenylate cyclase ii. Thyroid growth-stimulating immunoglobulins- directed against TSH receptor. Implicated in the proliferation of thyroid follicular epithelium iii. TSH biding inhibitor immunoglobulin- anti-TSH receptor Ab prevent TSH from binding to its receptor. 1. May coexist with stimulating IgG in the serum a. Explains spontaneous episodes of hypothyroidism b. T cell mediated autoimmune phenomenon i. Involved in the development of infiltrative opthalmopathy- forward displacement of the eyeball 1. Volume of retroorbital CT and extra-ocular muscle is increased as a result of a. Infiltration of retro orbital space by predominantly T cells b. Inflammatory edema and swelling of extra ocular muscles which may undergo fibrosis late in the course of the disease. c. Accumulation of extracellular matrix components (eg hyluronic acid, chondoritin sulfate) d. Increase number of adipocytes c. Genetic susceptibility is associated with: i. the presence of certain human leukocyte antigen (HLA) halotypes, especially HLA-DR3 ii. Polymorphism in genes coding the inhibitory T cell receptor CTLA-4 and tyrosine phosphatase PTPN22 5. Morphology a. Gross: i. enlarged (usually symmetrically) gland due to diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells ii. Smooth, soft and capsulate is intact b. Micro: i. Follicular epithelial cells prolifration results in formation of small papillae- papilization, (which is lack of fibrovascular core), which projects into follicular lumen ii. Colloid is pale reduce matter follow hyperactivity of epithelium. iii. Lymphoid chronic inflammatory infiltrate (predominantly T cells) present throught the interstitium. 6. Libratory i. Elevated serum free T3 and T4 Depressed TSH serum level ii. Radioiodine scans show diffuse uptake of iodine- dues to ongoing stimulation of thyroid follicles by TSIs, radioactive iodine uptake is increased 7. Thyroid storm – describe acute event of sever hyperthyroidism may lead to life threatening arrhythmia and most commonly seen in patent’s with underlying graves diseas. Diffuse and multinodular goiter 1. Goiter- enlargement of the thyroid gland (The most common manifestation of thyroid disease) 2. Diffuse and multinodular goiter reflects impaired synthesis of thyroid hormone (most often caused by dietary iodine deficiey) = > compensatory rise in TSH => hypertrophy and hyperplasia of follicular cells => enlargement of the gland => euthyroid metabolic state(when upon increase in working cell mass enoth hormone to overcome defficency) If the underlying disorder is sever (congenital biosynthesic defect) the compensatory response may be inadequate resuling in goiter hypothyroidism. 3. Goiter can be sporadic or endemic a. Endemic goiter- if ~10% of population show it ,ccurs in geographical areas where natural resources iodine is deficient (eg mountain areas Himalayas),resolve by diatry supply of iodine. b. Sporadic goiter- More common in young women, when there is an increased physiological demand for T4. Caused by several conditions: 1. Digestion of substances that interfere with thyroid hormone synthesis (e.g. excessive calcium or certain vegetables as cabbage) 2. Hereditary –dyshormonogenic due to enzyme defects 4. Morphology Diffuse :macro symmetric overall gland enlargment ,microscopically exhibits hypertrophy and hyperplasia of the follicular epithelial cells show crowding of columnar epithel may lead to papillaztion(pseudopapille protrude to colloid luman) At this stage, the amount of colloid in the follicles is decreased. However, when dietary iodine continue to be deficient or demands for thyroid hormone decreases, the stimulated follicular epithelial involutes to form enlarged colloid rich gland (colloid goiter). Multinodular: With time recurrent episodes of hyperplasia and involution combine to produce more irregular enlargement of the gland termed multinodular goiter .Grossmultilobulated, asymmetrically enlarged gland , On cut surface irregular nodules containing variable amounts of brown, gelatinous colloid. Older lesions often show areas of fibrosis, hemorrhage, calcification and cystic change. Microscopically- Colloid rich follicles lined by flattened, inactivated epithelium and areas of follicular epithelial hypertrophy and hyperplasia. Note Multinodular goitets are typically hormone silent, minority can manifest with thyrotoxicosis secondary to development of autonomous nodules that produce thyroid hormone independent of TSH stimulation (Plummer syndrome) 5. Clinical features: i. Caused by mass effect of the enlarged thyroid gland Cosmetic problem on the neck risk for Airway obstruction/Dyspnea , compression of large vessels in the neck (sup. Vena cava syndrome) ii. Hyperthyroidisem sings/hypo depends on patient iii. Incidence of malignancy in long standing multinodular goiter is low.

Answer 128

1. Chronic Lymphocytic (Hashimoto) thyroiditis a. Hashimoto's thyroiditis (chronic autoimmune thyroiditis) is the most common cause of hypothyroidism in iodine-sufficient areas of the world characterized by immune destruction of the thyroid gland and hypothyroidism b. Female>male: age 45-65= middle age c. Pathogenesis Caused by breakdown of self-tolerance to thyroid autoantigens see diffuse lymphocytic infiltration of the thyroid, which includes predominantly thyroid-specific B and T cells lead to tissue destruction…. 1. CD8+ cytotoxic T cell-mediated cell death- CD8+ cytotoxic T cell may cause thyrocyte destruction 2. Cytokine-mediated cell death- excessive T cell activation leads to production of inflammatory cytokines (INF-gamma) which results in activation of macrophages and may induce apoptosis of thyrocytes 3. Binding of antithyroid antibodies followed by antibody-dependent cell mediated cytotoxicity. ii. Increased susceptibility is associated with polymorphisms in multiple immune regulation-associated genes, the most significant of which is the linkage to cytotoxic T lymphocyte associated antigen-4 gene, which codes for a negative regulator of T cell function. HLA DR 5 d. Morphology - firm, pale, diffusely and symmetrically enlarged thyroid gland Micro: 1. Mononuclear inflammatory infiltrate (small lymphocytes and plasma cells) with germinal centers 2. Thyroid follicles : Atrophy Lined in many areas by epithelial cells distinguished by the presence of abundant eosinophilic granular cytoplasm (hurthle cells). Cells are characterized by numerous prominent mitochondria it’s a Metaplastic response of the low cuboidal epithelium to the injury 3. Increase CT and Fibrosis (fibrosing variant with atrophic small thyroid instead of goiter) e. Clinical presentation i. Painless enlragement of the thyroid (goiter) ii. Hypothyroidism T3,T4 levels fall accompanied by compensatory increase in TSH Initial inflammation may cause transient hyperthyroidism due to disruption of thyroid follicles (hashitoxicosis) iii. See anti thyroglobulin and antithyroid peroxidase antibodies in patients blood. iv. Have increased risk for development of b cell non hodjkin lymphoma from lymph follicle within the thyroid later in curse of disease. v. May be associated with other autoimmune disease (SLE, RA, sjogren syndrome) 2. Subacute Granulomatous (de Quervain ) Thyroiditis a. Clinical features i. Second most form of thyroiditis much less common then hasimotos, classically seen in younger female adult (~30 age) i. Presents as Tender (only one we know is tender ), firm, enlarged thyroid gland Preceded by a viral illness (majority of patients have upper respiratory infection)-not! a autoimmune attack ii. Self limiting hyperthyroidisem(no progress to hypo) in about 6-8 weeks b. Morphology - Gross: firm gland, intact capsule, and may be unilaterally or bilaterally enlarged. Histologically: 1. Disruption of thyroid follicles, with extravasation of colloid leading to polymorphonuclear infiltarate, which is replaced over time by lymphocytes, plasma cells and macrophages 2. Granulomatous inflammation in thyroid Extravasated colloid provokes an exuberant granulomatous reaction with giant cells 3. Healing occurs by resolution of inflammation and fibrosis 3. Subacute lymphocytic thyroiditis a. Self-limiting diseas often come in follow pregnancy (postpartum thyroiditis) b. Typically painless mild symmetric enlargement characterize by lymphocyte infiltration to thyroid (include germinal center ) c. Autoimmune etiology d. Clinical features Painless neck mass or features of thyroid hormone excess followed by return to euthyroid state within a few month In minority of patients condition may progress to hypothyroidism 4. Riedel Thyroiditis a. Rare disease of unknown etiology characterized by dense fibrosis of thyroid and surrounding structures (trachea and esophagus) b. Circulating Ab in most patients suggests autoimmune etiology c. Clinical features :Female>male; Irregular, hard thyroid fixed mass . May mimic carcinoma but patients are younger (40s), and malignant cells are absent d. Micro Dense fibrous replacement of the thyroid gland Chronic inflammation

Answer 129

Tóm tắt về U tuyến giáp và ung thư tuyến giáp U tuyến giáp lành tính (Thyroid Adenoma) a. Đặc điểm: Khối u lành tính từ biểu mô nang giáp, thường xuất hiện dưới dạng một nốt đơn lẻ. b. Cơ chế bệnh sinh: Trong các u độc, có đột biến trong con đường tín hiệu của thụ thể TSH dẫn đến việc tiết hormone tuyến giáp (TH) mà không cần TSH. Một số u không chức năng có đột biến ở gene RAS hoặc PIK3CA, liên quan đến các loại ung thư nang giáp. c. Hình thái: Nốt đơn lẻ, có vỏ bọc rõ ràng. Các tế bào sắp xếp thành nang đều, chứa chất keo, phân biệt tốt. Nếu tế bào có bào tương ưa axit và nhân nhỏ, được gọi là tế bào Hurthle (u tuyến Hurthle). d. Đặc điểm lâm sàng: Thường không đau, nốt lớn có thể gây khó nuốt. Đa số không chức năng, một số có thể sản xuất hormone giáp gây cường giáp. Sau khi tiêm iod phóng xạ, các u thường hấp thu iod kém hơn so với mô giáp bình thường. Ung thư tuyến giáp a. Ung thư nhú giáp (Papillary Carcinoma) Dịch tễ học: Phổ biến nhất (~85%), ung thư tuyến giáp chỉ chiếm khoảng 1% tổng số ca ung thư. Cơ chế bệnh sinh: Yếu tố môi trường: Tiếp xúc với bức xạ. Yếu tố di truyền: Kích hoạt con đường MAP kinase thông qua đột biến RET hoặc NTRK1, hoặc đột biến ở gene RAF. Hình thái: Hiển vi: Nhân sáng "orphan annie eye", mẫu hình nhú với lõi xơ mạch dày, có thể có thể có thể cát. Đặc điểm lâm sàng: Khối u không chức năng, có tỷ lệ sống sau 10 năm là 95%. Biến thể thường gặp nhất là dạng nang. b. Ung thư nang giáp (Follicular Carcinoma) Dịch tễ học: Chiếm 15% ung thư giáp, nữ nhiều hơn nam, thường gặp ở tuổi 40-60. Cơ chế bệnh sinh: Yếu tố môi trường: Thiếu iod trong chế độ ăn. Yếu tố di truyền: Đột biến trong con đường PI-3K/AKT hoặc gene PAX8/PPARG. Hình thái: Hiển vi: Tế bào đều, tạo thành các nang nhỏ chứa chất keo. Thâm nhập bao vỏ và có thể thấy tế bào Hurthle. Đặc điểm lâm sàng: Xuất hiện dưới dạng nốt lạnh đơn lẻ, hiếm khi hoạt động. c. Ung thư tủy giáp (Medullary Carcinoma) Đặc điểm: U thần kinh nội tiết từ tế bào C, tiết calcitonin. Cơ chế bệnh sinh: Yếu tố di truyền: Đột biến RET, thường gặp ở hội chứng MEN 2A hoặc 2B. Hình thái: Hiển vi: Tế bào u hình đa giác trong mô đệm amyloid. Đặc điểm lâm sàng: Xuất hiện dưới dạng khối ở cổ, có thể gây khó nuốt và khàn tiếng. d. Ung thư không biệt hóa (Anaplastic Carcinoma) Đặc điểm: Thường gặp ở nữ, trên 60 tuổi, khối u lớn, dễ di căn. Cơ chế bệnh sinh: Đột biến RAS hoặc PIK3CA, mất chức năng TP53. Hình thái: Hiển vi: Tế bào lớn đa hình, tế bào hình thoi. Tiên lượng: Rất xấu, tiến triển nhanh và gây tử vong. 1. Thyroid Adenoma a. Benign neoplasms derived from follicular epithelium appearing as solitary nodule.(multy nodular pattern is for multinodular goiter) b. Pathogenesis In toxic adenomas one who produce TH see mutations in compartments of TSH receptor signaling pathway Gain of thyroid autonomy (independ of TSH see TH secretion) such as mutations in Gene encoding TSH receptor and less common in Alpha subunit of G protein as signal trasducer part in signaling pathway of TSH receptor In some of non-functional follicular adenoma exhibit mutations of RAS of PIK3CA which shared with subsets of follicular carcinomas hence some of it may arise from adenoma… c. Morphology i. Solitary nodule compress non-neoplastic thyroid. Has well defined capsule .(multinodular goiter no capsule multiple nodules no compression of parenchyma) ii. Micro cells are arranged in uniform follicles that contain colloid-well differentiated. If Neoplastic cells have bright eosinophilic granular cytoplasm and small nucleus they called oxyphils/hurthle cells(and adenoma classified as hurthle cell adenoma) May exhibit focal nuclear pleomorphism, atypia, and prominent nucleoli- endocrine atypia. Not infiltrate capsule its completely intact unlike in follicular carcinoma. d. Clinical features i. Usually painless nodules, large masses may produce local symptoms like difficulty in swallowing. ii. Vast majority are not functional but some may produce thyroid hormone and cause hyperthyroidism (toxic adenoma) iii. After injection of radioactive iodine, most adenomas take up iodine less avidly than normal parenchyma. Therefore on radionuclide staining appears as cold nodules relative to normal gland Toxic adenoma, however appears at warm nodules in the scan 2. Carcinomas of the thyroid All carcinomas on gross look as solitary nodule may be encapsuled or diffuse infiltrative marigin…. And all usually cold nodules. Papillary carcinoma 1. Epidemiology a. Most common form of thyroid cancer(~85%) although thyroid cancer as itself is rear ~1% of cancer cases.. b. Tumor may occur at any age 2. Pathogenesis a. Environmental- radiation exposure b. Genetics- Activation of MAP kinase pathway featured in most of papillary subtypes, may done by one of the two major mechanism 1. Rearrangements of RET or NTRK I (neuroytophic thyrosine kinse I) – encode for tyrosine kinase receptor(fusion gene by usually non expressed in follicular epithel RET(encode tyr kinas part of receptor) and PTC gene constantly expressed gene (papillary thyroid carcinoma gene) so formed RET/PTC product gene and gain of function to pathway) 2. Point mutation in gene of RAF protein , an intermediate signaling component in the MAP kinase pathway 3. Gross May show as encapsulate or diffuse invasive form uni or multifocal Lesions may contain area of fibrosis and calcification and often are cystic Micro a. Diagnostic essential feature is the appearance of Clear "orphan annie eye" nuclei b. The tumor typically exhibits a papillary pattern with dense fibrovascular cores (true papilla) and along rims see neoplastic cells pileup on each other. c. Occasional psammoma bodies- concentrically calcified structure present in papillae 4. Clinical features a. Non-functional tumors b. Indolent lesion with 10-year survival rate at 95% Over a dozen variant of papillary thyroid carcinoma Most common- follicular variant Encapsulated Lower incidence of lymph node metastases(if do so to cervical nodes) c. Prognosis depends on age, extrathyroidal extension and present of distant metastases. Follicular carcinoma 1. Accounts for 15% of malignant thyroid tumors Female>male; age 40-60 2. Pathogenesis a. Environment- ionizing radiation and deficiency of dietary iodine more Frequent in areas with dietary iodine deficiency b. Genetics i. Mutation in the PI-3K/AKT signaling pathway resulting in constant activation of oncogenic pathway. 1. Gain of function point mutation or Amplification of PI3K 2. Loss of function mutation of PTEN (a tumor suppressor and a negative regulator of the pathway) ii. PAX8/PPARG fusion genes may impire the complete cell diffrantiation. 1. PAX8- homeobox gene that is important in thyroid development 2. Peroxisome proliferator-activated receptor gene- gene which codes for a nuclear hormone receptor 3. Morphologya. Microscopically-uniform cell appearance forming small follicles including colloid –not arranged areas with back to back follicle irregular shape areas only tumor cells no CT or c cells etc.. Encapsulated but invade the capsule! And may see hurthle cells b. Grossly may be widely invasive of minimally invasive minimally invasive carcinoma is sharply demarcated and may be indistinguishable from follicular adenoma on gross examination 4. Clinical features a. Manifests as solitary cold thyroid nodules. In rare cases may be hyperfictional b. Unlike carcinoma usually lymphatic spread it show Hematogenouse dissemination to lung, bone and liver( which other carcinomas show it ? hepatocellular renal cell carcinoma and choriocarcinomas ) Medullary carcinoma 1. Neuroendocrine neoplasm arise from C cell (parfollicular cells) and secretes calcitonin. In some cases, tumor cells elaborate other polypeptide hormones such as somatostatin, serotonin and VIP. 2. Majority are sporadic and minority are familial associated with MEN 2A or 2B syndromes or notassociated with MEN syndrome. a. Sporadic and familial not associated with MEN- occur in adult. 50-60 yo b. Familial associated with MEN- seen in younger patients including children. 3. Pathogenesis a. Genetics: i. Familial medullary thyroid cancer occur in multiple endocrine neoplasia type 2 and are associated with germline RET proto- oncogene mutation that leads to constitutive activation of receptor ii. RET mutations are also seen in sporadic cases. b. Environment- ionizing radiation 4. Morphology a. May arise as a solitary nodule or as multiple lesions on both thyroid lobes. b. Micro: i. Nests of polygonal neoplastic cells in amyloid stroma derived from altered calcitonin molecules. ii. Calcitonin is demonstrated within the cytoplasm of tumor cells and in stroma iii. EM reveleas variable number of intracytoplasmic membrane bound, electron-dense granules iv. Familial medullary carcinoma 1. Multicentricity- large lesion contain areas of necrosis and hemorrhage and may extend through the capsule of the gland 2. Multicentric C cell hyperplasia in the surrounding thyroid parenchyma a. It is believed to be precursor lesions from which medullary carcinoma arise. 5. Clinical features a. Manifests as a mass in the neck i. Associated with compression effects such as dysphagia and hoarseness b. In some cases manifests as secretion of peptide hormones i. Diarrhea caused by VIP c. Early detection of familial cases can be done by i. Patient's relatives for elevated calcitonin level ii. RET mutations Anaplastic carcinoma 1. Presentation Females>males; age >60 years Firm, enlargeing, bulky mass Tendency for early widespread metastasis and invasion of the trachea and esophagus a. Risk factor- past history of well differentiated thyroid carcinoma 2. Pathogenesis a. De novo or more common as Dedifferentiation of well-differentiated papillary or follicular carcinome b. Genetics Molecular alteration seen in well differenatiated carcinoma (RAS or PIK3CA mutation) Inactivation of TP53 is essentially restricted to anaplastic carcinoma c. Environment- ionizing radiation 3. Micro: undifferentiated, anaplastic cells a. large pleomorphic giant cells b. spindle cells with sacromatous appearance c. mixed spindle and giant cell lesions 4. Prognosis: very aggressive and rapidly fatal.

Answer 130

Tóm tắt về Tuyến Cận Giáp và Các Rối Loạn Liên Quan Tuyến Cận Giáp (Parathyroid Glands) - **Nguồn gốc**: Được phát triển từ các túi hầu, cũng là nơi phát triển tuyến ức. - **Cấu trúc**: Chủ yếu là tế bào chính, chứa các hạt tiết hormone cận giáp (PTH). Tế bào oxyphil có mặt rải rác, lớn hơn tế bào chính, có bào tương ưa axit và chứa nhiều ty thể. - **Hoạt động**: Được kiểm soát bởi mức canxi ion hóa trong máu. Khi mức canxi giảm, tuyến cận giáp tăng sản xuất và tiết PTH với các tác dụng: - Tăng tái hấp thu canxi ở ống thận. - Tăng bài tiết phosphate qua nước tiểu. - Tăng chuyển đổi vitamin D thành dạng hoạt động ở thận. - Tăng hoạt động của các tế bào hủy xương. - **Hệ quả**: Tăng mức canxi tự do, ngăn chặn tiết PTH thêm. - **Khối u tuyến cận giáp**: Thường gây chú ý do tiết quá nhiều PTH, thay vì ảnh hưởng khối lượng. Cường Cận Giáp (Hyperparathyroidism) 1. **Cường cận giáp nguyên phát (Primary Hyperparathyroidism)** - **Nguyên nhân chính của tăng calci máu.** - **95%** các trường hợp do u tuyến cận giáp hoặc tăng sản tuyến cận giáp không di truyền: - U tuyến (85-95%). - Tăng sản (5-10%). - Ung thư tuyến cận giáp (1%). - **Đột biến gene**: Liên quan đến hội chứng đa tuyến nội tiết MEN-1 và MEN-2A, và đột biến gene cyclin D1. - **Hình thái**: - U tuyến: Khối đơn độc, có vỏ sợi mỏng, thường chỉ ở một tuyến. - Tăng sản: Quá trình đa tuyến, thường gặp mẫu tăng sản tế bào chính. - Ung thư: Có thể là tổn thương bao bọc hoặc xâm lấn rõ ràng. 2. **Cường cận giáp thứ phát (Secondary Hyperparathyroidism)** - **Nguyên nhân**: Do bất kỳ tình trạng nào gây giảm canxi máu mạn tính, chủ yếu do suy thận. - **Cơ chế**: Suy thận giảm bài tiết phosphate, giảm tổng hợp vitamin D hoạt động, kích thích tăng hoạt động tuyến cận giáp. - **Hình thái**: Tăng sản tế bào chính hoặc tế bào trong suốt, phân bố khuếch tán hoặc đa nốt. - **Lâm sàng**: Canxi máu thấp hoặc bình thường, PTH tăng cao. 3. **Cường cận giáp tam phát (Tertiary Hyperparathyroidism)** - **Định nghĩa**: Tình trạng tiết PTH quá mức sau cường cận giáp thứ phát kéo dài, dẫn đến tăng canxi máu. - **Nguyên nhân**: Thường gặp ở bệnh nhân suy thận mạn, sau ghép thận. - **Cơ chế**: Tuyến cận giáp phì đại trở nên tự động, tiếp tục tiết PTH dù mức canxi máu bình thường hoặc cao. Suy Cận Giáp (Hypoparathyroidism) - **Nguyên nhân chính**: 1. **Cắt bỏ tuyến cận giáp**. 2. **Thiếu bẩm sinh**: Liên quan đến hội chứng Di George và khuyết tật tim, do đột biến trên nhiễm sắc thể 22q11.2. 3. **Tự miễn dịch**: Hội chứng thiếu hụt đa tuyến nội tiết do đột biến gene AIRE. - **Triệu chứng lâm sàng**: Do giảm canxi máu, bao gồm tăng kích thích cơ thần kinh, loạn nhịp tim, tăng áp lực nội sọ và co giật. - **Thay đổi hình thái**: Không rõ ràng, nhưng có thể bao gồm đục thủy tinh thể, vôi hóa hạch nền não, và bất thường răng.  The parathyroid glands are derived from the developing pharyngeal pouches that also give rise to the thymus.  They Most of the gland is composed of chief cells They contain secretory granules of parathyroid hormone (PTH). Oxyphil cells are found throughout the normal parathyroid either singly or in small clusters. They are slightly larger than the chief cells, have acidophilic cytoplasm, and are tightly packed with mitochondria.  The activity of the parathyroid glands is controlled by the level of free (ionized) calcium in the bloodstream, rather than by trophic hormones secreted by the hypothalamus and pituitary.  Normally, decreased levels of free calcium stimulate the-synthesis and secretion of PTH, with the following effects: - Increase in renal tubular reabsorption of calcium Increase in urinary phosphate excretion - Increase in the conversion of vitamin D to its active dihydroxy form in the kidneys - Enhancement of osteoclastic activity mediated indirectly by promoting the differentiation of osteoclast progenitor cells into mature osteoclasts  The net result of these activities is an increase in the level of free calcium, which inhibits further PTH secretion.  Tumors of the parathyroid glands, unlike thyroid tumors, usually come to attention because of excessive secretion of PTH, rather than mass effects. HYPERPARATHYROIDISM  Hyperparathyroidism occurs in two major forms, primary and secondary, and, less commonly, as tertiary hyperparathyroidism. PRIMARY HYPERPARATHYROIDISM  Important cause of hypercalcemia.  In more than 95% of cases, primary hyperparathyroidism is caused by a sporadic parathyroid adenoma or sporadic hyperplasia. - Adenoma—85% to 95% - Primary hyperplasia (diffuse or nodular)—5% to 10% - Parathyroid carcinoma—1%  The genetic defects identified in familial primary hyperparathyroidism: include multiple endocrine neoplasia syndromes, specifically MEN-1 and MEN-2A . Familial hypocalciuric hypercalcemia is a rare caused by inactivating mutations in the calciumsensing receptor gene on parathyroid cells, leading to constitutive PTH secretion. 1) Cyclin D1 gene inversions: Cyclin D1 is a positive regulator of the cell cycle. In ~40% of adenomas see over expression one mechanism include A chromosomal inversion on chromosome 11 results in relocation of the cyclin D1 gene adjacent to the region of the PTH gene leading to abnormal expression of cyclin D1 protein and increased proliferation. 2) MEN1 mutations both in sporadic and familial cases  Morphology: adenoma = - the typical parathyroid adenoma is a well circumscribed solitary nodule, invested by a delicate fibrous capsule.parathyroid adenomas are almost invariably confined to single gland the remaining glands are normal in size or somewhat shrunken, as a result of feedback inhibition by elevated serum calcium. - micro= parathyroid adenomas are composed predominantly of chief cells Cells pleomorphic nuclei are often seen within adenomas (so-called endocrine atypia) and must not be taken as a sign of malignancy, Mitotic figures are rare. Parathyroid hyperplasia  Typically a multiglandular process. In some cases may appear only one or two glands, complicating the distinction between hyperplasia and adenoma.  Microscopicallythe most common pattern seen is that of chief cell hyperplasia, which may involve the glands in a diffuse or multinodular pattern. “Waterclear cell hyperplasia.” – cells contain abundant glycogen in their cytoplasm. Stromal fat is inconspicuous within foci of hyperplasia. Parathyroid carcinomas - may be circumscribed lesions that are difficult to distinguish from adenomas, or they may be clearly invasive neoplasms. These tumors enlarge one parathyroid gland and consist of gray-white, irregular masses that sometimes exceed 10 g in weight. - The cells usually are uniform and resemble normal parathyroid cells diagnosis of carcinoma based on cytologic detail is unreliable, and invasion of surrounding tissues and metastasis are the only definitive criteria. Morphologic changes in other organs(result from increase calcium) - Skeletal changes = include increased osteoclastic activity, which results in erosion of bone matrix particularly in the metaphyses of long tubular bones. - Bone resorption is accompanied by increased osteoblastic activity and the formation of new bone trabeculae. In severe cases the cortex is grossly thinned and the marrow contains increased amounts of fibrous tissue accompanied by foci of hemorrhage and cysts (osteitis fibrosa cystica) also Aggregates of osteoclasts, reactive giant cells, and hemorrhagic debris (brown tumors of hyperparathyroidism). - Nephrolithiasis, as well as calcification of the renal interstitium and tubules (nephrocalcinosis) - Metastatic calcification may be seen in other sites, including the stomach, lungs, myocardium, and blood vessels.  clinical features he most common manifestation of primary hyperparathyroidism is an increase in serum ionized calcium - serum PTH is elevated( serum PTH is low with hypercalcemia caused by nonparathyroid diseases or malignancy). Other laboratory alterations referable to PTH excess include hypophosphatemia and increased urinary excretion of both calcium and phosphate.  symptoms that included “painful bones secondary to fractures of bones weakened by osteoporosis, renal stones, Gastrointestinal disturbances, and Central nervous system alterations, including depression, lethargy, and seizures Neuromuscular abnormalities, including weakness and hypotonia Secondary Hyperparathyroidism  Caused by any condition associated with a chronic low serum calcium levels leads to compensatory overactivity (hyperplasia)of the parathyroids.  Renal failure is by far the most common cause of secondary hyperparathyroidism. Associated with decreased phosphate excretion- elevated serum phosphate levels directly depress serum calcium levels and thereby stimulate parathyroid gland activity. In addition, loss of renal substances reduces the availability of α1-hydroxylase enzyme necessary for the synthesis of the active form of vitamin D, which in turn reduces intestinal absorption of calcium  Other caus is vitaD defficency.  The hyperplastic glands contain an increased number of chief cells, or cells with more abundant, clear cytoplasm (water-clear cells), in a diffuse or multinodular distribution. Fat cells are decreased in number.  Clinical- Patients with secondary hyperparathyroidism usually have a low-normal calcium and elevated parathyroid hormone. sings relate to renal failure e.g. renal osteodystrophy and other symptoms as above to lesser extent then primary cus calcium is normal. Tertiary Hyperparathyroidism  Definition- a state of excessive secretion of parathyroid hormone after longstanding secondary hyperparathyroidism and resulting in hypercalcemia.  Pathophysiology - Tertiary hyperparathyroidism is observed most commonly in patients with chronic secondary hyperparathyroidism and often after renal transplantation. The hypertrophied parathyroid glands fail to return to normal and continue to over secrete parathyroid hormone, despite serum calcium levels that are within the reference range or even elevated. In these cases, the hypertrophied glands become autonomic and cause hypercalcemia  The etiology is unknown but A change may occur in the set point of the calcium-sensing mechanism to hypercalcemic levels or may be due to monoclonal expansion of parathyroid cells (nodule formation within hyperplastic glands). Four-gland involvement occurs in most patients. HYPOPARATHYROIDISM  Less common then hyper state The major causes of hypoparathyroidism include the following: 1) Surgically removal of parathyroid gland 2) Congenital absence: This occurs together with thymic aplasia (Di George syndrome) and cardiac defects, secondary to deletions on chromosome 22q11.2 3) Autoimmune hypoparathyroidism: This is a hereditary polyglandular deficiency syndrome arising from autoantibodies to multiple endocrine organs (parathyroid, thyroid, adrenals, and pancreas). This condition is caused by mutations in the autoimmune regulator gene (AIRE)  The major clinical manifestations of hypoparathyroidism are secondary to hypocalcemia and include: - increased neuromuscularirritability (tingling, muscle spasms or tetany) - cardiac arrhythmias - increased intracranial pressures and seizures.  Morphologic changes generally are inconspicuous but may include cataracts, calcification of the cerebral basal ganglia, and dental abnormalities.

Answer 131

Tóm tắt về Tuyến Thượng Thận và Các Rối Loạn Liên Quan Cấu trúc của Tuyến Thượng Thận - **Vỏ thượng thận** có ba lớp tế bào đặc trưng: - **Zona glomerulosa**: Sản xuất mineralocorticoid, quan trọng nhất là aldosterone. - **Zona fasciculata**: Sản xuất glucocorticoid, chủ yếu là cortisol. - **Zona reticularis**: Sản xuất hormone sinh dục (estrogen và androgen). - **Tủy thượng thận**: Gồm các tế bào chromaffin, tổng hợp và tiết catecholamine, chủ yếu là epinephrine. Cường chức năng vỏ thượng thận (Hyperadrenalism) 1. **Hội chứng Cushing (Hypercortisolism)** - **Nguyên nhân**: 1. Dùng glucocorticoid ngoại sinh. 2. Nguyên nhân nội sinh: a. **Bệnh Cushing**: Do bệnh lý tuyến yên, tăng tiết ACTH, phổ biến ở phụ nữ trưởng thành. b. **Tiết ACTH ngoại lai**: Thường do ung thư tế bào nhỏ ở phổi, carcinoid, hoặc ung thư tủy tuyến giáp. c. **U vỏ thượng thận nguyên phát** (u lành hoặc ung thư): Gây hội chứng Cushing không phụ thuộc ACTH. - **Hình thái học**: - Tuyến yên: Thay đổi hyaline Crooke. - Tuyến thượng thận: Có thể teo vỏ (do dùng glucocorticoid ngoại sinh), tăng sản khuếch tán, hoặc có nốt lớn/nhỏ. - U vỏ thượng thận: U lành thường có màu vàng, được bao bọc bởi vỏ mỏng, ung thư thường không có vỏ, lớn hơn và nặng hơn. - **Triệu chứng lâm sàng**: - Tăng huyết áp, tăng cân, béo phì vùng trung tâm, mặt tròn (moon facies). - Teo cơ, yếu cơ, tăng đường huyết, loãng xương, suy giảm miễn dịch. - Tăng sắc tố da (trong trường hợp tiết ACTH từ tuyến yên hoặc ngoại lai). 2. **Cường aldosteron (Hyperaldosteronism)** - **Nguyên nhân**: - **Nguyên phát**: Sản xuất aldosteron tự động, thường do u tuyến vỏ thượng thận (hội chứng Conn) hoặc tăng sản nốt hai bên tuyến thượng thận. - **Thứ phát**: Do tăng tiết renin (giảm tưới máu thận, giảm thể tích máu, hoặc mang thai). - **Hình thái học**: - U tuyến sản xuất aldosteron: Khối u nhỏ, màu vàng sáng, có các thể xoắn (spironolactone bodies) sau khi điều trị bằng spironolactone. - Tăng sản nốt hai bên: Tăng sản tế bào giống tế bào của zona glomerulosa. - **Triệu chứng lâm sàng**: - Tăng huyết áp, hạ kali máu, yếu cơ, dị cảm, rối loạn thị giác. 3. **Hội chứng sinh dục thượng thận (Adrenogenital Syndromes)** - **Nguyên nhân**: - **U tuyến hoặc ung thư vỏ thượng thận**: Sản xuất quá mức androgen. - **Tăng sản thượng thận bẩm sinh (CAH)**: Do đột biến di truyền gây thiếu hụt enzyme 21-hydroxylase. - **Hình thái học**: - Tăng sản thượng thận bẩm sinh: Tuyến thượng thận phì đại, lớp vỏ dày, nâu, do mất lipid. - **Triệu chứng lâm sàng**: - Ở nữ: Mụn trứng cá, mọc lông nhiều, nam hóa, rối loạn chức năng sinh sản. - Ở nam: Tăng kích thước cơ quan sinh dục ngoài, dậy thì sớm, oligospermia ở người lớn. - Thiếu hụt cortisol và aldosterone có thể dẫn đến suy thượng thận cấp tính. Suy chức năng cận giáp (Hypoparathyroidism) - **Nguyên nhân chính**: 1. Cắt bỏ tuyến cận giáp. 2. Thiếu bẩm sinh (hội chứng Di George). 3. Tự miễn dịch (đột biến gene AIRE). - **Triệu chứng lâm sàng**: Do giảm canxi máu, bao gồm tăng kích thích cơ thần kinh, loạn nhịp tim, tăng áp lực nội sọ, và co giật. - **Thay đổi hình thái**: Không rõ ràng, nhưng có thể bao gồm đục thủy tinh thể, vôi hóa hạch nền não, và bất thường răng. Tổng kết Các rối loạn liên quan đến tuyến thượng thận và cận giáp có thể gây ra nhiều triệu chứng và biến chứng nghiêm trọng. Việc hiểu rõ nguyên nhân và cơ chế bệnh sinh của từng rối loạn sẽ giúp chẩn đoán và điều trị hiệu quả hơn.  The cortex consists of three layers of distinct cell types: Zona glomerulosa- Mineralocorticoids, the most important being aldosterone, which are generated in here Broad zona fasciculate - Glucocorticoids (principally cortisol), which are synthesized primarily in here Zona reticularis - Sex steroids (estrogens and androgens), which are produced largely in here  The adrenal medulla is composed of chromaffin cells, which synthesize and secrete catecholamines, mainly epinephrine. ADRENOCORTICAL HYPERFUNCTION (HYPERADRENALISM) Include: (1) Cushing syndrome, characterized by an excess of cortisol; (2) hyperaldosteronism; (3) adrenogenital or virilizing syndromes, caused by an excess of androgens. Hypercortisolism and Cushing Syndrome  Cushing syndrome, clinical manifestation of condition that produces an elevation in glucocorticoid levels.  Causes: 1) Administration of exogenous glucocorticoids (iatrogenic). 2) Endogenous: a. Cushing disease  Primary hypothalamic pituatiry diseas manifest with increase ACTH realis more common in Women at early adulthood. 70% of endogenous Cushing syndrome.  the pituitary gland contains an ACTH-producing microadenoma that does not produce mass effects in the brain; In the remaining patients corticotroph cell hyperplasia (which may be primary or, much less commonly, secondary to excessive ACTH release by a hypothalamic corticotropinreleasing hormone (CRH)–producing tumor).  ACTH increase manifest on adrenal gland as nodular cortical hyperplasia is in turn responsible for the hypercortisolism. b. secretion of ectopic ACTH by non-pituitary neoplasms  most common tumor in connection is Small cell carcinoma of the lung other neoplasms, including carcinoids, medullary carcinomas of the thyroid .  The adrenal glands undergo bilateral cortical hyperplasia secondary to elevated ACTH, but the rapid downhill course of patients with these cancers often cuts short the adrenal enlargement. C. Primary adrenocortical neoplasms (adenoma or carcinoma) and rarely, primary cortical hyperplasia  This form of Cushing syndrome is also designated ACTH-independent Cushing syndrome, or adrenal Cushing syndrome, because the adrenals function autonomously.  The biochemical hallmark of adrenal Cushing syndrome is elevated levels of cortisol with low serum levels of ACTH.  Morphology The pituitary- in Cushing syndromeThe most common alteration Crooke hyaline change the normal granular, basophilic cytoplasm of the ACTH-producing cells in the anterior pituitary is replaced by homogeneous, lightly basophilic material = This alteration is the result of the accumulation of inter mediate keratin filaments in the cytoplasm. adrenal glands also depend on the cause of the hypercortisolism: (1) cortical bilateral atrophy – in iatrogenic glucocorticoids admenistration (2) diffuse hyperplasia- found in ACTH dependent Cushing syndrome, both glands are enlraged Variable nodularity, yellow color from the presence of lipid rich cells (3) Macronodular or micronodular hyperplasia- in primary cortical hyperplasia= cortex is replaced by macro/micro nodules (1-3 mm) if see dark pigment = lipofuscin. (4) adenoma or a carcinoma - Adrenocortical adenomas are yellow tumors surrounded by thin or well developed capsules, and most weigh less than 30 g ,On histo = they are composed of cells similar to those encountered in the normal zona fasciculata - The carcinomas associated with Cushing syndrome, by contrast, tend to be larger than the Adenomas, nonencapsulated masses ,frequently exceeding 200 to 300 g in weight, having all of the anaplastic characteristics of cancer. - Atrophy can be seen in adjacent/ contralateral side due to ACTH suppression.  Clinical Features Hypertension and weight gain. characteristic centripetal distribution of adipose tissue becomes apparent, with resultant truncal obesity “moon facies,” Hypercortisolism causes selective atrophy of fast-twitch (type II) myofibers, with resultant decreased muscle mass and proximal limb weakness. Glucocorticoids induce gluconeogenesis resultant hyperglycemia, glucosuria, and polydipsia, mimicking diabetes mellitus. The catabolic effects on proteins cause loss of collagen and resorption of bone = the skin is thin, fragile, and easily bruised; cutaneous striae are particularly common in the abdominal area. Bone resorption results in osteoporosis fractures Because glucocorticoids suppress the immune response mental disturbances Extra adrenal Cushing syndrome caused by pituitary or ectopic ACTH secretion usually is associated with increased skin pigmentation. Hyperaldosteronism  a group of closely related conditions characterized by chronic excess aldosterone secretion.  Hyperaldosteronism may be primary, or it may be secondary to an extra adrenal cause aldosterone release occurs in response to activation of the renin-angiotensin system = characterized by increased levels of plasma renin and is encountered in association with o Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis) o Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome) o pregnancy (caused by estrogen-induced increases in plasma renin substrate)  Primary hyperaldosteronism- a primary, autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system and decreased plasma renin activity. causes of primary hyperaldosteronism: o Bilateral idiopathic hyperaldosteronism, characterized by bilateral nodular hyperplasia of the adrenal glands. o Adrenocortical neoplasm, either an aldosterone-producing adenoma = conn syndrome (the most common cause) or, rarely, an adrenocortical carcinoma. In approximately 35% of cases o Rarely, familial hyperaldosteronism may result from a genetic defect that leads to overactivity of the aldosterone synthase gene, CYP11B2.  Morphology: - Aldosterone-producing adenomas are almost always solitary, small well-circumscribed lesions. They are bright yellow on cut section and composed of lipid-laden cortical cells more closely resembling fasciculata cells than glomerulosa cells the cells tend to be uniform in appearance A characteristic feature of is the presence of eosinophilic, laminated cytoplasmic inclusions, known as spironolactone bodiesthese typically are found after treatment with the antihypertensive agent spironolactone(antagonist) - Bilateral idiopathic hyperplasia is marked by diffuse or focal hyperplasia of cells resembling those of the normal zona glomerulosa.  Clinical Features The clinical hallmark of hyperaldosteronism is hypertension = cardiovascular compromise (e.g., left ventricular hypertrophy and reduced diastolic volumes) ,stroke and myocardial infarction. Hypokalemia results from renal potassium wasting and, when present, can cause a variety of neuromuscular manifestations, including weakness, paresthesias, visual disturbances, and occasionally frank tetany Adrenogenital Syndromes  Excess production of androgens from zona reticularis Unlike gonadal androgens, adrenal androgen formation is regulated by ACTHthus, excessive secretion can present as an isolated syndrome or in combination with features of Cushing disease.  The adrenal cortex secretes two compounds—dehydroepiandrosterone and androstenedione—which require conversion to testosterone in peripheral tissues for their androgenic effects.  The adrenal causes = include adrenocortical neoplasms and congenital adrenal hyperplasia (CAH). Adrenocortical neoplasms associated with symptoms of androgen excess (virilization) are more likely to be carcinomas than adenomas.CAH Congenital adrenal hyperplasias – group of autosomal recessive disorders; 21-hydroxylase deficiency due to mutations in the CYP21A2 gene accounts for approximately 95 percent of cases. In these conditions, decreased cortisol production results in a compensatory increase in ACTH secretion due to absence of feedback inhibitionThe resultant adrenal hyperplasia causes increased production of cortisol precursor steroids, which are then channeled into synthesis of androgens with virilizing activity. deficiency may range in degree from a total lack to a mild loss. Morphology: o In all cases of CAH, the adrenals are hyperplastic bilaterally, sometimes expanding to 10 to 15 times their normal weights. o The adrenal cortex is thickened and nodular, and on cut section, the widened cortex appears brown as a result of depletion of all lipid. o The proliferating cells mostly are compact, eosinophilic, lipid-depleted cells, intermixed with lipid-laden clear cells. o adrenomedullary dysplasia also has recently been reported in patients with the salt-losing 21-hydroxylase deficiencyThis is characterized by incomplete migration of the chromaffin cells to the center of the gland, with pronounced intermingling of nests of chromaffin and cortical cells in the periphery. Clinical features:  Depending on the nature and severity of the enzymatic defect, the onset of clinical symptoms may occur in the perinatal period, later childhood, or (less commonly) adulthood.  In 21-hydroxylase deficiencyThe most severely affected individuals with classic CAH due to 21-hydroxylase deficiency present during the neonatal period and early infancy with adrenal insufficiency and salt wasting or in the first few years of life with virilization In females -Androgen excess causing variable clinical features such as acne, hirsutism, virilization, and reproductive dysfunction. In males- androgen excess is associated with enlargement of the external genitalia and other evidence of precocious puberty in prepubertal patients and with oligospermia in older patients. the enzymatic defect is severe enough to produce mineralocorticoid deficiency, with resultant salt (sodium) wasting.  In some forms of CAH e.g., 11β-hydroxylase deficiency the accumulated intermediary steroids have mineralocorticoid activitywith resultant sodium retention and hypertension Cortisol deficiency places persons with CAH at risk for acute adrenal insufficiency

Answer 132

Tóm tắt về Tủy Thượng Thận và Các Khối U Liên Quan Tủy Thượng Thận (Adrenal Medulla) - **Cấu trúc**: Gồm các tế bào chromaffin và tế bào hỗ trợ (sustentacular cells), có nguồn gốc từ mào thần kinh. - **Chức năng**: Tế bào chromaffin tổng hợp và tiết catecholamine (chủ yếu là epinephrine) dưới tác động của các sợi thần kinh trước hạch trong hệ thần kinh giao cảm. - **Hệ thống paraganglion ngoại tuyến thượng thận**: Bao gồm các tế bào tương tự, phân bố khắp cơ thể. Các Khối U Thần Kinh (Neuroblastic Tumors) - Bao gồm neuroblastoma, ganglioneuroblastoma và ganglioneuroma, phát sinh từ các tế bào thần kinh giao cảm nguyên thủy. - **Nguồn gốc**: Từ mào thần kinh trong quá trình phát triển bào thai, chủ yếu đến tủy thượng thận và hệ thần kinh giao cảm. - **U tế bào chromaffin**: Pheochromocytoma và paraganglioma phát sinh từ các tế bào chromaffin, cũng có nguồn gốc từ mào thần kinh. Pheochromocytoma - **Đặc điểm**: Khối u này gồm các tế bào chromaffin, tổng hợp và tiết catecholamine, gây ra một dạng tăng huyết áp có thể điều trị phẫu thuật. - **Quy tắc 10%**: 1. 10% pheochromocytoma nằm ngoài tuyến thượng thận (paraganglioma). 2. 10% pheochromocytoma thượng thận là hai bên, tỉ lệ này tăng lên 50% ở các trường hợp liên quan đến hội chứng gia đình. 3. 10% pheochromocytoma thượng thận là ác tính. - **Nguyên nhân di truyền**: 25% bệnh nhân có đột biến gene di truyền, liên quan đến các hội chứng như MEN2, NF1, và bệnh von Hippel-Lindau (VHL). - **Hình thái học**: - Kích thước từ nhỏ, dễ nhận biết đến lớn, có thể xuất huyết. - Màu vàng-nâu khi tiếp xúc với kali dichromate. - Tế bào chính có hình đa giác, sắp xếp thành các nốt nhỏ. - Tế bào hỗ trợ có nhiệm vụ cấu trúc. - Chẩn đoán ác tính dựa trên sự hiện diện của di căn. - **Triệu chứng lâm sàng**: - Tăng huyết áp, nhịp tim nhanh, đánh trống ngực, đau đầu, đổ mồ hôi, run rẩy. - Chẩn đoán bằng cách đo lượng catecholamine và chất chuyển hóa trong nước tiểu. - Điều trị pheochromocytoma là phẫu thuật cắt bỏ. Neuroblastoma - **Nguồn gốc**: Từ các tế bào thần kinh giao cảm nguyên thủy trong tủy thượng thận và hệ thần kinh giao cảm. - **Phổ biến**: Khối u ác tính rắn thứ hai ở trẻ em sau khối u não, thường gặp ở trẻ từ 0-4 tuổi. - **Nguyên nhân di truyền**: 1-2% trường hợp do di truyền với đột biến gene ALK. - **Hình thái học**: - Khoảng 40% phát sinh trong tủy thượng thận, còn lại dọc theo chuỗi giao cảm, chủ yếu ở vùng bụng và trung thất sau. - Màu xám-nâu, mềm, có thể có hoại tử, chảy máu. - Tế bào nhỏ, nguyên thủy với nhân tối màu và ranh giới tế bào kém rõ ràng, tạo thành các tấm tế bào. - Pseudorosette Homer-Wright: Các tế bào khối u sắp xếp quanh không gian trung tâm chứa neuropil. - Ganglioneuroblastoma: U có sự trưởng thành thành tế bào hạch lớn hơn. - Ganglioneuroma: U có nhiều tế bào hạch trưởng thành, không còn tế bào nguyên thủy. - **Tiến triển và tiên lượng**: - Giai đoạn và tuổi của bệnh nhân là yếu tố quyết định tiên lượng. - Trẻ dưới 18 tháng có tiên lượng tốt hơn. - Hình thái học và mức độ khuếch đại gene NMYC cũng ảnh hưởng đến tiên lượng. - Trẻ dưới 2 tuổi thường có khối u bụng, sốt, và giảm cân. - Di căn phổ biến đến gan, phổi, xương, và tủy xương. Tổng kết Các rối loạn và khối u liên quan đến tuyến thượng thận và cận giáp có thể gây ra nhiều triệu chứng và biến chứng nghiêm trọng. Việc hiểu rõ nguyên nhân và cơ chế bệnh sinh của từng rối loạn sẽ giúp chẩn đoán và điều trị hiệu quả hơn.  Adrenal medulla- populated by cells derived from the neural crest (chromaffin cells) and their supporting (sustentacular) cells.  The chromaffin cells, so named because of their brown-black color after exposure to potassium dichromate, synthesize and secrete catecholamines in response to signals from preganglionic nerve fibers in the sympathetic nervous system.  Similar collections of cells are distributed throughout the body in the extraadrenal paraganglion system. The spectrum of neuroblastic tumors (including neuroblastomas, ganglioneuroblastomas, and ganglioneuromas) that arise from primitive sympathetic ganglion cells. The cells that comprise neuroblastic tumors originate from the neural crest during fetal development, and are destined for the adrenal medulla and sympathetic nervous system. By contrast, pheochromocytomas and paragangliomas arise from a different type of cell, the chromaffin cell, that also migrates from the neural crest to the adrenal gland Pheochromocytoma  Pheochromocytomas are neoplasms composed of chromaffin cells, which, synthesize and release catecholamines. Hence special importance (although uncommon) they give rise to a surgically correctable form of hypertension.  Pheochromocytomas usually subscribe to a convenient “rule of 10s”: 1) 10% of pheochromocytomas are extraadrenal, occurring in sites such as the organ of Zuckerkandl and the carotid body, where they usually are called paragangliomas. 2) 10% of adrenal pheochromocytomas are bilateral; this proportion may rise to 50% in cases that are associated with familial syndromes. 3) 10% of adrenal pheochromocytomas are malignant  One “traditional” 10% rule that has since been modified pertains to familial cases. It is now recognized that as many as 25% of persons with pheochromocytomas and paragangliomas harbor a germ line mutation associated with 3 syndromes: 1. RET, which causes type 2 MEN syndromes; 2. NF1 Defect in neurofibromin gene a protein -tumor suppressor gene that downregulates p21 ras oncoprotein; highest levels in neural tissue which causes type 1 neurofibromatosis, 3. VHL, which causes von Hippel-Lindau disease VHL associated with the following:  Pheochromocytoma  Cerebellar hemangioblastoma  Renal cell carcinoma  Renal and pancreatic cysts One study found that this syndrome was present in nearly 19% of patients with pheochromocytomas. VHL disease is caused by mutations in the VHL gene encodes a protein that plays a role in cilia formation, regulation of cellular senescence, and the oxygen-sensing pathway. and also associated with three genes encoding subunits within the succinate dehydrogenase complex which is involved in mitochondrial oxidative phosphorylation.  Morphology - Pheochromocytomas range in size from small, circumscribed lesions confined to the adrenal to large, hemorrhagic masses. On cut surface, smaller pheochromocytomas are yellow-tan, well-defined lesions that compress the adjacent adrenal - Incubation of the fresh tissue with potassium dichromate solutions turns the tumor dark brown - Histo = Chief cells: polygonal cells, may be spindled. Arranged in cell nests - "Zellballen" (literally cell balls) highly vascular. (salt and pepper chromatin) - coarsely granular chromatin. Granular cytoplasm basophilic pleomorphism. - Sustentacular cells (structural support cell). - Surrounding adrenal cortex is typically compressed. - not uncommon to see pleomorphisem the definitive diagnosis of malignancy in pheochromocytomas is based exclusivel on the presence of metastases.(involve regional lymph nodes as well as more distant sites, including liver, lung, and bone.) Clinical Features  Hypertension = associated with tachycardia, palpitations, headache, sweating, tremor  Sudden cardiac death may occur, probably secondary to catecholamine-induced ventricular arrhythmias.  The laboratory diagnosis of pheochromocytoma is based on demonstration of increased urinary excretion of free catecholamines and their metabolites  Isolated benign pheochromocytomas are treated with surgical excision. NEUROBLASTOMA  The term neuroblastic includes tumors of the sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cells populating these sites(neuroblasts); neuroblastoma is most prominent member of these group.  It is the second most common solid malignancy of childhood after brain tumors, peak incidence 0-4 years  Neuroblastomas demonstrate several unique features in their natural history, including spontaneous regression and spontaneous or therapy-induced maturation.  Most occur sporadically, but 1% to 2% are familial, with autosomal dominant transmission, and in such cases the neoplasms may involve both of the adrenals or multiple primary autonomic sites.  Germ line gain of function mutations in the anaplastic lymphoma kinase gene (ALK)  is a major cause of familial predisposition to neuroblastoma. Somatic gain-of-function ALK mutations MORPHOLOGY:  In childhood, about 40% of neuroblastomas arise in the adrenal medulla,The remainder occur anywhere along the sympathetic chain, with the most common locations being the paravertebral region of the abdomen (25%) and posterior mediastinum (15%).  Macro = , neuroblastomas range in size from small nodules (the in situ lesions) to large masses On cut surface they are composed of soft, gray-tan tissue. Larger tumors have areas of necrosis, cystic softening, and hemorrhage. Some neuroblastomas are sharply demarcated with a fibrous pseudocapsule, but others are far more infiltrative and invade surrounding structures.  MICRO= classic neuroblastomas are composed of small, primitive-appearing cells with dark nuclei and poorly defined cell borders growing in sheets The background often demonstrates a faintly eosinophilic fibrillary material (neuropil) that corresponds to neuritic processes of the primitive neuroblasts. Homer- Wright pseudo-rosettes can be found in which the tumor cells are concentrically arranged about a central space filled with neuropil (the absence of an actual central lumen garners the designation “pseudo-”).  immunochemical detection of neuron-specific enolase and demonstration of catecholamine containing secretory granules.  ganglioneuroblastoma- neoplasms show signs of maturation Larger cells having more abundant cytoplasm with large vesicular nuclei and a prominent nucleolus, representing ganglion cells in various stages of maturation, may be found in tumors admixed with primitive neuroblasts  ganglioneuroma- lesions contain many more large cells resembling mature ganglion cells in the absence of residual neuroblast  Maturation of neuroblasts into ganglion cells usually is accompanied by the appearance of Schwann cells, and fibroblasts is a histologic prerequisite for the designation of ganglioneuroblastoma and ganglioneuroma;(appearance of only ganglion cells is not enough) Clinical Course and Prognosis  Many factors influence prognosis, but the most important are the stage of the tumor and the age of the patient. 1) Staging of neuroblastomas- stage 4S (S means special), because the outlook for these patients is excellent, despite the spread of disease.the primary tumor would be classified as stage 1 or 2 but for the presence of metastases, which are limited to liver, skin, and bone marrow, without bone involvement. Infants with 4S tumors have an excellent prognosis with minimal therapy, and it is not uncommon for the primary or metastatic tumors to undergo spontaneous regression. 2) Age is the other important determinant of outcome, outlook for children younger than 18 months is much more favorable than for older children at a comparable stage of disease. 3) Morphology is an independent prognostic variable in neuroblastic tumors; evidence of schwannian stroma and gangliocytic differentiation is indicative of a favorable histologic pattern. 4) Amplification of the NMYC oncogene in neuroblastomas is present in advanced-stage disease; the greater the number of copies, the worse the prognosis.  Children younger than 2 years with neuroblastomas generally present with protuberant abdomen resulting from an abdominal mass, fever, and weight loss. In older children the neuroblastomas may remain unnoticed until metastases cause hepatomegaly, ascites, and bone pain.  Neuroblastomas may metastasize widely through the hematogenous and lymphatic systems = to liver, lungs, bones, and the bone marrow.  In neonates, disseminated neuroblastomas may manifest with multiple cutaneous metastases associated with deep blue discoloration to the skin = “blueberry muffin baby”).  About 90% of neuroblastomas, regardless of location, produce catecholamines which constitutes an important diagnostic feature Despite the elaboration of catecholamines, hypertension is much less frequent with these neoplasms than with pheochromocytomas

Answer 133

Tóm tắt về Hội chứng Đa U Nội Tiết (MEN Syndromes) Tổng quan Hội chứng Đa U Nội Tiết (MEN) là nhóm các bệnh di truyền dẫn đến các tổn thương tăng sinh (tăng sản, u lành, và ung thư) ở nhiều cơ quan nội tiết. Các đặc điểm của các khối u nội tiết trong bối cảnh MEN so với các khối u đơn lẻ không di truyền bao gồm: 1. Các khối u này xuất hiện ở tuổi trẻ hơn so với ung thư không di truyền. 2. Xuất hiện ở nhiều cơ quan nội tiết, có thể đồng thời hoặc liên tiếp. 3. Thường là đa ổ ngay trong một cơ quan. 4. Thường được tiền phát bởi giai đoạn tăng sản nội tiết không có triệu chứng. 5. Thường xâm lấn mạnh và tái phát cao hơn so với các khối u nội tiết đơn lẻ. MEN Type 1 (MEN1) - **Di truyền**: Theo kiểu trội nhiễm sắc thể thường. - **Gene MEN1**: Nằm ở 11q13, là gene ức chế khối u, mã hóa protein menin, có vai trò điều hòa phiên mã và ổn định bộ gen. Mất chức năng của cả hai allele dẫn đến hình thành khối u. - **Cơ quan thường bị ảnh hưởng**: Tuyến cận giáp, tụy và tuyến yên (3 Ps). 1. **Tuyến cận giáp**: Tăng sản tuyến cận giáp nguyên phát là biểu hiện phổ biến nhất của MEN1 (80-95% bệnh nhân), xuất hiện quanh tuổi 40-50, có thể là tăng sản hoặc u lành. 2. **Tụy**: U nội tiết tụy là nguyên nhân hàng đầu gây tử vong trong MEN1, thường có tính xâm lấn và di căn. Thường gặp u tiết hormone như gastrinoma gây hội chứng Zollinger-Ellison và insulinoma gây hạ đường huyết. 3. **Tuyến yên**: U tuyến yên tiết prolactin là phổ biến nhất, có thể gây to đầu chi khi có u tiết somatotropin. MEN Type 2 (MEN2) - **Di truyền**: Theo kiểu trội nhiễm sắc thể thường, liên quan đến đột biến gene RET ở locus 10q11.2. - **Phân loại**: MEN2A và MEN2B, khác nhau về kiểu gen-kiểu hình. **MEN2A** - **Cơ quan thường bị ảnh hưởng**: 1. **Tuyến giáp**: Ung thư tủy giáp phát triển ở hầu hết các trường hợp không được điều trị, thường là đa ổ và có thể tìm thấy tăng sản tế bào C xung quanh. 2. **Tủy thượng thận**: Pheochromocytoma phát triển ở 50% bệnh nhân, thường là không ác tính. 3. **Tuyến cận giáp**: 10-20% bệnh nhân phát triển tăng sản tuyến cận giáp gây cường cận giáp nguyên phát. **MEN2B** - **Đột biến**: Đột biến gene RET duy nhất thay đổi một acid amin. - **Cơ quan thường bị ảnh hưởng**: 1. **Tuyến giáp và tủy thượng thận**: Tương tự MEN2A. 2. **Không phát triển cường cận giáp nguyên phát**. 3. **Biểu hiện ngoài nội tiết**: Bao gồm ganglioneuroma ở các vị trí niêm mạc (đường tiêu hóa, môi, lưỡi) và hình thể marfanoid (xương dài quá mức, giống hội chứng Marfan). - **Khác biệt chính**: - **MEN2A**: Không có các bất thường phenotypic như neuroma niêm mạc và hình thể marfanoid. - **Ung thư tủy giáp**: MEN2A có dạng ít xâm lấn hơn MEN2B. - **Tăng sản tuyến cận giáp**: Phổ biến trong MEN2A nhưng rất hiếm trong MEN2B. **Một dạng phụ thứ ba** của MEN2 là ung thư tủy giáp gia đình (FMTC) chỉ có ung thư tủy giáp mà không có các biểu hiện khác của MEN2.  The MEN syndromes are a group of inherited diseases resulting in proliferative lesions (hyperplasias, adenomas, and carcinomas) of multiple endocrine organs.  Like other inherited cancer disorders endocrine tumors arising in the context of MEN syndromes have certain distinctive features that are not shared with their sporadic counterparts: 1) These tumors occur at a younger age than that typical for sporadic cancers. 2) They arise in multiple endocrine organs, either synchronously or metachronously. 3) Even in one organ, the tumors often are multifocal. 4) The tumors usually are preceded by an asymptomatic stage of endocrine hyperplasia involving the cell of origin of the tumor 5) These tumors are usually more aggressive and recur in a higher proportion of cases than similar endocrine tumors that occur sporadically Multiple Endocrine Neoplasia Type 1  MEN type 1 is inherited in an autosomal dominant pattern.  The gene (MEN1) is located at 11q13 and is a tumor suppressor gene (This gene encodes protein- menin, that regulates transcription and genome stability. Menin appears to be located in the nucleus where it has binding partners including histone modifiers defective for the transforming growth factor-beta signaling pathway); thus, inactivation of both alleles of the gene is believed to be the basis for tumorigenesis.  Organs most commonly involved are the parathyroid, the pancreas, and the pituitary—the “3 Ps.” 1) Parathyroid: Primary hyperparathyroidism is the most common manifestation of MEN-1 (80% to 95% of patients) appear around age of 40 -50 . Parathyroid abnormalities include both hyperplasia and adenomas. 2) Pancreas: Endocrine tumors of the pancreas are the leading cause of death in MEN-1. These tumors usually are aggressive and manifest with metastatic disease. Pancreatic endocrine tumors often are functional (i.e., secrete hormones). Zollinger-Ellison syndrome, associated with gastrinomas, and hypoglycemia, related to insulinomas, are common endocrine manifestations . 3) Pituitary: The most frequent pituitary tumor in patients with MEN-1 is a prolactinsecreting macroadenoma. In some cases, acromegaly develops in association with somatotropin-secreting tumors Multiple Endocrine Neoplasia Type 2  MEN type 2 actually comprises two distinct groups of disorders that are unified by the occurrence of activating gain-of-function mutations of the RET proto-oncogene at chromosomal locus 10q11.2. The RET proto-oncogene encodes a putative tyrosine kinase receptorwhich appears to play a critical role in the normal function of pathways involved in enteric nervous system neurogenesis and renal organogenesis.  MEN-2 is inherited in an autosomal dominant pattern  A strong genotype-phenotype correlation has been recognized for the MEN-2 syndromes, and differences in mutation patterns account for the variable features in the two subtypes. MEN-2 is inherited in an autosomal dominant pattern. MEN 2A Organs commonly involved in MEN type 2A include 1) Thyroid: Medullary carcinoma of the thyroid develops in virtually all untreated cases. The tumors commonly are multifocal, and foci of C cell hyperplasia can be found in the adjacent thyroid. Familial medullary thyroid cancer is a variant of MEN-2A characterized by medullary thyroid cancers typically occurs at an older age and follows a more indolent course. 2) Adrenal medulla: Adrenal pheochromocytomas develop in 50% of the patients most are non malignant 3) Parathyroid: Approximately 10% to 20% of patients develop parathyroid gland hyperplasia with manifestations of primary hyperparathyroidism. MEN 2B  Patients with MEN-2B harbor a distinct germline RET mutation involving a single– amino acid change.  Organs commonly involved include the thyroid and the adrenal medulla.  The spectrum of thyroid and adrenal medullary disease is similar to that in MEN-2A, with the following differences: 1) Primary hyperparathyroidism does not develop in patients with MEN-2B. 2) Extraendocrine manifestations are characteristic in patients with MEN-2B. These include ganglioneuromas of mucosal sites (gastrointestinal tract, lips, tongue) and a marfanoid habitus, in which overly long bones of the axial skeleton give an appearance resembling that in Marfan syndrome all persons carrying germline RET mutations are advised to have prophylactic thyroidectomy to prevent the inevitable development of medullary carcinomas. Major diffarences:  Phenotype - MEN 2A patients do not have the phenotypic abnormalities of mucosal neuromas and marfanoid habitus found in MEN 2B patients  Medullary thyroid carcinoma - MEN 2A patients have a less virulent form of medullary thyroid carcinoma than do MEN 2B patients  Parathyroid hyperplasia - MEN 2A patients may have parathyroid hyperplasia, which is exceedingly rare in MEN 2B patients A third subtype of MEN 2 is familial medullary thyroid carcinoma only (FMTC only).

Answer 134

Tóm tắt về Xương và Các Rối Loạn Liên Quan Cấu trúc của Xương Xương là một loại mô liên kết khoáng hóa đặc biệt, bao gồm: - **Thành phần hữu cơ (35%)**: Gồm các tế bào xương và protein osteoid (collagen type 1). - **Thành phần vô cơ (65%)**: Chủ yếu là canxi hydroxyapatite (Ca10(PO4)6(OH)2). Rối loạn Bẩm sinh 1. **Dysostoses**: - Bất thường ở một hoặc một nhóm xương, có thể dẫn đến sự thiếu xương, xương thừa hoặc xương bị hợp nhất không đúng cách. - Nguyên nhân: Đột biến trong các gene homeobox ảnh hưởng đến di chuyển và ngưng tụ của các tế bào trung mô nguyên thủy. 2. **Osteodysplasias**: - Bất thường trong quá trình hình thành xương hoặc tăng trưởng xương. - Nguyên nhân: Đột biến ảnh hưởng đến các con đường truyền tín hiệu hoặc các thành phần của chất nền ngoại bào. - **Achondroplasia và thanatophoric dwarfism**: Do đột biến điểm ở gene FGFR3, ức chế sự tăng trưởng của các tấm sụn đầu xương. - **Osteogenesis imperfecta (bệnh xương giòn)**: Đột biến ở gene collagen type 1, dẫn đến xương dễ gãy. - **Osteopetrosis**: Đột biến ảnh hưởng đến chức năng của tế bào hủy xương, gây ra xương dày đặc nhưng không bền vững. Rối loạn Mắc phải 1. **Osteoporosis (Loãng xương)**: - **Đặc điểm**: Giảm khối lượng xương (osteopenia), dễ dẫn đến gãy xương. - **Dịch tễ học**: Phổ biến nhất ở phụ nữ mãn kinh và người cao tuổi. - **Cơ chế bệnh sinh**: Sự cân bằng giữa tạo xương bởi tế bào tạo xương và tiêu xương bởi tế bào hủy xương bị lệch về phía tiêu xương. - **Nguyên phát**: - Loãng xương sau mãn kinh: Do tăng hoạt động của tế bào hủy xương do thiếu estrogen. - Loãng xương do tuổi già: Giảm chức năng và sản xuất chất nền của tế bào tạo xương. - Các yếu tố nguy cơ: Di truyền, thiếu hụt dinh dưỡng, ít vận động, hút thuốc lá, uống rượu. - **Thứ phát**: Do thuốc (glucocorticoid), thiếu hụt dinh dưỡng, rối loạn nội tiết (đái tháo đường, cường cận giáp, cường giáp). - **Hình thái học**: Xương vỏ mỏng, các trabeculae giảm độ dày và mất kết nối, các ống Haversian giãn rộng. - **Triệu chứng lâm sàng**: Đau xương, gãy xương ở các xương chịu lực (đốt sống, cổ xương đùi, xương quay xa), giảm chiều cao, gù lưng, nguy cơ thuyên tắc phổi. - **Chẩn đoán**: Khó chẩn đoán do thường không có triệu chứng cho đến khi gãy xương. - **Điều trị**: Liệu pháp thay thế estrogen, tập thể dục chịu trọng lượng, bổ sung canxi và vitamin D. 2. **Rickets và Osteomalacia**: - **Nguyên nhân**: Thiếu hụt vitamin D hoặc rối loạn chuyển hóa vitamin D. - **Rickets**: Ở trẻ em đang phát triển. - **Osteomalacia**: Ở người lớn. - **Cơ chế bệnh sinh**: Thiếu hụt vitamin D gây hạ canxi máu, kích thích sản xuất PTH, tăng hấp thu canxi từ ruột và xương, giảm bài tiết canxi qua thận, nhưng gây thiếu hụt phosphate, dẫn đến suy giảm khoáng hóa xương. - **Hình thái học**: - **Rickets**: Sụn đầu xương không được khoáng hóa đủ, phát triển quá mức, mất trật tự thay thế sụn bằng chất nền osteoid, xương biến dạng (chân vòng kiềng, ngực gà). - **Osteomalacia**: Chất nền osteoid mới không được khoáng hóa đủ, xương yếu, dễ gãy và vi gãy, chủ yếu ảnh hưởng đến thân đốt sống và cổ xương đùi. Tổng kết Hiểu rõ cấu trúc và các rối loạn liên quan đến xương giúp chúng ta có cái nhìn toàn diện về các bệnh lý xương và áp dụng các phương pháp điều trị phù hợp để cải thiện sức khỏe xương. Reminder: Bones are composed of a unique type of mineralized connective a mixture of organic matrix (35%) and inorganic elements (65%). The inorganic mineral Component consists mainly of calcium hydroxyapatite Ca10(PO4)6(OH)2 The organic component includes the cells of bone and the proteinaceous osteoid (collagen 1). Congenital Disorders * Dysostoses- Abnormalities in a single or group of bones. Can result in the absence of bones, supernumerary bones, or inappropriately fused bones; some of these result from mutations in homeobox genes affecting localized migration and condensation of primitive mesenchymal cells. * Osteodysplasias- Abnormalities in bone genesis/abnormal growth. These can be caused by mutations that affect signal transduction pathways or components of the extracellular matrix: Achondroplasia and thanatophoric dwarfism occur as a consequence of point mutation in FGFR3 lead to activation (may be AD inherited or spontaneous ), Signals transmitted by FGFR3 inhibit the proliferation and function of growth plate chondrocytes; consequently, the growth of normal epiphyseal plates is suppressed, and the length of long bones is severely stunted. Thanatophoric dwarfism is a rear lethal variant of dwarfism (thanatophoric means “deathloving”). This disease also caused by mutations FGFR3. Affected heterozygotes exhibit extreme shortening of the limbs, deformed front of the skull, and an extremely small thorax, which is the cause of fatal respiratory failure in the perinatal period. Osteogenesis imperfecta (brittle bone disease) is a group of disorders caused by mutations in the genes for type 1 collagen that interfere with its normal production, with resultant bone fragility and susceptibility to fractures. Osteopetrosis is caused by mutations that interfere with osteoclast function and is associated with dense but architecturally unsound bone owing to defective bone resorption. acquired disorders Osteoporosis 1. disease Decreased bone mass (osteopenia), so patient is prone to bones fracture 2. Epidemiology Most common bone disorder in the USA Most commonly occurs in postmenopausal Caucasian women and elderly 3. Pathogenesis- occurs when dynamic balance between bone formation by osteoblasts and bone resorption by osteoclasts tilts in favor of resorption a. More common Primary cause: the two most common forms are senile and postmenopausal i. postmenopausal osteoporosis due to increased osteoclastic activity caused by the relative absence of estrogen. Estrogen deficiency- leads to increased cytokin production (IL1, IL6, TNF) from cells in the bone. These stimulate RANK hence stimulate osteoclasts action. ii. senile osteoporosis due to aging related losses of osteoblast function replicative and matix production of osteoblasts progressively diminished, while osteoclasts retain their youthful vigor. iii. Primary osteoporosis is multifactorial: Genetic factors – Vitamin D receptors polymorphism /Exercise/ Nutritional deficiencies such in ca in adolescent reduce bone mass as adult./ Cigarette smoking and alcohol b. Secondary causes: i. Drugs - Prolong glucocorticoid therapy increased bone resorption and reduces bone synthesis ii. Nutritional deficiencies/malabsorption - can affect bone integrity by altering the quality of the organic matrix (e.g., vitamin C is involved in collagen cross-linking) or by influencing bone mineralization (e.g., vitamin D is involved in calcium uptake). iii. Endocrine disorders – diabetes 1, hyperparathyroidism, hyperthyroid etc.… 4. Morphology- The bone cortex thinned and the trabeculae are reduced in thickness and lose their interconnections also with dilated haversian canals. 5. Clinical features a. Clinical presentation i. Bone pain and fractures mainly in Weight-bearing bones : 1. Vertebrae 2. Femoral neck 3. Distal radius ii. Loss of weight and kyphosis iii. Pulmonary embolism is a common complication b. Diagnosis- difficult to diagnosis as its asymptomatic until fractures are seen c. Treatment Estrogen replacement therapy (increasingly associated with cardiovascular risks) Weight-bearing exercise Calcium and vitamin D Rickets and Osteomalacia 1. Manifestation of vitamin D deficiency or its abnormal metabolism a. Rickets in growing children b. Osteomalacia in adults Vita d is fat soluble vitamin The major source of vitamin D for humans is its endogenous synthesis in the skin by photochemical conversion of a precursor, 7-dehydrocholesterol to forms cholecalciferol, known as vitamin D3; 2. The fundamental defect is an impairment of mineralization and a resultant accumulation of of unmineralized matrix (osteoid) 3. Causes: a. Diet deficient in calcium and vitamin D/ Malabsorption disorders b. Limited exposure to sunlight c. Renal disorder causing decrease synthesis of hydroxylase 1,25-(OH)2-D d. Phosphate depletion 4. Pathogenesis - Deficiency of vitamin D tends to cause hypocalcemia which then stimulates PTH production which: i. Activates renal alpha1-hydroxylase, increasing the amount of vit. D and calcium absorption ii. Mobilize calcium from bone iii. Decrease renal calcium excretion Increase renal excretion of phosphate. Thus, serum level of calcium is restored, but hypophosphatemia develops, so mineralization of the bone is impaired plus there is high bone turnover. 5. Morphology a. Rickets- The changes that occur in the growing bones of children with rickets are accomplished by inadequate calcification of epiphyseal cartilage i. micro rickets: 1. Overgrowth of epiphyseal cartilage due to inadequate provisional calcification and failure of the cartilage cells to mature and disintegrate 2. Disruption of the orderly replacement of cartilage by osteoid matrix, with enlargement of the osteochondral junction lot of unclcifide osteoid 3. Abnormal overgrowth of capillaries and fibroblasts in the disorganized zone resulting from microfructures and stress on the inadequately mineralizied, poorly formed bone. The gross skeletal changes Deformation of the skeleton due to the loss of structural rigidity of the developing bone (Bowing of the legs and bending of long bones in upper limbs Pigeon breast deformity- inward bending of the ribs with anterior protrusuin of sternumplus plus petable masses “rachitic rosary.”). Severity of changes depend on duration of problem severity and stress on skeleton. b. Osteomalacia i. The newly formed osteoid matrix laid down by osteoblasts in inadequately mineralized. Unmineralized osteoid can be visualized as a thickened layer of matrix arranged about the more basophilic, normally mineralized trabeculae. ii. Macro: Contours of the bone are not affected, but bone is weak Vulnerable to gross fractures and microfractures, mostly affect vertebral bodies and femoral neck

Answer 135

Hormon Cận Giáp và Các Rối Loạn Liên Quan Hormon Cận Giáp (PTH) - **Chức năng**: PTH được tiết ra khi mức canxi trong máu giảm và có trách nhiệm tăng mức canxi trong huyết thanh thông qua các cơ chế sau: 1. **Kích hoạt tế bào hủy xương**: Tăng cường sự tiêu xương và huy động canxi. PTH trung gian tác động này bằng cách tăng biểu hiện RANKL trên tế bào tạo xương. 2. **Tăng tái hấp thu canxi ở ống thận**: Tăng bài tiết phosphate qua nước tiểu. 3. **Tăng tổng hợp vitamin D hoạt động ở thận**: Tăng hấp thu canxi từ ruột. Cường Cận Giáp (Hyperparathyroidism) - **Định nghĩa**: Mức PTH cao không thích hợp hoặc quá mức. - **Phân loại**: 1. **Nguyên phát**: Tiết PTH tự chủ từ tuyến cận giáp. 2. **Thứ phát**: Liên quan đến bệnh thận. - Sự tổng hợp 1,25(OH)2 D không đủ từ thận, ảnh hưởng đến hấp thu canxi ở đường tiêu hóa. - Tăng phosphate trong suy thận ức chế enzyme alpha 1-hydroxylase của thận, làm suy giảm tổng hợp vitamin D. - **Hệ quả**: - Thay đổi xương nghiêm trọng do hoạt động không ngừng của tế bào hủy xương. - Toàn bộ bộ xương bị ảnh hưởng, giảm khối lượng xương dẫn đến nguy cơ gãy xương, biến dạng xương và các vấn đề khớp tăng lên. - Giảm mức PTH về bình thường có thể hoàn toàn đảo ngược các thay đổi xương. - **Hình thái học**: 1. **Tăng hoạt động của tế bào hủy xương**: Tiêu xương. 2. **Xương vỏ và xương trabeculae**: Được thay thế bằng mô liên kết lỏng lẻo. 3. **Tiêu xương rõ rệt ở vùng dưới màng xương**: Thấy rõ nhất ở mặt quay của các ngón tay giữa số 2 và 3. 4. **Vi thể**: - Tăng số lượng tế bào hủy xương, thâm nhập vào trung tâm của các trabeculae xương (viêm xương hoại tử) và mở rộng các ống Haversian. - Tăng mô liên kết mạch máu lỏng lẻo trong không gian tủy xương. - Lắng đọng hemosiderin phản ánh các giai đoạn xuất huyết do vi gãy xương. - U nâu của cường cận giáp: Tập hợp các tế bào hủy xương, tế bào khổng lồ phản ứng và mảnh vụn xuất huyết. - Viêm xương xơ hóa nang: Thay đổi nang có thể bị nhầm lẫn với u xương nguyên phát. - **Triệu chứng lâm sàng**: - Liên quan đến sự bất thường của cân bằng canxi. - Được tóm tắt như sau: “stones, bones, moans and groans": - **Stones**: Sỏi thận. - **Bones**: Thay đổi cấu trúc xương. - **Moans**: Trầm cảm và các bất thường tâm thần khác liên quan đến tăng canxi máu. - **Groans**: Các bất thường tiêu hóa liên quan đến mức canxi huyết thanh cao. Bệnh Paget của Xương - **Đặc điểm**: Gồm các giai đoạn lặp đi lặp lại của hoạt động tế bào hủy xương và tiêu xương (giai đoạn tiêu xương), tiếp theo là tạo xương mạnh mẽ (giai đoạn hỗn hợp hủy tạo xương), và cuối cùng là giai đoạn cạn kiệt hoạt động tế bào (giai đoạn xơ hóa xương). - **Hệ quả**: Tăng khối lượng xương nhưng xương mới hình thành bị rối loạn và yếu, dẫn đến xương có thể phình to và biến dạng. - **Cơ chế bệnh sinh**: - Bệnh được cho là một quá trình viêm (viêm xương biến dạng). - Nhiễm virus Paramyxovirus: Kích thích tiết IL-1 và IL-6 từ các tế bào bị nhiễm, cũng như yếu tố kích thích đại thực bào (M-CSF) được sản xuất trong xương Paget, kích hoạt tế bào hủy xương. - 10% bệnh nhân có đột biến gene SQSTM1, tăng sinh tế bào hủy xương. - **Hình thái học**: - Có thể xuất hiện dưới dạng tổn thương đơn độc (monostotic) hoặc nhiều vị trí (polyostotic). - Trong giai đoạn tiêu xương, tế bào hủy xương nhiều và lớn bất thường, có nhiều nhân. - Trong giai đoạn hỗn hợp, bề mặt xương được lót bởi tế bào tạo xương nổi bật. - Tủy xương được thay thế bằng mô liên kết lỏng lẻo chứa tế bào gốc xương và nhiều mạch máu để đáp ứng nhu cầu chuyển hóa tăng cao của mô. - Xương mới hình thành được tái cấu trúc thành xương vảy không bình thường với mô hình khảm đặc trưng. - Khi hoạt động tế bào tạo xương chấm dứt, mô xơ quanh xương được thay thế bởi tủy xương bình thường. Mặc dù xương vỏ dày lên, nó mềm hơn bình thường và dễ bị biến dạng và gãy dưới áp lực. - **Triệu chứng lâm sàng**: - Bệnh Paget có thể là đơn ổ (15%) hoặc đa ổ (85%); bộ xương trục hoặc xương đùi gần bị ảnh hưởng trong 80% trường hợp. - Mặc dù bệnh Paget có thể gây ra các biến chứng thần kinh cơ và tim mạch, hầu hết các trường hợp nhẹ về mặt lâm sàng. - Tăng phosphatase kiềm trong huyết thanh và tăng bài tiết hydroxyproline trong nước tiểu phản ánh sự chuyển hóa xương mạnh mẽ. - Trong giai đoạn tăng sinh của bệnh, thường gặp các triệu chứng đau đầu và rối loạn thị giác và thính giác do tổn thương xương sọ. - Các tổn thương cột sống gây đau lưng và có thể liên quan đến gãy xương và chèn ép rễ thần kinh. - Xương dài ở chân thường bị biến dạng do không thể tái cấu trúc xương Paget phù hợp với áp lực chịu trọng lượng. - Xương dài dễ gãy, đặc biệt dễ gãy phấn. - Sarcoma (1% trường hợp) thường là osteosarcoma. 1. Parathyroid hormone realis upon reduced ca levels and responsible to increase serums ca level (which in torn inhibit its realis) through the following effects: a. Osteoclast activation, increasing bone resorption and calcium mobilization. PTH mediates the effect indirectly by increased RANKL expression on osteoblast b. Increased resorption of calcium by renal tubules- Increase urinary excretion of phosphate c. Increased synthesis of active vitamin dby kidneys, which in turns enhances calcium absorption from the gut 2. Hyperparathyroidism- excessive or inappropriate level of PTH a. Two forms i. Primary- autonomous parathyroid secretion ii. Secondary- associated with renal disease 1. Inadequate synthesis of 1,25(OH) 2 D by the kidney, affects GI calcium abrosption 2. Hyperphosphatemia of renal failure suppresses renal alpha 1- hydroxylase, impairing vitamin D synthesis. b. Leads to significant skeletal changes related to unabated osteoclast activity. c. Entire skeleton is affaected d. As the bone mass decreases, affected patients are increasingly susceptible to fractures, bone deformation, and joint problems. e. Reduction in PTH levels to normal can completely reverse bone changes. f. Morphology: i. Hallmark of PTH exess- increased osteoclasic activity, with bone resorption ii. Cortical and trabecular bone are replaced by loose CT iii. Bone resorption is pronounced in subperiosteal regions best seen along the radial aspect of the middle phalanges of the 2 and 3 finger. iv. Microscopically 1. Increased number of osteoclasts boring into centers of bony trabecules (dissecting osteitis) and expanding haversian canals (cortical cutting cones) 2. Increase loose fibrovascular tissue in marrow space 3. Hemosederin deposits reflect episodes of hemorrhage resulting from microfractures 4. Brown tumor of hyperparathyroidism is sometimes seencollection of osteoclasts, reactive giant cells and hemorrhagic debris 5. Osteitis fibrosa cystic- cystic change, which can be confused with primary bone neoplasm. a. A classic feature is the presence of multiple, localized, lytic lesions, which represent hemorrhagic cysts or masses of fibrous tissue b. These eccentric and well-demarcated lesions are separated from the soft tissue by a periosteal shell of bone. v. Symptoms of primary hyperparathyroidism 1. related to the abnormality of calcium homeostasis 2. summarized as “ stones, bones, moans and groans" a. “stones” refer to kidney stones and the b. “bones” to the skeletal changes c. "moans” describe psychiatric depression and other abnormalities associated with hypercalcemia d. “groans” characterize the gastrointestinal irregularities associated with a high serum calcium level. Renalis osteodystrophia. PAGET DISEASE  Characterized by repetitive episodes of regional osteoclastic activity and bone resorption (osteolytic stage), followed by exuberant bone formation (mixed osteoclastic-osteoblastic stage), and finally by an apparent exhaustion of cellular activity (osteosclerotic stage).  The net effect of this process is a gain in bone mass; however, the newly formed bone is disordered and weak, so bones may become enlarged and misshapen.  Paget disease usually presents in mid- to late adulthood.  Pathogenesis  The disease is assigned to an inflammatory process - osteitis deformans.  Paramyxovirus infection underlies Paget disease; which induce IL-1 and IL-6 secretion from infected cells, and these cytokines, as well as macrophage colonystimulating factor (M-CSF)—are produced in pagetic bone  activate osteoclasts.  10% of affected patients have mutations in the gene SQSTM1, which encodes a protein that appears to increase osteoclastogenesis  Morphology:  May manifest as a solitary lesion (monostotic) or may occur at multiple sites (polyostotic)  In the initial lytic phase, osteoclasts (and their associated Howship lacunae) are numerous, abnormally large, and have increased numbers of nuclei.  Osteoclasts persist in the mixed phase, but the bone surfaces become lined by prominent osteoblasts.  The marrow is replaced by loose connective tissue containing osteoprogenitor cells, as well as  numerous blood vessels needed to meet the increased metabolic demands of the tissue.  The newly formed bone is remodeled into abnormal lamellar bone with a pathognomonic mosaic -> pattern  As the osteoblastic activity ceases, the periosseous fibrovascular tissue is replaced by normal marrow. Although thickened, the resulting cortex is softer than normal and prone to deformation and fracture under stress.  Clinical features  Paget disease is monostotic (tibia, ilium, femur, skull, vertebrae, and humerus) in 15% of cases and polyostotic in the remainder; the axial skeleton or the proximal femur is involved in 80% of cases.  Involvement of the ribs, fibulae, and small bones of the hands and feet is unusual.  Although Paget disease can produce neuromuscular, and cardiovascular complications, most cases are clinically mild  Elevations in serum alkaline phosphatase and increased urinary excretion of hydroxyproline reflect exuberant bone turnover.  In some patients, the early hypervascular bone lesions cause warmth of the overlying skin and subcutaneous tissue.  In the proliferative phase of the disease involving the skull, common symptoms include headache and visual and auditory disturbances.  Vertebral lesions cause back pain and may be associated with disabling fractures and nerve root compression.  Affected long bones in the legs often are deformed, as a consequence of the inability of pagetoid bone to remodel appropriately in response to the stress of weight bearing.  Brittle long bones in particular are subject to chalkstick fractures.  The sarcomas (occurs in 1%) usually are osteogenic

Answer 136

Viêm Xương Tủy (Osteomyelitis) 1. **Định nghĩa**: Viêm xương tủy là tình trạng viêm của xương và tủy xương. 2. **Nguyên nhân**: - Có thể là do nhiễm trùng hệ thống nhưng thường xảy ra như một ổ bệnh riêng biệt. Viêm Xương Tủy Sinh Mủ (Pyogenic Osteomyelitis) 1. **Đường lây nhiễm**: - **Lan truyền qua máu**: - Phổ biến nhất. - Xâm nhập xương sau khi có vi khuẩn trong máu. - Thường ảnh hưởng đến đầu xương (metaphysis). - **Lan từ vị trí nhiễm trùng lân cận**. - **Cấy ghép sau chấn thương**: Sau gãy xương hở hoặc phẫu thuật chỉnh hình. 2. **Vi sinh học**: - **Staphylococcus aureus**: Phổ biến nhất, có khả năng bám dính vào màng xương. - **E. coli và liên cầu nhóm B**: Quan trọng trong viêm xương tủy cấp ở trẻ sơ sinh. - **Salmonella**: Phổ biến ở bệnh nhân bệnh hồng cầu hình liềm. - **Nhiễm trùng vi khuẩn hỗn hợp**: Thường gặp trong viêm xương tủy do chấn thương xương. 3. **Triệu chứng lâm sàng**: - Thường biểu hiện như bệnh toàn thân cấp tính. - Sốt và tăng bạch cầu. - Đau cục bộ, đỏ và sưng. 4. **Hình thái học**: - Phụ thuộc vào mức độ mãn tính và vị trí nhiễm trùng. - Xương bị kẹt nhanh chóng trở nên hoại tử (sequestrum). - Áp xe dưới màng xương (ở trẻ em, nơi màng xương gắn lỏng vào vỏ xương). - Viêm mủ và suy giảm tuần hoàn có thể gây hoại tử. - Vỡ màng xương có thể dẫn đến hình thành áp xe trong mô mềm xung quanh và có thể dẫn đến rò rỉ mủ. - **Involucrum**: Xương mới hình thành bao quanh sequestrum. 5. **Chẩn đoán**: - **X-quang**: Tập trung lytic với phù nề xung quanh và viền xơ. - **Cấy máu**. - **Sinh thiết xương và cấy**. 6. **Điều trị**: Kháng sinh và/hoặc dẫn lưu phẫu thuật. 7. **Biến chứng**: - Gãy xương. - Viêm nội tâm mạc. - Amyloidosis thứ phát. - Hình thành đường rò. - Ung thư biểu mô tế bào vảy (SCC) tại vị trí đường rò dai dẳng. - Sarcoma xương (hiếm). Viêm Xương Tủy Do Lao (Tuberculous Osteomyelitis) 1. **Tỷ lệ mắc**: Gặp ở 1-3% các trường hợp lao phổi. 2. **Đường lây nhiễm**: - Thường qua đường máu, ưa thích xương dài và đốt sống. - Lan truyền trực tiếp (từ hạch bạch huyết trung thất đến đốt sống). 3. **Hình thái học**: - Thường là tổn thương đơn độc. - Màng hoạt dịch là vị trí nhiễm ban đầu phổ biến do áp lực oxy cao. - Nhiễm trùng lan sang đầu xương kề cận, gây viêm hạt và hoại tử bã đậu. 4. **Triệu chứng lâm sàng**: - **Lao đốt sống**: Dạng nghiêm trọng của viêm xương tủy. - Biến dạng đốt sống, sụp đốt sống và lệch ra sau (bệnh Pott) dẫn đến các rối loạn thần kinh. - Lan truyền nhiễm trùng đến mô mềm xung quanh và phát triển áp xe cơ psoas. Tổng kết Viêm xương tủy là một tình trạng nhiễm trùng nghiêm trọng của xương và tủy xương, có thể do nhiều nguyên nhân khác nhau như nhiễm khuẩn hoặc lao. Hiểu rõ cơ chế lây nhiễm, triệu chứng, và phương pháp chẩn đoán và điều trị là rất quan trọng để quản lý hiệu quả bệnh lý này và ngăn ngừa các biến chứng nghiêm trọng. Osteomyelitis 1. Inflammation of the bone and marrow. 2. Can be secondary to systemic infection but more frequently occurs as a primary isolated focus of a disease Pyogenic osteomyelitis 1. Route of infection a. Hematogenous spread i. Most common ii. Seeding of bone after bacteremia iii. Commonly affects the metaphysic b. Spread from adjacent site of infection c. Traumatic implantation after compound fractures or orthopedic procedure 2. Microbiology a. Staphylococcus aureus (most common) i. Its propensity to infevt bone maybe related to the expression of surface proteins that allow adhesion to bone matrix b. E. coli: important cause of acute osteomylitis in neonates c. Group B streptococci: important cause of acute osteomylitis in neonates d. Salmonella: common in sickle cell disease e. Mixed bacterial infection- responsible for osteomyelitis secondary to bone trauma 3. Clinical features a. Classically manifests as acute systemic illness b. Fever and leukocytosis c. Localized pain, erythema and swelling 4. Morphology a. Depends on chronicity and location of the infection b. Entrapped bone rapidaly becomes necrotic i. Sequestrum: the necrotic bone c. Subperiosteal abscess (in children, where the periosteum is loosely attached to the cortex) d. Suppurative inflammation and vascular insufficiency may cause necrosis e. Rapture of periosteum can lead to abscess formation in the surrounding soft tissues that may lead to a draining sinus. f. Involucrum: new bone formation that surrounds the sequestrum 5. Diagnosis a. X-ray i. Lytic focus with surrounding edema and sclerotic rim b. Blood culture c. Bone biopsy and culture 6. Treatment: antibiotics and/ or surgical drainage 7. Complications a. Fracture b. endocarditis c. Secondary amyloidosis d. Sinus tract formation e. SCC of the skin at the site of persistent draining sinus tract f. Osteogenic sarcoma (rare) Tuberculous osteomyelitis 1. Occurs in 1-3% of cases of pulmonary TB 2. Route of infection: a. Usually through bloodstream- favors long bones and vertebrae b. Direct spread (from mediastinal lymph node to vertebrae) 3. Morphologya. Often solitary lesions b. Synovium is a common site of intial infection as its oxygen pressure is high c. Infection spreads to adjacent epiphysis i. Elicits granulomatous inflammation and caseous necrosis 4. Clinical features a. TB of the vertebral bodies is a clinically serious form of osteomyelitis i. Vertebral deformity, collapse and posterior displacement (Pott disease) leading to neurologic deficits. ii. Extension of infection to adjacent soft tissues and development of psoas muscle abscess

Answer 137

Các Khối U Xương Lành Tính và Ác Tính Khối U Xương Lành Tính 1. **Osteoma** - **Đặc điểm**: - Khối u lành tính thường gặp ở đầu và cổ, bao gồm các xoang cận mũi. - Xuất hiện ở tuổi trung niên dưới dạng các khối cứng, phát triển chậm trên bề mặt xương. - Có thể gây ra các vấn đề cơ học tại chỗ (ví dụ, tắc nghẽn xoang) và biến dạng thẩm mỹ. - **Liên quan đến hội chứng Gardner**: Xuất hiện nhiều khối u. - **Vi thể**: Gồm hỗn hợp xương đan và xương vảy. - **Tiên lượng**: Không xâm lấn tại chỗ và không chuyển sang ác tính. 2. **Osteoid Osteoma và Osteoblastoma** - **Đặc điểm**: - Khối u lành tính của tế bào tạo xương. - Xuất hiện trong tuổi thiếu niên và 20 tuổi, phổ biến hơn ở nam giới. - Osteoid osteomas nhỏ hơn 2 cm, thường gặp ở xương dài (xương đùi và xương chày), gây đau cục bộ, thường nặng hơn vào ban đêm và được giảm đau bằng aspirin. - Osteoblastomas lớn hơn và thường gặp ở cột sống, gây đau khó khu trú và không đáp ứng với aspirin. - **Hình thái học**: - **Vi thể**: Cả hai khối u có cấu trúc xương đan xen, bao quanh bởi các tế bào tạo xương và mô liên kết mạch máu lỏng lẻo chứa các tế bào khổng lồ. - **Đại thể**: Khối u tròn đến oval, có mô tan màu nâu vàng. - **Tiên lượng**: Hiếm khi chuyển sang ác tính trừ khi được điều trị bằng xạ trị. Khối U Xương Ác Tính 1. **Osteosarcoma** - **Đặc điểm**: - Khối u ác tính sản xuất xương từ tế bào trung mô ác tính. - Là khối u ác tính xương nguyên phát phổ biến nhất sau u tủy và u lympho, chiếm khoảng 20% các khối u xương nguyên phát. - Thường gặp ở vùng metaphysis của xương dài, đặc biệt quanh đầu gối. - **Yếu tố nguy cơ**: Bệnh Paget, đột biến RB gia đình, bức xạ. U xương tự phát xảy ra ở đột biến TP53. - **Hình thái học**: - **Đại thể**: Khối u màu xám trắng, thường xuất huyết và thoái hóa nang. Khối u thường phá hủy lớp vỏ xương và tạo thành khối mô mềm xâm lấn. - **Vi thể**: Tế bào u có kích thước và hình dạng đa dạng, thường có nhân lớn và không đều. Các tế bào ác tính sản xuất xương (osteoid) là tiêu chí chẩn đoán osteosarcoma. - **Lâm sàng**: - Thường biểu hiện dưới dạng khối u đau, tăng kích thước. - Hình ảnh X-quang thường cho thấy khối lớn, phá hủy, hỗn hợp giữa tiêu xương và tạo xương với viền xâm lấn không rõ ràng. - Tam giác Codman (bóng tam giác giữa vỏ xương và màng xương nâng lên) đặc trưng của osteosarcoma. - Osteosarcomas thường lan truyền qua đường máu, gây di căn phổi. 2. **Osteochondroma** - **Đặc điểm**: Khối u xương có mũ sụn bên trên. - Xuất hiện trong tuổi thiếu niên và trưởng thành sớm. - Bệnh lý di truyền trội nhiễm sắc thể thường (đa u xương sụn). - Liên quan đến đột biến gene EXT1 hoặc EXT2 ở tế bào sụn. - **Hình thái học**: - Kích thước từ 1-20 cm, có mũ sụn hyaline. - **Lâm sàng**: - Khối u phát triển chậm, có thể gây đau. - Osteochondroma đơn lẻ hiếm khi chuyển thành chondrosarcoma hoặc các sarcoma khác, nhưng chuyển ác tính thường xảy ra ở bệnh nhân đa u xương sụn di truyền. 3. **Chondroma** - **Đặc điểm**: Khối u lành tính của sụn hyaline. - Khi xuất hiện trong tủy xương, gọi là enchondroma, thường ở vùng metaphysis của xương ngắn, đặc biệt là xương bàn tay và chân. - Bệnh Ollier và hội chứng Maffucci có nhiều chondromas. - **Hình thái học**: - Enchondromas là các nốt màu xám xanh, trong suốt, thường nhỏ hơn 5 cm. - Vi thể: Gồm sụn hyaline có chondrocytes lành tính về mặt tế bào học. - **Lâm sàng**: - Trên X-quang, nốt sụn chưa khoáng hóa tạo ra vùng mờ hình oval, bao quanh bởi viền xương đậm (dấu hiệu O-ring). - Chondroma đơn lẻ hiếm khi chuyển thành ác tính, nhưng những khối u liên quan đến enchondromatoses có nguy cơ cao hơn. Khối U Xương Ác Tính 1. **Chondrosarcoma** - **Đặc điểm**: Khối u ác tính của mô liên kết sản xuất sụn. - Thường xuất hiện ở bệnh nhân trên 40 tuổi, nam nhiều hơn nữ. - **Hình thái học**: - **Conventional chondrosarcoma**: Xuất hiện trong tủy xương, tạo thành khối u mở rộng, sáng bóng, thường xói mòn vỏ xương. - **Vi thể**: Gồm sụn hyaline ác tính và sụn nhầy. - **Lâm sàng**: - Thường xuất hiện ở xương chậu, vai và xương sườn. - Biểu hiện dưới dạng khối u đau, tăng kích thước. - Metastasize qua đường máu đến phổi và xương. Tổng kết Các khối u xương có thể lành tính hoặc ác tính, với đặc điểm, hình thái học và lâm sàng khác nhau. Hiểu rõ các loại khối u này giúp chẩn đoán và điều trị hiệu quả, từ đó cải thiện chất lượng sống và tiên lượng cho bệnh nhân. BENIGN 1) OSTEOMA  Osteomas are benign lesions most commonly encountered in the head and neck, including the paranasal sinuses  They typically present in middle age as solitary, slowly growing, hard, exophytic masses on a bone surface.  Multiple lesions are a feature of Gardner syndrome  MICRo = , osteomas recapitulate cortical type bone and are composed of a mixture of woven and  lamellar bone.  Although they may cause local mechanical problems (e.g., obstruction of a sinus cavity) and cosmetic deformities, they are not locally aggressive and do not undergo malignant transformation. 2) OSTEOID OSTEOMA AND OSTEOBLASTOMA  Benign tumor of the osteoblast  Osteoid osteomas and osteoblastomas are benign neoplasms with very similar histologic features.  appear during the teenage years and 20s, with a male predilection  They are distinguished from each other primarily by their size and clinical presentation.  Osteoid osteomas arise most often beneath the periosteum or within the cortex in the proximal femur and tibia or posterior spinal elements = mainly long bones,and are by definition less than 2 cm in diameter, Localized pain, most severe at night, is an almost universal complaint with osteoid osteomas, and usually is relieved by aspirin.  osteoblastomas are larger and most often in the vertebral column. they also cause pain, although it often is more difficult to localize and is not responsive to aspirin.  . Malignant transformation is rare unless the lesion is treated with irradiation.  Morphology: MACRO = both lesions are round-to-oval masses of hemorrhagic, grittyappearing tan tissue. A rim of sclerotic bone is present at the edge of both types of tumors = it is much more conspicuous in osteoid osteomas. MICRO = examination, both neoplasms are composed of interlacing trabeculae of woven bone surrounded by osteoblasts The intervening stroma is loose, vascular connective tissue containing variable numbers of giant cells. MALIGNANT 1) OSTEOSARCOMA  Osteosarcoma is a bone-producing malignant mesenchymal tumormalignant proliferation of osteoblast.  After myeloma and lymphoma, osteosarcoma is the most common primary malignant tumor of bone, accounting for approximately 20% of primary bone cancers;  Although any bone Can be involved, most tumors arise in the metaphyseal region of the long bones of the extremities, with almost 60% occurring about the knee, 15% around the hip, 10% at the shoulder, and 8% in the jaw.  Risk factores: paget disease, familial RB, radiation. Spontaneous osteosarcoma occur in TP53 mutation.  Several subtypes of osteosarcoma are distinguished on the basis of the site of involvement within the bone (e.g., medullary versus cortical),degree of differentiation, number of involved sites, presence of underlying disease, and histologic features;  the most common type of osteosarcoma is primary, solitary, intramedullary, and poorly differentiated, producing a predominantly bony matrix.  Morphology: Macro = are gritty-appearing, gray-white tumors, often exhibiting hemorrhage and cystic degeneration. Tumors frequently destroy the surrounding ortices, producing soft tissue masses, Extensibly infiltrating.  Micro = Tumor cells vary in size and shape and frequently have large hyperchromatic nuclei; bizarre tumor giant cells are common, as are mitotic figures. The production of mineralized or unmineralized bone (osteoid) by malignant cells is essential for diagnosis of osteosarcoma  When malignant cartilage is abundant, the tumor is called a chondroblastic osteosarcoma.  Clinical : - Osteosarcomas typically manifest as painful enlarging masses, although a pathologic fracture can be the first sign. - Radiographic imaging usually shows a large, destructive, mixed lytic and blastic mass with indistinct infiltrating margins = The tumor frequently breaks through the cortex and lifts the periosteum, resulting in reactive periosteal bone formation. - A triangular shadow on the x-ray film between the cortex and raised periosteum (Codman triangle) is characteristic of osteosarcomas. - Osteosarcomas typically spread hematogenously; ademonstrable pulmonary metastases, BENIGN 1) OSTEOCHONDROMA  Tumors of bone with overlying cartilage cap.  Solitary osteochondromas typically are first diagnosed in late adolescence and early adulthood (  multiple osteochondromas become apparent during childhood, occurring as multiple hereditary osteochondromas,autosomal dominant disorder.  Inactivation of both copies of the EXT1 or EXT2 genes through mutation in chondrocytes is implicated in both sporadic and hereditary osteochondromas These tumor suppressor genes encode glycosyltransferases essential for polymerization of heparin sulfate, an important component of cartilage.  Osteochondromas develop only in bones of endochondral origin arising at the metaphysis near the growth plate of long tubular bones, especially about the knee Occasionally they develop from bones of the pelvis, scapula, and ribs and in these sites = long bones  Morphology: - Range from 1-20 cm in size, and have a cartiligneous cup - Hyaline cartilage  Clinical Features - Osteochondromas are slow-growing masses that can be painful - Solitary osteochondromas rarely progress to chondrosarcoma or other sarcomas, but malignant transformation occurs more frequently in those with multiple hereditary osteochondromas. 2) CHONDROMA  Chondromas are benign neoplasms of hyaline cartilage.  When they arise within the medulla, they are termed enchondromastypically are solitary and located in the metaphyseal region of tubular bones, the favored sites being the short  tubular bones of the hands and feet.  Ollier disease is characterized by multiple chondromas preferentially involving one side of the body, and Maffucci syndrome is characterized by multiple chondromas associated with soft tissue spindle cell hemangiomas.  when on the bone surface, they are called juxtacortical chondromas.  Pathogenesis: - Enchondromas occurring in Ollier disease and Maffucci syndrome frequently contain point mutations in either isocitrate dehydrogenase I (IDH1) or IDH2 that create a new enzyme activity. (The same IDH mutations occur as somatic mutations in acute myeloid leukemias and gliomas), the mutations occurred early during embryonic development, an example of genetic mosaicism.  Morphology: - Enchondromas are gray-blue, translucent nodules usually smaller than 5 cm in greatest dimension. - Micro = , they are well circumscribed and composed of hyaline cartilage containing cytologically benign chondrocytes. - At the periphery, there is endochondral ossification, while the center frequently calcifies and dies. I - in the hereditary multiple chondromatoses, the islands of cartilage exhibit greater cellularity and atypia, making them more difficult to distinguish from chondrosarcoma.  Clinical Features - On x-ray imaging, the unmineralized nodules of cartilage produce well-circumscribed oval lucencies surrounded by thin rims of radiodense bone (O-ring sign). - Solitary chondromas rarely undergo malignant transformation, but those associated with enchondromatoses are at increased risk for such change. (Maffucci syndrome is associated with an increased risk for development of other types of malignancies, including ovarian carcinomas and brain gliomas.) MALIGNANT CHONDROSARCOMA  Chondrosarcoma is a malignant connective tissue tumor (sarcoma) whose cells manufacture and secrete neoplastic cartilage matrix.  It is subclassified according to site (e.g., intramedullary versus juxtacortical) and histologic variants  most patients are age 40 or older, with men >female.  MORPHOLOGY: - Conventional chondrosarcoma, the most common variant, arises within the medullary cavity of the bone to form an expansile glistening mass that often erodes the cortex It is composed of malignant hyaline and myxoid cartilage. - Myxoid chondrosarcomas are viscous and gelatinous in consistency, and the matrix oozes from the cut surface. The adjacent cortex is thickened or eroded, and the tumor grows with broad pushing fronts into marrow spaces and the surrounding soft tissue - Tumor grade is determined by cellularity, degree of cytologic atypia, and mitotic activity Low-grade tumors high grade - Approximately 10% of patients with conventional lowgrade chondrosarcomas have a second high-grade poorly differentiated component (dedifferentiated chondrosarcomas) - Other histologic variants include clear cell and mesenchymal chondrosarcomas. Clinical features: - Chondrosarcomas commonly arise in the pelvis, shoulder, and ribs; in contrast with enchondromas, chondrosarcomas rarely involve the distal extremities. - They typically manifest as painful, progressively enlarging masses. - the more radiolucent the tumor the greater the likelihood that it is high grade. - Metastasize hematogenously to the lung and skeleton.

Answer 138

Các Khối U Xương Lành Tính và Ác Tính Khối U Xương Lành Tính 1. **Osteochondroma** - **Đặc điểm**: - Khối u xương có mũ sụn bên trên. - Osteochondromas đơn lẻ thường được chẩn đoán ở tuổi thiếu niên muộn và trưởng thành sớm. - Osteochondromas nhiều xuất hiện ở trẻ em, dưới dạng u xương sụn di truyền nhiều (bệnh di truyền trội nhiễm sắc thể thường). - Đột biến gây bất hoạt cả hai bản sao của gene EXT1 hoặc EXT2 trong tế bào sụn có liên quan đến cả osteochondromas lẻ tẻ và di truyền. - Các gene ức chế khối u này mã hóa glycosyltransferase cần thiết cho sự polyme hóa của heparin sulfate, một thành phần quan trọng của sụn. - Osteochondromas phát triển ở các xương có nguồn gốc từ sụn, xuất hiện ở metaphysis gần đĩa tăng trưởng của các xương ống dài, đặc biệt là quanh đầu gối. Đôi khi chúng phát triển từ các xương của xương chậu, xương bả vai, và xương sườn. - **Hình thái học**: - Kích thước từ 1-20 cm, có mũ sụn hyaline. - **Triệu chứng lâm sàng**: - Osteochondromas phát triển chậm, có thể gây đau. - Osteochondromas đơn lẻ hiếm khi chuyển sang chondrosarcoma hoặc các sarcoma khác, nhưng sự chuyển đổi ác tính xảy ra thường xuyên hơn ở những người có osteochondromas di truyền nhiều. 2. **Chondroma** - **Đặc điểm**: - Chondromas là các khối u lành tính của sụn hyaline. - Khi chúng phát triển trong tủy xương, chúng được gọi là enchondromas, thường là đơn lẻ và nằm ở vùng metaphysis của xương ống, với các vị trí ưa thích là xương ngắn của tay và chân. - Bệnh Ollier được đặc trưng bởi nhiều chondromas liên quan ưu tiên đến một bên cơ thể, và hội chứng Maffucci được đặc trưng bởi nhiều chondromas kết hợp với u máu tế bào hình thoi ở mô mềm. - Khi nằm trên bề mặt xương, chúng được gọi là chondromas cạnh vỏ. - **Cơ chế bệnh sinh**: - Enchondromas xuất hiện trong bệnh Ollier và hội chứng Maffucci thường chứa các đột biến điểm trong isocitrate dehydrogenase I (IDH1) hoặc IDH2 tạo ra hoạt tính enzyme mới. Các đột biến này xảy ra sớm trong quá trình phát triển phôi, là một ví dụ của hiện tượng khảm di truyền. - **Hình thái học**: - Enchondromas là các nốt màu xám xanh, trong suốt, thường nhỏ hơn 5 cm. - Vi thể: Được bao quanh rõ ràng và gồm sụn hyaline chứa các chondrocytes lành tính về mặt tế bào học. - Tại ngoại vi, có sự ossification nội sụn, trong khi trung tâm thường bị canxi hóa và chết. Trong các chondromatoses di truyền, các đảo sụn thể hiện sự tăng tế bào và dị hình, làm cho chúng khó phân biệt hơn với chondrosarcoma. - **Triệu chứng lâm sàng**: - Trên hình ảnh X-quang, các nốt sụn chưa khoáng hóa tạo ra các vòng mờ hình oval được bao quanh bởi các viền xương đặc (dấu hiệu O-ring). - Chondroma đơn lẻ hiếm khi chuyển sang ác tính, nhưng những u liên quan đến enchondromatoses có nguy cơ cao hơn. Hội chứng Maffucci liên quan đến nguy cơ phát triển các loại ung thư khác, bao gồm ung thư buồng trứng và gliomas não. Khối U Xương Ác Tính 1. **Chondrosarcoma** - **Đặc điểm**: - Chondrosarcoma là một khối u ác tính của mô liên kết, các tế bào sản xuất và tiết ra ma trận sụn. - Thường được phân loại dựa trên vị trí (ví dụ, nội tủy so với cạnh vỏ) và các biến thể về mặt mô học. - Hầu hết bệnh nhân trên 40 tuổi, nam giới nhiều hơn nữ giới. - **Hình thái học**: - **Chondrosarcoma thông thường**: Xuất hiện trong khoang tủy xương, tạo thành một khối mở rộng sáng bóng thường làm xói mòn vỏ xương. Gồm sụn hyaline ác tính và sụn nhầy. - **Chondrosarcoma nhầy**: Có kết cấu nhớt và gelatin, và ma trận nhầy chảy ra từ bề mặt cắt. - Cạnh vỏ xương dày lên hoặc bị xói mòn, và khối u phát triển với các rìa đẩy rộng vào các không gian tủy xương và mô mềm xung quanh. - Độ ác tính của khối u được xác định bởi độ tăng tế bào, mức độ dị hình tế bào học và hoạt động phân bào. Khoảng 10% bệnh nhân có chondrosarcoma độ thấp thông thường có thành phần độ cao kém phân biệt (chondrosarcoma không phân biệt). - Các biến thể mô học khác bao gồm chondrosarcoma tế bào sáng và chondrosarcoma trung mô. - **Triệu chứng lâm sàng**: - Chondrosarcomas thường xuất hiện ở xương chậu, vai và xương sườn; ngược lại với enchondromas, chondrosarcomas hiếm khi ảnh hưởng đến các chi xa. - Thường biểu hiện dưới dạng khối u đau, tăng kích thước dần. - Khối u càng mờ trên X-quang, khả năng cao là khối u độ cao. - Metastasize qua đường máu đến phổi và xương. Tổng kết Hiểu rõ các đặc điểm, hình thái học và triệu chứng lâm sàng của các khối u xương lành tính và ác tính giúp chúng ta có thể chẩn đoán và điều trị hiệu quả, từ đó cải thiện chất lượng sống và tiên lượng cho bệnh nhân. BENIGN 1) OSTEOCHONDROMA  Tumors of bone with overlying cartilage cap.  Solitary osteochondromas typically are first diagnosed in late adolescence and early adulthood (  multiple osteochondromas become apparent during childhood, occurring as multiple hereditary osteochondromas,autosomal dominant disorder.  Inactivation of both copies of the EXT1 or EXT2 genes through mutation in chondrocytes is implicated in both sporadic and hereditary osteochondromas These tumor suppressor genes encode glycosyltransferases essential for polymerization of heparin sulfate, an important component of cartilage.  Osteochondromas develop only in bones of endochondral origin arising at the metaphysis near the growth plate of long tubular bones, especially about the knee Occasionally they develop from bones of the pelvis, scapula, and ribs and in these sites = long bones  Morphology: - Range from 1-20 cm in size, and have a cartiligneous cup - Hyaline cartilage  Clinical Features - Osteochondromas are slow-growing masses that can be painful - Solitary osteochondromas rarely progress to chondrosarcoma or other sarcomas, but malignant transformation occurs more frequently in those with multiple hereditary osteochondromas. 2) CHONDROMA  Chondromas are benign neoplasms of hyaline cartilage.  When they arise within the medulla, they are termed enchondromastypically are solitary and located in the metaphyseal region of tubular bones, the favored sites being the short  tubular bones of the hands and feet.  Ollier disease is characterized by multiple chondromas preferentially involving one side of the body, and Maffucci syndrome is characterized by multiple chondromas associated with soft tissue spindle cell hemangiomas.  when on the bone surface, they are called juxtacortical chondromas.  Pathogenesis: - Enchondromas occurring in Ollier disease and Maffucci syndrome frequently contain point mutations in either isocitrate dehydrogenase I (IDH1) or IDH2 that create a new enzyme activity. (The same IDH mutations occur as somatic mutations in acute myeloid leukemias and gliomas), the mutations occurred early during embryonic development, an example of genetic mosaicism.  Morphology: - Enchondromas are gray-blue, translucent nodules usually smaller than 5 cm in greatest dimension. - Micro = , they are well circumscribed and composed of hyaline cartilage containing cytologically benign chondrocytes. - At the periphery, there is endochondral ossification, while the center frequently calcifies and dies. I - in the hereditary multiple chondromatoses, the islands of cartilage exhibit greater cellularity and atypia, making them more difficult to distinguish from chondrosarcoma.  Clinical Features - On x-ray imaging, the unmineralized nodules of cartilage produce well-circumscribed oval lucencies surrounded by thin rims of radiodense bone (O-ring sign). - Solitary chondromas rarely undergo malignant transformation, but those associated with enchondromatoses are at increased risk for such change. (Maffucci syndrome is associated with an increased risk for development of other types of malignancies, including ovarian carcinomas and brain gliomas.) MALIGNANT CHONDROSARCOMA  Chondrosarcoma is a malignant connective tissue tumor (sarcoma) whose cells manufacture and secrete neoplastic cartilage matrix.  It is subclassified according to site (e.g., intramedullary versus juxtacortical) and histologic variants  most patients are age 40 or older, with men >female.  MORPHOLOGY: - Conventional chondrosarcoma, the most common variant, arises within the medullary cavity of the bone to form an expansile glistening mass that often erodes the cortex It is composed of malignant hyaline and myxoid cartilage. - Myxoid chondrosarcomas are viscous and gelatinous in consistency, and the matrix oozes from the cut surface. The adjacent cortex is thickened or eroded, and the tumor grows with broad pushing fronts into marrow spaces and the surrounding soft tissue - Tumor grade is determined by cellularity, degree of cytologic atypia, and mitotic activity Low-grade tumors high grade - Approximately 10% of patients with conventional lowgrade chondrosarcomas have a second high-grade poorly differentiated component (dedifferentiated chondrosarcomas) - Other histologic variants include clear cell and mesenchymal chondrosarcomas. Clinical features: - Chondrosarcomas commonly arise in the pelvis, shoulder, and ribs; in contrast with enchondromas, chondrosarcomas rarely involve the distal extremities. - They typically manifest as painful, progressively enlarging masses. - the more radiolucent the tumor the greater the likelihood that it is high grade. - Metastasize hematogenously to the lung and skeleton.

Answer 139

 Ewing sarcoma and primitive neuroectodermal tumors (PNETs) are primary malignant small round cell tumors of bone and soft tissue.  best viewed as variants of the same tumor, differing only in degree of neuroectodermal differentiation and clinical features.  PNETs demonstrate clear neural differentiation, whereas Ewing sarcomas are undifferentiated.  After osteosarcoma, it is the second most common pediatric bone sarcoma.  Most patients are 10 to 15 years of age, and 80% are younger than 20 years.  Whites>blacks  The common chromosomal abnormality is a translocation that causes fusion of the EWS gene on 22q12 with a member of the ETS family of transcription factors.  The most common fusion partners are the FL1 gene on 11q24 and the ERG gene on 21q22. The resulting chimeric protein functions as a transcription factor = effects on differentiation, proliferation, and survival have all been proposed.  Morphology: - Ewing sarcoma/PNET arises in the medullary cavity and invades the cortex and periosteum to produce a soft tanwhite tumor mass, frequently with hemorrhage and necrosis. - It is composed of sheets of uniform small, round cells that are slightly larger than lymphocytes; typically, there are few mitotic figures and little intervening stroma) - The cells have scant glycogen-rich cytoplasm. - The presence of Homer-Wright rosettes (tumor cells circled about a central fibrillary space) indicates neural differentiation.  Clinical Features - Ewing sarcoma/PNET typically manifests as a painful enlarging mass in the diaphyses of long tubular bones (especially the femur) and the pelvic flat bones. - studies show a destructive lytic tumor with infiltrative margins and extension into surrounding - soft tissues= There is a characteristic periosteal reaction with deposition of bone in an onion-skin pattern. - The 5-year survival rate is currently 75% for patients presenting with localized tumors. MEDULLOBLASTOMA  Medulloblastoma occurs predominantly in children and exclusively in the cerebellum.  Neuronal and glial markers are nearly always expressed  the prognosis for untreated patients is dismal however medulloblastoma is exquisitely radiosensitive.  Tumors of similar histologic type and a poor degree of differentiation can be found elsewhere in the nervous system, where they are called primitive neuroectodermal tumors (PNETs).  Morphology: - In children, medulloblastomas are located in the midline of the cerebellum; lateral tumors occur more often in adults. - The tumor often is well circumscribed, gray, and friable and may be seen extending to the surface of the cerebellar folia and involving the leptomeninges - Medulloblastomas are extremely cellular, with sheets of anaplastic (“small blue”) cells - Individual tumor cells are small, with little cytoplasm and hyperchromatic nuclei; - mitoses are abundant. - Often, focal neuronal differentiation is seen in the form of the Homer Wright or neuroblastic rosette,; they are characterized by primitive tumor cells surrounding central neuropil (delicate pink material formed by neuronal processes).  Clinical features: - In general, tumors with MYC amplifications are associated with poor outcomes, while those linked with mutations in genes of the WNT signaling pathway have a more favorable course. - Many tumors also have mutations that activate the sonic hedgehog (shh) pathway, which has a critical role in tumorigenesis

Answer 140

CEREBRAL EDEMA Accumulation of excess fluid within the brain parenchyma. Result in Widened gyri, narrowing of sulci, compression of ventricles may be focal or diffuse  We have 2 types of edema (occur together particularly after injury):  Vasogenic edema- occur when the integrity of the normal BBB is disrupted, allowing fluid to shift from the vascular compartment into the extracellular spaces of the brain. Can be either generalized or localized (e.g increase permeability of blood vessel due to inflammation or tumor). Vasogenic oedema often associated with focal lesions such as primary metastatic tumors or Abscess. disorders is increased vascular permeability leading to vasogenic edema. For instance, blood vessels in glioblastom and other malignant brain tumors do not have tight junctions, explaining the fluid leakage and cerebral edema that accompanies these tumors. Cytokines generated during infectious and inflammatory processes enhance transmigration of circulating leukocytes and may even loosen tight junctions, thus facilitating the migration of inflammatory cells into the brain. HIE disrupts the BBB. More subtle BBB dysfunction may result in impaired glucose transport and accumulation of Aβ.  Cytotoxic edema- increase in the IC fluid, secondary to neuronal & glial cell membrane injury, as might be follow generalized hypoxic-ischemic insult or with exposure to some toxins.  Interstitial edema: It is the result of increased intracerebral influx of CSF through the ependymal lining. Fluid from the ventricles enters into the periventricular white matter. typically a complication of hydrocephalus.  Brain is softer; appears to "overfill" the cranial vault In generalized edema the gyri are flattened, the sulci are narrowed, and the ventricular cavities are compressed. INTRACRANIAL PRESSUER  Brain enclosed in rigid skull that may house only constant volume if something is added it generate Increased intracranial pressure is a rise in the pressure inside the skull that can result from or cause brain injury.  causes: a. Rise in pressure of the cerebrospinal fluid increased CSF volume meningitis b. ;tumor; c. hydrocephalus; d. the added mass of epidural, subdural, and intracranial hematomas and e. Cerebral edema which develops around large contusions, from diffuse vascular injury, and as a result of HIE.  Increases in pressure can damage the brain by 1. Decreasing perfusion collapse brain capillaries resulting in global ischemia. 2. Displacing tissue across dural barriers inside the skull or through openings in the skull (herniation) HERNIATION  Displacement of brain tissue in between the dural barrios or out of skull .accurse When the volume inside skull increases beyond the limit permitted by compression of veins and displacement of CSF, with increase intracranial pressure. Herniation leads to vascular compromise of the compressed tissue  infraction, additional swelling and further herniation # main types of herniation’s: 1. Subfalcine (cingulate) herniation- unilateral or asymmetric expansion of a cerebral hemisphere displaces the cingulate gyrus under the edge of the falx. This may be associated with compression of branches of the anterior cerebral artery. 2. Transtentorial (uncinate) herniation -the medial aspect of the temporal lobe is compressed against the free margin of the tentorium. As the temporal lobe is displaced, the third cranial nerve is compromised, resulting in pupillary dilation and impairment of ocular movements on the side of the lesion ("blown pupil") anisocoria. The posterior cerebral artery may also be compressed, resulting in ischemic injury to the primary visual cortex. If the displaced temporal lobe is large enough, the pressure can compress the contralateral cerebral peduncle against the tentorium, resulting in hemiparesis(weakness in one side of body) ipsilateral to the side of the herniation (a so-called false localizing sign). The compression of the peduncle creates a deformation known as Kernohan’s notch(are a subdural hematoma and uncal herniation on the same side. Notching of the midbrain is seen on the opposite side (Kernohan’s notch). This damages the contralateral pyramidal tract fibers in the midbrain and causes hemiparesis on the side of subdural hematoma.). Progression of transtentorial herniation is often accompanied by linear or flame-shaped hemorrhages in the midbrain and pons, termed Duret hemorrhages. 3. Tonsillar herniation- displacement of the cerebellar tonsils through the foramen magnum. This pattern of herniation is life-threatening, because it causes brain stem compression and compromises vital respiratory and cardiac centers in the medulla. 4. Retrograde transtentorial herniation 5. Herniation out of skull not by foramen magnum HYDROCEPHALUS  Accumulation of excessive CSF within the ventricles of the brain. Normal total volume of CSF in the adult ranges from140 to 270 ml produced in rate of 600-700 ml per day normally: choroid plexus => CSF in ventricle mainly lateral and 3rdoutflow through magendie and luska foramina => subarachnoid space => absorbed by arachnoid granulation => venous sinus => Jugular vein => heart.  Reasons: 1. Impa ird flow 2. Impaired resorption 3. Rarely - over production of CSF (e.g tumor of choroid plexus) #We have 2 types : 1. Non-communicating Hydrocephalus- caused by CSF flow obstruction, preventing CSF flowing into arachnoid space. A portion of the ventricles enlarges while the reminder doesn't. Mainly due obstruction of foramen of Monro, compressing cerebral aqueduct 2. communicating Hydrocephalus- (non obstructive) Caused by impaired CSF reabsorption in the absence of CSF flow obstruction btw the ventricles and the subarachnoid space. The entire ventricle system is enlarged. When hydrocephalus develops in infancy before closure of the cranial sutures, there is enlargement of the head. Hydrocephalus developing after fusion of the sutures, in contrast, is associated with expansion of the ventricles and increased intracranial pressure, without a change in head circumference. hydrocephalus ex vacuo -dilation of the ventricular system with a compensatory increase in CSF volume secondary to a loss of brain parenchyma, as may occur after infarcts or with a degenerative disease.

Answer 141

MALFORMATION Neural Tube Defects  Formation of the neural tube gives rise to the ventricular system, brain and spinal cord.  NTDs are the most common congenital abnormalities of the CNS and, overall, the second most common type of congenital abnormality after congenital heart disease.  Spina bifida is a set of malformations of the spinal cord caused by failure of closure of the neural tube and lack of fusion of the vertebral arches  Folate deficiency during the initial weeks of gestation increases risk through uncertain mechanisms; Screening for elevated α-fetoprotein has increased the early detection of neural tube defects.  The most common defects involve the posterior end of the neural tube, from which the spinal cord forms. spina bifida occulta, the vertebral arches are absent Meningocele is a bulge in the lumbosacral area consisting of a meningeal sac protruding through the bone defect. meningomyelocele, the sac contains malformed spinal cord tissue. In severe cases, there is no sac at all, and neural tissue from the open neural plate lies on the dorsal surface of the fetus.  malformation of the anterior end of the neural tube Anencephaly, the brain initially protrudes through a defect in the cranial vault and is gradually destroyed because of mechanical injury and vascular disruption. Eventually, all that is left is a small, vascular mass of disorganized neural tissue Encephalocele is a protrusion of brain through a defect of the skull, usually in the occipital area. The protruding part is destroyed because of mechanical disruption and ischemia. The intracranial part of the brain around the defect is malformed and disrupted. Large occipital encephaloceles are incompatible with life because of damage of the brainstem. craniorachischisis, is due to defective closure of the hindbrain-cervical junction. Forebrain malformation  The neurons and glial cells that form the brain are generated around the ventricles of the brain and migrate to the cortex.  Various mutations in genes that control migration result in these malformations, which include the following:  The volume of the brain is abnormally large (megalencephaly) –like from hydrocephalus in utero or small (microencephaly) - fetal alcohol syndrome, and HIV-1 infection acquired in utero.  Lissencephaly (agyria) or, with more patchy involvement, pachygyria, is characterized by absent gyration leading to a smooth-surfaced brain. The cortex is abnormally thickened and usually has only four layers.  Polymicrogyria is characterized by an increased number of irregularly formed gyri that result in a bumpy or cobblestone-like surface. These changes can be focal or widespread. The normal cortical architecture can be altered in various ways, and adjacent gyri often show fusion of the superficial molecular layer.  Holoprosencephaly is characterized by a disruption of the normal midline devison of the forebrain. Mild forms may just show absence of the olfactory bulbs and related structures (arrhinencephaly). In severe forms the brain is not divided into hemispheres or lobes, and this anomaly may be associated with facial midline defects such as cyclopia. Several single-gene defects including mutations in sonic hedgehog have been linked to holoprosencephaly.  Other examples are focally disordered cortex (confusingly called dysplastic cortex) and neurons stranded beneath the cortex, sometimes as nodules and other times as bands Posterior fossa anomalies  Result in abnormalities of the cerebellum.  The Chiari type II malformation is a syndrome characterized by a) myelomeningocele lumbar b) abnormalities of the posterior fossa The abnormality of the posterior fossa consists of a large foramen magnum, low insertion of the tentorium and a shallow posterior fossa. As a result of these deformities, the cerebellum and brainstem are crowded and displaced into the cervical canal. The cerebellum may also prolapse upward through the tentorial opening. c) hydrocephalus.  The far milder Chiari type I malformation has low-lying cerebellar tonsils that extend through the foramen magnum.  Syndromes characterized by “missing” cerebellar tissue include Dandy-Walker malformation, is a spectrum of posterior fossa abnormality key feature of which is complete or partial agenesis of the cerebellar vermis. The cerebellar hemispheres are preserved. There is obstruction of CSF flow out of the fourth ventricle, the mechanism of which is not understood. As a result of this obstruction, the fourth ventricle dilates and the membrane that forms its roof balloons, creating a large posterior fossa cyst. PERINATAL BRAIN INJURY  A variety of exogenous factors can injure the developing brain.  Injuries that occur early in gestation may destroy brain tissue without evoking reactive changes, sometimes making them difficult to distinguish from malformations.  Brain injury occurring in the perinatal period is an important cause of childhood neurologic disability.  Cerebral palsy is a term for nonprogressive neurologic motor deficits characterized by spasticity, dystonia, ataxia or athetosis, and paresis attributable to injury occurring during the prenatal and perinatal periods.  Signs and symptoms may not be apparent at birth and only declare themselves later, well after the event.  The two major types of injury that occur in the perinatal period are hemorrhages and infarcts; These differ from the otherwise similar lesions in adults in terms of their locations and the tissue reactions they engender.  In premature infants, there is an increased risk of intraparenchymal hemorrhage within the germinal matrix, most often adjacent to the anterior horn of the lateral ventricle. Hemorrhages may extend into the ventricular system and from there to the subarachnoid space, sometimes causing hydrocephalus.  Infarcts may occur in the supratentorial periventricular white matter (periventricular leukomalacia), especially in premature babies. The residua of these infarcts are chalky yellow plaques consisting of discrete regions of white matter necrosis and mineralization. When severe enough to involve the gray and white matter, large cystic lesions can develop throughout the hemispheres, a condition termed multicystic encephalopathy.

Answer 142

VIRAL ENCEPHALITIS # A parenchymal infection of the brain that is almost invariably associated with meningeal inflammation –meningioencephalitis. #Inflammation of the brain is most often caused by viruses. It may be diffuse (i.e., involve the entire brain) or localized to a part of the brain. #characteristic histologic features: -perivascular and parenchymal mononuclear cell infiltrates -microglial nodules -neuronophagia # The nervous system is particularly susceptible to viruses such as rabies and polio # In addition to direct infection of the nervous system, the CNS can also be injured by immune mechanisms after systemic viral infections. Intrauterine viral infection may cause congenital malformations, as occurs with rubella. FUNGAL ENCEPHALITIS  Fungal infections usually produce parenchymal granulomas or abscesses, often associated with meningitis.  The most common fungal infections have distinctive patterns:  Candida albicans usually produces multiple microabscesses, with or without granuloma formation.  Mucormycosis is the term used to describe rhinocerebral infections caused by several fungi belonging to the order Mucorales. It typically presents as an infection of the nasal cavity or sinuses of a diabetic patient with ketoacidosis. It may spread to the brain through vascular invasion or by direct extension through the cribriform plate. The proclivity of Mucor to invade the brain directly sets it apart from other fungi, which tend to reach the brain by hematogenous dissemination from distant sites.  Aspergillus fumigatus tends to cause a distinctive pattern of widespread septic hemorrhagic infarctions because of its marked predilection for blood vessel wall invasion and subsequent thrombosis.  Cryptococcus neoformans can cause both meningitis and meningoencephalitis, often in the setting of immunosuppression. It can be fatal in as little as 2 weeks or may exhibit indolent behavior, evolving over months or years. The CSF may have few cells but elevated protein, and the mucoid encapsulated yeasts can be visualized on India ink preparations. Extension into the brain follows vessels in the Virchow-Robin spaces. As organisms proliferate, these spaces expand, giving rise to a “soap bubble”– like appearance.  In endemic areas, Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis also can infect the CNS, especially in the setting of immunosuppression OTHER MENINGOENCEPHALITIDES  Cerebral Toxoplasmosis. Cerebral infection with the protozoan Toxoplasma gondii can occur in immunosuppressed adults or in newborns who acquire the organism transplacentally from a mother with an active infection. In adults, the clinical symptoms are subacute, evolving during a 1- or 2-week period, and may be both focal and diffuse. Due to inflammation and breakdown of the blood-brain barrier at sites of infection, there’s edema around lesions (socalled ring enhancing lesions). In newborns who are infected in utero, the infection classically produces the triad of chorioretinitis, hydrocephalus, and intracranial calcifications. The CNS abnormalities are most severe when the infection occurs early in gestation during critical stages of brain development. Necrosis of periventricular lesions gives rise to secondary calcifications as well as inflammation and gliosis, which can lead to obstruction of the aqueduct of Sylvius and hydrocephalus.  Morphology When the infection is acquired in immunosuppressed adults, the brain shows abscesses, frequently multiple, most often involving the cerebral cortex (near the gray-white junction) and deep gray nuclei. Acute lesions consist of central foci of necrosis with variable petechiae surrounded by acute and chronic inflammation, macrophage 33# infiltration, and vascular proliferation. Both free tachyzoites and encysted bradyzoites may be found at the periphery of the necrotic foci  Cysticercosis - is the consequence of an end-stage infection by the tapeworm Tenia solium If ingested larval organisms leave the lumen of the GI, where they would otherwise develop into mature tapeworms, they encyst. Common within the brain andsubarachnoid space. Cysticercosis typically manifests as a mass lesion and can cause seizures. . The organism is found within a cyst with a smooth lining. The body wall and hooklets from mouth parts are most commonly recognized. If the encysted organism has died, there can be an intense inflammatory infiltrate in the surrounding brain, often including eosinophils, which may be associated with marked gliosis.  Amebiasis - manifests with different clinical syndromes, depending on the responsible pathogen. Naegleria spp., associated with swimming in nonflowing warm fresh water, cause a rapidly fatal necrotizing encephalitis. Acanthamoeba causes a chronic granulomatous meningoencephalitis.

Answer 143

Meningitis-Infection may be limited to the subarachnoid space (leptomeningitis) or may spread into the brain (meningoencephalitis). Such infection may be classified as acute or chronic. According to the appearance of the cerebrospinal fluid one can classify meningitis as purulent (bacterial) or serous (viral). #infectious meningitis can be divided to: 1. Acute pyogene (bacterial) 2.  Most common bacteria: -group B strep., E coli, listeria monocytogen affect neonates -Neisseria meningitis children+ young adult -sterp. Pneumonia adults+eldary  Signs: -systemic sign of infection along with meningeal irritation & neurologic impairment including headache, neck stiffness, fever, photofobia, Nausea and vomiting, mental confusion, somnolence, Brudzinski sign, Kernig sign.  Diagnosis: Lumbar punction - neutrophils Protein Glucose + gram stain Morphology: -exudates within the lepromeninges over the brain surface. -pus - The subarachnoid space is filled with a purulent exudate -associated with brain abscess -neutrophils in the subarachnoid space 3. Aseptic (viral)  may occur as part of a systemic viral disease (e.g., varicella, mumps, and measles), or it may be limited to the CNS. The latter may besporadic (e.g., herpes virus infection) or epidemic (e.g., arboviruses), and is often associated with encephalitis.  usually self-limiting  Most common viruses : -hemophilus influenza in non vaccinated infants -coxsackievirus most common cause of viral meningitis. Fecel-oral trans.  Signs: -fever -photophobia -meningeal irritation  Diagnosis: -LP: lymphocytes Normal glucose Moderate protein elevation  Morphology: -Brain swelling -Mild to moderate lymphocytes infiltrate. 4. Chronic (TB, spirochetal) Mainly caused by : -mycobacteria ( m.tuberculosis) -spirochetes (treponema pallidum)  Tuberculous meningitis  Signs: headache, malaise (feeling of general discomfort or uneasiness), mental confusion, vomiting.  Diagnosis: protein level Moderate increase in CSF and mononuclear cells. Glucose lever reduced/normal. *special for m. tuberculosis: tuberculoma- circumscribed intraparenchymal mass. *Chronic tuberculous meningitis is a cause of arachnoids fibrosis, which may produce hydrocephalus  Morphology: -subarachnoid space contain gelatinous (fibrinous exudates in the base of the brain) obliterating the cisterns and closing cranial nerves. -white granules scattered over the leptomeninges - Arteries running through the subarachnoid space may show obliterative endarteritis with inflammatory infiltrates in their walls and marked intimal thickening. - The infection may spread through the CSF to the choroid plexuses and ependymal surface.  Spirochetal infections:  Neurosyphilis is a tertiary stage of syphilis and occurs in only about 10% of individuals with untreated infection. 1. meningovascular neurosyphilis: -involving the base of the brain. -may be an associated with obliterative endarteritis 2. Paretic neurosyphilis is caused by invasion of the brain by Treponema pallidum -manifests as: progressive loss of mental and physical functions with mood alterations, terminating in severe dementia. - parenchymal damage particularly in the frontal lobe, characterized by loss of neurons with proliferation of microglia and gliosis. 3. Tabes dorsalis is another form of neurosyphilis, resulting from damage to the sensory nerves in the dorsal roots producing impaired joint position sense and resultant ataxia (locomotor ataxia); loss of pain sensation, leading to skin and joint damage (Charcot joints); other sensory disturbances, particularly characteristic "lightning pains"; and absence of deep tendon reflexes.  Individuals with HIV infection are at increased risk.  Lyme disease caused by Borrelia burgdorferi # complications of meningitis. o Hydrocephalus resulting from obstruction of CSF due to scarring of meninges o Neurologic defects due to destruction of underlying brain o Epilepsy due to focal damage of the brain or scarring of meninges o Abscess formation in the brain or subdural spaces (especially in children) o Spinal or cranial nerve compression or constriction as in tabes dorsalis

Answer 144

Transmissible spongiform encephalopathies (TSEs) are neurodegenerative disease caused by pirion protein accumulation results from abnormal folding of prions The normal prion protein a membrane glycoprotein, which is water-soluble and proteinase-sensitive. Abnormal prions result from a change in the folding pattern of PrPc ,( PrP normally is rich in α-helices, but PrPsc has a high content of β-sheets) which makes it resistant to the action of proteases and causes it to precipitate as insoluble form. This conversion results in neuronal degeneration and loss by an unknown mechanism. The unique feature of prion diseases is that they are self-propagating and transmissible. Once PrPSc is generated endogenously or introduced into the body from the environment, it converts normal prions into abnormal ones.  The majority of human prion diseases are sporadic- PrPc also may change its conformation spontaneously, accounting for sporadic cases of prion disease (sCJD).  . About 15% are familial- Certain mutations in the gene encoding PrPc (PRNP gene ) accelerate the rate of spontaneous conformational change; these variants are associated with early onset familial forms of prion disease (fCJD).  A few are environmentally acquired (iatrogenic-growth hormone treatment from individual with sick PrP and from eating BSE- contaminated meat). Initially, intracytoplasmic vacuoles appear in neurons and glial cell. As the disease progresses, vacuolization becomes more pronounced and the cortical neuropil develops a spongy appearance, hence the term spongiform encephalopathy Creutzfeldt-Jakob Disease  Creutzfeldt-Jakob disease (CJD) is the most common spongiform encephalopathy Usually sporadic; rarely can arise due to exposure to prioninfected human tissue (e.g., human growth hormone or corneal transplant)  A rapidly progressive dementing illness, with a typical duration from first onset of subtle changes in memory and behavior to death in less then year Presents as rapidly progressive dementia associated with ataxia (cerebellar involvement) and startle myoclonus Spike-wave complexes are seen on EEG.  Morphology  The progression to death in CJD usually is so rapid that there is little macroscopic evidence of brain atrophy.  Main finding is a spongiform transformation of the cerebral cortex and deep gray matter structures (caudate, putamen);  No inflammatory infiltrate is present.  Presence of proteinase K–resistant PrPsc in tissue, can be seen Variant Creutzfeldt-Jakob Disease  Variant CfD is a special form of disease that is related to exposure to bovinespongiform encephalopathy ('mad cow'). Consequence of exposure to the prion disease of cattle, called bovine spongiform encephalopathy.  Fetures :  The disease affected young adults  Behavioral disorders figured prominently in early disease stages Neurologic syndrome progressed more slowly than in other forms of CJD.  Similar pathologic appearance to that in other types of CJD, with spongiform change and absence of inflammation.  In vCJD, however, there are abundant cortical amyloid plaques, surrounded by the spongiform change  Familial fatal insomnia is an inherited form of prion disease characterized by severe insomnia and an exaggerated startle response.

Answer 145

# Neurodegenerative diseases: Definition of Neurodegeneration: progressive, slow, irreversible neuronal loss so such as diseas characterized by loss of neurons within the gray matter; often due to accumulation of protein which damages neurons (e.g. Aβ &Tau in Alzheimer, Tau in frontotemporal lobar degeneration alpha synuclein in Alzheimer and TDP-43 in FLD) Two main groups of clinical manifestation denoted, with overlaps: 1) Dementias- diseases the affect the cerebral cortex, result in loss of memory, language, and planning 2) Movement disorders- those that affect the BG and brain stem DEMENTIA - Impairment of memory and other cognitive functions (e.g. word‐finding, abstract reasoning, advance planning, concentration) with normal consciousness Ataxia- lack of coordination of muscle movements implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum ALZHEIMER DISEASE  Alzheimer disease- Degenerative disease of the cerebral cortex; it is the most common cause of dementia in the elderly (75% of cases).  Most cases (95%) are sporadic and seen in the elderly, Risk increases with age (doubles every 5 years after the age of 60).Epsilon 4 allele of apolipoprotein E is associated with increased risk, epsilon 2 allele With decreased risk, epsilon 4 allele carriers got increased convention of APP into Abeta amyloid product  Early-onset in Familial cases associated with the inheritance of gene mutation in presenilin1 and presenilin 2 proteins also in Down syndrome see early onset commonly occurs around 40 years of age The APP gene is located on chromosome 21, and the risk of AD also is higher in those with an extra copy of the APP gene, such as patients with trisomy 21 (Down syndrome)  Pathogenesis:the amyloid procerssor prot –APP is membrane prot on neurons it broken down by alpha secretase enzyme into processable product but if broken down by beta amyloid converting enzyme or gamma secretase it creat unprocessable product the Abeta who accumulate ext. cellular as amyloid  Small aggregates of Aβ may also be pathogenic, as they alter neurotransmission and are toxic to neurons and synaptic endings.  Large deposits, in the form of plaques, also lead to neuronal death, elicit a local inflammatory response that can result in further cell injury  The presence of Aβ also leads to hyperphosphorylation of the neuronal microtubule binding protein tau; this causes tau to redistribute from axons into dendrites and cell bodies, where it aggregates into tangles, which also contribute to neuronal dysfunction and cell death.  Morphology: The disease usually becomes clinically apparent as: 1. Slow-onset memory loss (begins with short-term memory loss and progresses to long-term memory toss) and progressive disorientation 2. impairment of higher intellectual function (judgment, abstract thinking, problem solving, language, visual–spatial function), with alterations in mood and behavior. 3. Later, progressive disorientation, memory loss and aphasia indicate severe cortical dysfunction, and over the next 5 to 10 years, the patient becomes profoundly disabled, mute, and immobile. 4. Death due to infections not direct the diseas… Macro gross appearance of brain in autopsy diffused cerebral atrophy (widening of the cerebral sulci and narrowing of gyri; a compensatory ventricular enlargement (hydrocephalus ex vacuo-widening due to atrophy of cerebral matter not due to increased CSF)) Micro histologic appearance:  Neuriticplaques (an extra cellular lesion) spherical mass primarily composed of amyloid fibrils and interwoven neuronal processes (neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite.)Plaques can be found in the hippocampus and amygdala as well as in the neocortex. Termed diffuse plaques; these typically are found in the superficial cerebral cortex, the basal ganglia, and the cerebellar cortex and may represent an early stage of plaque development.  Neurofibrillary tangles visible as basophilic fibrillary structures in the cytoplasm of the neurons that displace or encircle the nucleus created from abnormally hyper phosphorylated tau They are commonly found in cortical neurons, especially in the entorhinal cortex, as well as in the pyramidal cells of the hippocampus, the amygdala, the basal forebrain, and the raphe nuclei. FRONTOTEMPORAL LOBAR DEGENERATION  Category of disorders resulting in dementia share clinical features -progressive deterioration of language and changes in personality (in FLD the behavior and language disorder come befor memory impiremnt unlike in AD) stemming from the degeneration and atrophy of temporal and frontal lobes; The clinical syndromes commonly are referred to as frontotemporal dementias.  Morphology: Atrophy of the brain that predominantly affects the frontal and temporal lobes. Different subgroups are characterized by neuronal inclusions involving the affected regions;  In some cases the defining inclusions contain tau (FTLD-tau), but the configuration of the tau inclusions differs from the tau-containing tangles of AD. FTLD-tau sometimes is caused by mutations in the gene encoding tau. One wellrecognized subtype of FTLD-tau is Pick disease, which is associated with smooth, round inclusions known as Pick bodies. Tau is an microtubule associated protein of cytoskeleton  The other major form of FTLD is characterized by aggregates containing the PDNA/RNA-binding protein TDP-43 (FTLD-TDP43). This form of FTLD is associated with predominantly frontal lobe cognitive impairment. It is sometimes caused by mutations in the gene encoding TDP-43, which is also mutated in a subset of cases of amyotrophic lateral sclerosis. LEWY BODY DEMENSIA  Lewy body dementia -is a sporadic neurodegenerative disease It combines the neurological manifestations of dementia and parkinsonism. If in Parkinson diseas appearance of dementia comes in the late phases in LBD see early appearance of dementia in 1st year of diagnosis together with parkinsonian manifestation.  Patients with it present with fluctuating attention and cognition and visual hallucinations. Motor parkinsonian manifestations (bradykinesia slow voluntary movement, rigidity, and less frequently tremor) vary in severity and may appear later. Patients also experience depression, sleep disorder, and autonomic dysfunction.  The brain is not as atrophic as it is in AD, Prominent histologic correlate is the presence of Lewy bodies in neurons in the cortex and brainstem. Lewy bodies are abnormal collections of alpha-synuclein protein within the cytoplasm of neurons. Staining for α-synuclein also reveals the presence of abnormal neurites that contain aggregated protein — called Lewy neuritis.

Answer 146

Neuro degenerative diseas are group of disease Characterized by loss of neurons within the gray matter; often due to accumulation of protein which damages neurons B. Degeneration of the cortex leads to dementia. C. Degeneration of the brainstem and basal ganglia leads to movement disorders. PARKINSON DISEASE  Neuro-Degenerative disease with primary loss of dopaminergic neurons in the substantia nigra (pars compacta). the Nigrostriatal pathway of basal ganglia uses dopamine to promote the initiation of voluntary movement (promote direct pathway and inhibit indirect pathway act on putamen).  Etiology- The vast majority of PD cases are sporadic with Unknown etiology 2nd most Common neurodegenerative disorder after AD related to aging - seen in approximately 2% of older adults. About 5-10 % of patients have a monogenic, autosomal dominant or recessive form of PD:The first autosomal dominant form of PD identified is that caused by mutations of α-synuclein, a synaptic protein encoded by SNCA on 4q22. The gene most commonly associated with autosomal recessive PD is Parkin the parkin protein involved in ubiqintin pathway of protein degragtion Patients with GAucher disease (GD), including carriers of GBA1 mutations, have a 20- to 30-fold risk for developing PD. Can be induced by drugs such as dopamine antagonists or toxins that selectively injure dopaminergic neurons. rare cases were related to MPTP exposure prodrug converted to neurotoxin harming dopaminergic neurons resulting in clinical appearing PD (A contaminant in illicit drugs). Pathomechanisem-PD affects the dopamine-producing neurons of the substantia nigra (SN). The key pathology in PD is α-synuclein accumulation Α-synuclein is toxic for the cell and Its accumulation impairs the functions of mitochondria, lysosomes, and endoplasmic reticulum, and interferes with micro tubular transport. Dopamine is produced by SN neurons from DOPA (also a precursor of melanin) and transported along the axons of these neurons to the striatum. The triad of rigidity, bradykinesia and tremor at rest correlates with degeneration of the dopaminergic nigrostriatal pathway and dopamine depletion in the striatum. Morphology:  A typical gross finding is pallor of the substantia nigra and locus ceruleus.  Due to Loss of the pigmented, catecholaminergic neurons in these regions  Lewy bodies -may be found in the neuron bodie large α-synuclein aggregates form round eosinophilic cytoplasmic inclusions that often have a dense core surrounded by a pale halo. (composed of αsynuclein and other proteins, including neurofilaments and ubiquitin. )  Lewy neurites-fibrils made of insoluble polymers of a-synuclein that are deposited in neuronal processes and in glial cells.  As implied by the dementia, Lewy bodies and Lewy neurites eventually appear in the cerebral cortex  Subtle Lewy bodies and Lewy neuritis can be found in many brain regions outside of the substantia nigra and in nondopaminergic neurons; These lesions appear first in the medulla and then in the pons, before involvement of the substantia nigra.  Clinical features  Progresses over 10 to 15 years, eventually producing severe motor slowing to the point of near immobility. Clinical features ('TRAP'): 1. Tremor—pill rolling tremor at rest; disappears with movement 2. Rigidity—cogwheel rigidity in the extremities 3. Akinesia/bradykinesia—slowing of voluntary movement; 4. Postural instability and shuffling gait  Death usually is the result of intercurrent infection or trauma from frequent falls caused by postural instability.  Dementia apper in late part of diseas .  Causes to Parkinsonism:  When dementia arises within 1 year of the onset of motor symptoms, it is referred to Lewy body dementia (LBD).  Idiopathic Parkinson disease (paralysis agitans) is the most common cause  Ischemia of basal ganglia (relatively common)  Head trauma, repetitive (e.g., boxers)  Shy–Drager syndrome (idiopathic parkinsonism associated with hypotension and other autonomic symptoms) AMYOTROPHIC LATERAL SCLEROSIS (ALS) Amyotrophic Lateral Sclerosis (ALS) is a fatal degenerative disorder of upper and lower motor neurons Affects men more than women (>50y), usually beginning with subtle asymmetric distal extremity weakness  The balance between upper and lower motor neuron involvement can vary, although most patients exhibit involvement of both. The disease eventually involves the respiratory muscles, leading to recurrent bouts of pulmonary infection, which is the usual cause of death.  Pathogenesis  Most cases are sporadic, 5% to 10% are familial, mostly with AD inheritance. and have a younger onset. Several gene mutations have been discovered in this group. These mutations affect protein stability, RNA biology, cytoskeletal maintenance, and other functions. Mutations of the same genes are also found in a significant proportion of sporadic ALS cases.  the most frequent genetic cause is mutations in the superoxide dismutase gene, SOD-1 which generate abnormal misfolded forms of the SOD-1 protein - may trigger the unfolded protein response and cause apoptotic death of neurons.  The next two common causative genes both encode DNA/RNA binding proteins, TDP-43 and FUS Mutations in TDP-43 also can cause frontotemporal lobar degeneration (FTLD) or a disease with overlapping features of both ALS and FTLD.  Another recently identified gene which accounts for a significant proportion of FALS cases is C9ORF72 on 9p21. This mutation causes hexanucleotide repeat expansion in a noncoding region of the gene and is associated with FTD and TDP-43 inclusions  The pathology of ALS is degeneration and loss of motor neurons in the anterior horns -loss of lower motor neurons and of upper motor neurons (Betz cells). Lower motor neuron loss causes muscle weakness, atrophy, and fasciculations; upper motor neuron involvement causes spasticity, hyperactive tendon reflexes, and Babinski signsAn additional consequence of upper motor neuron loss is degeneration of thecorticospinal tracts in the lateral portion of the spinal cord (“lateral sclerosis”).  Dementia appears at the onset or develops later in a significant proportion of ALS patients.  ALS is relentlessly progressive. The majority of patients die, usually from respiratory paralysis, within 2-3 years from the onset of symptoms.  Primary lateral sclerosis is an ALS variant which affects upper motor neurons only  In some patients, degeneration of the lower brain stem cranial motor nuclei occurs early and progresses rapidly, a pattern of disease referred to as bulbar amyotrophic lateral sclerosis. With this disease pattern, abnormalities of swallowing and speaking dominate.  Morphology  The most gross changes are found in anterior roots of the spinal cord, which are thin and gray (rather than white)- There is a reduction in the number of anterior horn cell associated loss of anterior root myelinated fibers. In especially severe cases, the precentral gyrus (motor cortex) may be mildly atrophic  Remaining lower motor neurons often harbor cytoplasmic inclusions that contain TDP-43, except in those cases in which the underlying cause is a mutation in SOD-1.  With the loss of innervations from the death of anterior horn cells, skeletal muscles show neurogenic atrophy. HUNTIGNTON DISEASE  Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative movement disorder beginning about the age of 40. Associated with: degeneration of the striatum (caudate and putamen), involuntary jerky movements and behavioral changes.  Pathogenesis:  Caused by CAG trinucleotide repeat expansions in a gene located on ch. 4 that encodes the protein huntingtin. Denote that larger numbers of repeats results in earlier-onset disease and further expansions of the pathologic CAG repeats can occur during spermatogenesis, so paternal transmission may be associated with earlier onset in the next generation, a phenomenon referred to as anticipation.  The expanded huntingtin protein conjugated with ubiquitin, forms aggregates (inclusions) in the nuclei and dendrites of affected neurons. These inclusions can be detected by immunohistochemistry using antibodies to huntingtin. These findings suggest that there is an error in the proteolytic degradation of the expanded huntingtin these aggregates may sequester transcription factors, disrupt protein degradation pathways, impair mitochondrial function, or alter brain-derived neurotrophic factor (BDNF) signaling.  Severe loss of GABAergic neurons from affected regions of the striatum (caudate nucleus and putamen) lead to loss of inhibitory signal on cortex leading to clinical symptoms  Morphology:  In remaining striatal neurons and in the cortex, there are intranuclear inclusions that contain aggregates of ubiquitinated huntingtin protein  Gross examination of the brain reveals atrophy of the caudate nucleus and putamen and dilatation of the anterior horns of the lateral ventricles  Clinical presentation : The disease is progressive with average age at presentation is 40 years and resulting in death after a course of about 15 years. Presents with chorea - an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. Early cognitive symptoms include forgetfulness (later there may be progression to a severe dementia) and behavioral changes including depression- HD carries an increased risk of suicide.

Answer 147

CEREBROVASCULAR DISEASES Brain disorders arise from pathologic processes involving blood vessels constitute a major cause of death in the developed world. Most common the damage appear Due to ischemia (85% of cases) but also can be the result of a hemorrhage (15% , out off 10% is intracerebral and 5%is subarachnoidal). 3 types of cerebrovascular pathologies : (1) thrombotic occlusion of vessels (2) embolic occlusion of vessels (3) Vascular rupture. “Stroke” is a clinical term for symptoms that arise from cerebrovascular problems, particularly when symptoms begin acutely. Thrombosis and embolism cause ischemic injury or infarction of specific regions of the brain, depending on the vessel involved. A similar pattern of injury occurs diffusely when there is complete loss of perfusion. Hemorrhage accompanies rupture of vessels, leading to direct tissue damage as well as secondary ischemic injury. ISCHEMIC ENCEPHALOPATHY (global focal ischemia) The brain tissue requires a constant delivery of glucose and oxygen from the blood.it needs about 15% of cardiac output and responsible for 20% of body total oxygen consumption Neurons are dependent on serum glucose as an essential energy source and are particularly susceptible to ischemia (undergo necrosis within 3 - 5 minutes). Cerebral blood flow remains constant over a wide range of blood pressure and intracranial pressure due to autoregulation of vascular resistance and it not influence from regulatory mechanisms . Ischemia is when no blood supply so bout sugar and o2 cant rich hypoxia when no o2 supply alone o Functional hypoxia: cause by decrease partial pressure of O2 (e.g altitude), impaired oxygen carrying capacity (e.g anemia) or inhibition of 02 by tissue (e.g poisoning). o Ischemia: either transient or permanent, due to tissue hypoperfusion (e.g hypotension) Such as injureis may be global or focal: Global Cerebral Ischemia widespread ischemic/hypoxic injury to the brain . can occur in the setting of sever systemic hypotension systolic pressures of less than 50mmHgsuch as in cardiac arrest, shock, and severe hypotension #main reasons: -low perfusion (e.g due to atherosclerosis) -acute decrease in blood flow (e.g cardiogenic shock) -chronic hypoxia (e.g., anemia) -repeated episodes of hypoglycemia. #clinical outcome: different upon different severity and duration of insult  In mild situations: transient confusional state, usually full recovery  In moderate situations: infracts in regions that are fed by the very end of the circulation- watershed areas. Damage to highly vulnerable regions: In severe situations: widespread neuronal death irrespective from regional sensitivity , diffuse necrosis. If such as patient survive he remain in persistent vegetative state . Other patients meet the clinical criteria for "brain death," including evidence of diffuse cortical injury and brain stem damage, including absent reflexes and respiratory drive. #morphology:  Swollen brain , wide gyri and narrow sulci poor demarcated gray and white zone.  The histopatho changes that accompany irreversible infury have 3 catagories: 1. 12-24 hours: early changes, acute neuronal change (red neurons). 2. 24 hours-2 weeks: Subacute changes, include necrosis of tissue, influx of macrophages, vascular proliferation, and reactive gliosis. 3. After 2 weeks: Repair,characterized by removal of all necrotic tissue, loss of organized CNS structure, and gliosis . In the cerebral cortex the neuronal loss and gliosis produce an uneven destruction of the neocortex. VASCULAR DEMENTIA B. 2nd most common cause of dementia as cerebrovascular diseas ie hypertension atherosclerosis lead to modrate global ischemic demage to cortex and hippocampus leading to dementia –treatment improve prognosis Focal cerebral ischemia Focal cerebral ischemia occurs when there is impierd blood flow in a particular cerebral vessel so there is reduces blood flow to the particular brain region, increasing the risk of cell death to that area And the development of infarction. # It can be either caused by thrombosis or embolism the main reason is cerebral arterial occlusion- mainly thromboembolism cardiac mural thromboemboli. #collateral blood supply may limit the damage to some regions. #Middle cerebral artery is the most vulnerable. emboli tend to lodge in vessels branches or areas of stenosis. #transiant ischemic attak when symptom last less then 24 hr if more its an ischemic stroke=infarction BRAIN INFRACTIONS Cerebral infarction is focal brain necrosis due to complete and prolonged ischemia that affects all tissue elements, neurons, glia, and vessels # The majority of thrombotic occlusions causing cerebral infarctions are due to atherosclerosis; the most common sites of primary thrombosis are the carotid bifurcation, middle cerebral artery, and basilar artery. # there are 2 types: Non hemorrhagic- Thrombotic stroke is due to rupture of an atherosclerotic plaque. Atherosclerosis usually develops at branch points (e.g., bifurcation of internal Carotid and middle cerebral artery in the circle of Willis).Results in a pale infarct at the periphery of the cortex Can be treated with thrombolytic therapy. Hemorrhagic-result from reperfusion of ischemic tissue, . Hemorrhagic infarcts are most common in embolism(common source of emboli is the left side of the heart e.g., atrial Fibrillation). Blood leaks from collateral / occluding thrombus or embolus breaks up . Most Usually involves the middle cerebral artery and Results in a hemorrhagic infarct at the periphery of the cortex. Lacunar stroke occurs secondary to hyaline arteriolosderosis, a complication of hypertension. i. Most commonly involves lenliculostriale vessels, resulting in small cystic areas of infarction #morphology: MACRO: Macroscopically may not be detectable for 6‐12 hours 48‐72 hours Softening and disintegration of the infarcted region. May be oedema and herniation. Weeks to months: Cyst formation MICRO: Ischemic neuronal change –red neurons after about 12 hr initial microscopic finding Initial influx of neutrophils from the blood stream enter the infarct through damaged vessels about 48 hr. from unset . Then in the following about 2 weeks macrophages immigrate (They ingest the products of degradation of neurons and myelin and may stay months to years in the lesion) also see at point core of infract disintegrate and capillary in periphery proliferate Astrocyte at edge of lesion enlarged divide and send network of glial cell processes Results in formation of a fluid-filled cystic space surrounded by gliosis This is completed in approximately 2 months the blood brain barrier is once again sealed No scar formation! INTRACRANIAL HEMORRHAGE #Hemorrhage within the skull can occur in a variety of locations and be linked to veraity of causes:  Epidural hematoma usually associated with trauma  Subdural hematoma  Subarachnoid hematoma- most commonly seen with aneurysms  Intracerebral (parenchymal) hemorrhage-link to hypertention about 15% of death of chronic hypertention patient  Intraventricular hemorrhage, also known as hematocephalus internus. Primary Brain Parenchymal Hemorrhage #Spontaneous intraparenchymal hemorrhages occur most commonly in mid to late adult life~60 years . Most are caused by rupture of a small intraparenchymal vessel. #Hypertension is the most common underlying cause. With hemorrhages typically occur in the basal ganglia, thalamus, pons, and cerebellum. #morphology: extravasated blood compressing brain parenchyma so With time brown rim surrounding a cavity develops (neurons necrosis like in hemorrhagic infarction). #cerebral amyloid angiopathy-amyloid deposit in blood vessel wall of medium –small b.v. weakening the b.v. may lead to rupture (unlike hypertension related this one manifested as lobar hemorrhage) #also may cause from trauma epidural hematoma #Collection of blood between the dura and the skull, Classically due to fracture of the temporal bone with rupture of the middle meningeal artery; bleeding separates the dura from the skull leading to formation of Lens-shaped lesion on CT This sack is filling with blood in interval without any clinical sing may precede eliciting neurologic signs even rapture put pressure on brain -Herniation is a lethal complication. subdural hematoma #Subdural hemorrhage -Collection of blood underneath the dura;stems from traumatically severed ‘‘bridging veins’’ that connect superficial cerebral veins and the dural venous sinuses. This venous bleeding may stop on its own as soon as the pressure outside the veins exceeds the pressure inside the vascular lumen. Increased rate of occurrence in the elderly due to age-related cerebral atrophy,which stretches the veins Subarachnoid Hemorrhage and Saccular Aneurysms #Bleeding into the subarachnoid space, Most frequently (85%) due to rupture of a berry aneurysm; other causes include AV malformations and an anticoagulated state Present as a sudden headache with nuchal rigidity.LP show xanthochromia (yellowish appearance of cerebrospinal fluid) - morphology: bleeding in the base of the brain. a) Saccular aneurysms-(berry aneurysms) most common non traumatic cause, Berry aneurysms are thin-walled saccular outpouching» that lack a media layer , increasing the risk tor rupture. Most frequently located in the anterior circle of Willis at branch points of the anterior communicating artery 3. Associated with Marfan syndrome and autosomal dominant polycystic kidney disease c) Charcot–Bouchard aneurysms (also known as miliary aneurysms or microaneurysms) are aneurysms of the brain vasculature which occur in small blood vessels (less than 300 micrometre diameter). Charcot–Bouchard aneurysms are most often located in the lenticulostriate vessels of the basal ganglia and are associated with chronic hypertension. [1] Charcot–Bouchard aneurysms are a common cause of cerebral hemorrhage. b) Traumatic

Answer 148

SUBARACHNOID HEMORRHAGE # The most common causes are berry aneurysm & vascular malformation. #1/3 of the cases associated with ruptures with increase ICP. # Blood under arterial pressure is forced into the subarachnoid space stricken headache rapidly loss of consciousness (coma). #25%-50% die in the 1st rupture, recurrent bleeding is common in survivors. 1) Saccular (berry) aneurysm:  No media in the saccular outpouching.  Mainly (90%) in anterior circulation near major arterial branch points.  High risk in patient with autosomal dominant polycytic diseas (ADPCD).  Although they are sometimes congenital they are not present at birth but develop over time.  COMPLICATIONS: due to healing and fibrosis process of the meninges, there is a risk for CSF flow obstruction = hydrocephalus.  Morphology of saccular aneurysm: unruptured = thin outpouch of an artery, with lack of media beyond the neck.  Rupture- mainly happen in the apex of the sac = releasing blood into the subarachnoid space or the substance of the brain or both.  At times, rather than rupturing, a saccular aneurysm enlarges to form a mass that compresses cranial nerves and produces palsies on parenchymal structures and induces neurologic symptoms. Classically, for example, a posterior communicating artery aneurysm compresses the third cranial nerve, leading to an isolated oculomotor nerve palsy with a dilated pupil. **the most common aneurysms in the brain: 1. Berry aneurysms: These small saccular aneurysms are typically found in and around the circle of Willis at the base of the brain. They develop at the site of arterial branching corresponding to the congenital weakest part of the vessels. The rupture of these aneurysms leads to a usually fatal subarachnoid and/or intraparenchymal/intraventricular hemorrhage. 2. Atherosclerotic aneurysms: These aneurysms may involve the extraparenchymal or intracerebral arteries. Most often, they are asymptomatic and rarely rupture. 3. Hypertensive microaneurysms: 2. VASCULAR MALFORMATION #4 types: 1. Arteriovenous malformation (AVM’S) 2. Cavernous malformation. 3. Capillary telangiectasia 4. Venous angiomas. AVM:  The most common. Affect males twice as frequently as females (most congenital).  Result from defective formation of capillaries in a normal part of the brain. The arterial blood thus enters directly into the veins, usually by way of arteriovenous anastomoses that form at the defective site.  AVMs have a high blood flow, often pulsate, and may be a source of mixed parenchymal/subarachnoidal bleeding and seizures.  Manifest between the ages of 10 and 30 years.  Presenting as a seizure disorder, an intracerebral bleeding or subarachnoid.  Complications – intracerebral hemorrhage or subarachnoid hemorrhage. The risk of bleeding makes AVM the most dangerous type of vascular malformation.  Pathophysiology: multiple AVM’s can be seen in the setting of hereditary hemorrhagic telangiectasia, an autosomal dominant condition, often associated with the TGF pathway. MORPHOLOGY: 1. AVM: *macro: subarachnoid vessels resemble a tangles network of wormlike vascular channels. *micro: enlarged blood vessels separated by gliotic tissue. 2. Cavernous malformation: distended, loosely organized cascular channels with thin collagenized walls without intervening nervous tissue. Occur mostly in the cerebellum, pons and subcortical regions. 3. Capillary telangiectasia: microscopic foci of dilated thin walled vascular channels separated by relatively normal brain parenchyma that occur mostly in the pons. 4. Venous angiomas (varices): consist of aggregates of ectatic venous channels

Answer 149

TBI- traumatic brain injury: cerebral contusion, laceration, concussion. TBI occurs when an external force traumatically injuries the brain. For example: coupcountercoup injury (like in car accident) Cerebral contusion:  A form of traumatic brain injury - bruise of the brain tissue. Like bruises in othe tissues, cerebral contusions can be associated with multiple hemorrhages of blood vessels into the brain tissue. A contusion is caused by rapid tissue displacement, disruption of vascular channels, and subsequent hemorrhages, tissue injuries and edema.  Since they are closest to the skull, the crests of the gyri are the part of the brain that is most commonly damaged in traumatic injury.  Contusions are common in regions of the brain overlying rough and irregular inner skull surfaces, such as the orbitofrontal regions and the temporal lobe tips. Cerebral lacerations:  A type of TBI that occurs when the tissue of the brain is mechanically cut or torn. The injury is similar to cerebral contusion (except for the fact that the pia-arachnoid membranes are torn over at the site of injury in laceration and are not torn in contusion).  Penetration of the brain (e.g. by bullet) – causes laceration, with tissue tearing, vascular disruption and hemorrhages. MORPHOLOGY:  Macro: Contusion have wedge shaped appearance with the widest aspect closest to the point of impact. Within hours  blood extravasation into the white matter and subarachnoid space.  Micro: after 24 h = neuronal body change (nuclear pyknosis, cyto.eosinophilia, cellular disintegration). Inflammatory cells- neutrophils, macrophages. In contrast with ischemic lesions, in which superficial layers of the cortex may be preserved. Trauma affects mostly the superficial layers!!!! Diffuse axonal injury – widespread injury to the axons within the brain (white matter), sometimes with devastating consequences. :Concussion  The most common type of TBI.  Reversible altered concussion from head injury in the absence of contusion.  Characteristics: transient neurologic dysfunction includes loss of consciousness, temporary respiratory arrest and loss of reflexes.  Neurologic recovery is complete but amnesia for the event persist Epidermal hematoma:  Collection of blood between the dura and the skull.  Due to fracture of temporal bone with rupture of middle meningeal artery.  Lens shaped lesion on CT  compression of the brain surface: 1. lucid intervals may precede neurologic signs. 2. herniation is lethal complication.  May expand rapidly and constitutes a neurosurgical emergency necessitating prompt drainage and repair to prevent death. Subdural hematoma:  Collection of blood underneath the dura.  Due to tearing of bridging veins between dura and arachnoid (atrophy of the brain, children, trauma are common causes).  Usually arises with trauma, but can also occur to patients with atrophied brain = the bridging veins are stretched = tearing!  Presents with progressive neurologic signs: Herniation is lethal complication! Morphology: (subdural) The blood is collected on the brain surface contour, not entering to the sulci. Flattened brain, arachnoid is clear.

Answer 150

Brain tumors: Half-3/4 of the tumors are primary tumors. The rest are metastatic. Unique features of brain tumors:  These tumors do not have detectable premalignant or in situ stages comparable to those of carcinomas.  Even low grade lesions may infiltrate large regions of the brain leading to serious clinical deficits. The anatomic site of the neoplasm can influence the outcome due to local effects (e.g. a benign meningioma may cause cardio-respiratory arrest from compression of the medulla) or non resectability (e.g. brain stem gliomas).  Even the most highly malignant gliomas rarely spread outside the CNS.  Most common metastatic cancers- lung, breast, kidney. Metastatic tumors present as multiple, well circumscribed lesions, most of them at the grey-white junction. GLIOMAS  Gliomas are tumors of the brain parenchyma that histologically resemble different types of glial cells; The major types of glial tumors are astrocytomas, oligodendrogliomas, and ependymomas. Astrocytoma Diffuse Astrocytoma  Most common adult gliomas, out of glioblastoma Malignant, high grade tumor of astrocytes is the most common primary brain tumor of adults. usually are found in the cerebral hemispheres.  On the basis of histologic features, they are stratified into three groups: Well-differentiated astrocytoma (grade II), anaplastic astrocytoma (grade III), and Glioblastoma (grade IV), with increasingly grim prognosis as the grade increases.  Astrocytoma’s are associated with a variety of acquired mutations: In glioblastoma, loss-of-function mutations in the p53 and Rb and gain-of-function mutations in the oncogenic PI3K pathways have central roles in tumorigenesis.  Morphology  Macro: Lower grade astrocytomas create gray tumor mass that look as expanded white matter , In glioblastoma, see necrotic hemorrhagic infiltrating mass.  Micro: Well-differentiated astrocytomas are characterized by a mild increase in the number of glial cell little nuclear pleomorphism, and an intervening feltwork of fine, glial fibrillary acidic protein (GFAP)-positive astrocytic cell processes that give the background a fibrillary appearance. Anaplastic astrocytomas show regions that are more densely cellular and have greater nuclear pleomorphism; mitotic figures are present. Glioblastoma has a histologic appearance similar to that of anaplastic astrocytoma, as well as necrotic foci (often with pseudopalisading nuclei around it ) and vascular endothel proliferation increase in layers of capillary wall create glomeruloid appearance Pilocytic Astrocytoma Relatively benign tumor, typically affecting children and young adults. Most commonly – located in the cerebellum, 3rd ventricle, optic pathway and spinal cord (mainly under the tentorium) Morphology: macro: CYST, with mural nodule in the wall of the cyst micro: the tumor is composed of bipolar cells, with long, thin, hair like processes that are GFAP positive. Rosental fibers – eosinophilic granular bodies are present. Oligodendroglioma:  Malignant tumor of the oligodendrocytes. Mainly adults tumor, may present with seizures (due to frontal lobe involvement)  Good prognosis even with high grade. well-differentiated (WHO grade II) anaplastic (WHO grade III) oligodendrogliomas a more aggressive subtype with higher cell density, nuclear anaplasia and mitotic activity  Genetic: chromosomal deletion of 1p and 19q.  Morphology: calcified tumor in the white matter, found mostly in the cerebral hemispheres mainly in the frontal or temporal lobes. Micro: “fried egg” appearance of the tumor cells. The tumor is composed of sheets of neoplastic cells with spherical nuclei surrounded by a clear halo cytoplasem and see blood vassels in background Ependemoma:  Most often arise next to the ependymal lined ventricular system, including the central canal of the spinal cord.  In adults – the spinal cord the most common location. in children most commonly arsise in the 4th ventricle, may present with hydrocephalus (it grows into the ventricular space  blocks CSF = hydrocephalus).  Morphology: ependymomas typically are solid /papillary masses extending from the ventricular floor. The tumors are composed of cells with round nuclei and abundant granular chromatin. Tumor cells may form round structures (rosettes) also perivascular pseudorosettes in which tumor cells are arranged around vessels with an intervening zone containing thin ependymal processes. Anaplastic ependymomas show increased cell density, high mitotic rates, necrosis, and less evident ependymal differentiation. NEURONAL TUMORS  Central neurocytoma is a low- is an extremely rare, ordinarily benign intraventricular brain tumour that typically forms from the neuronal cells of the septum pellucidum.adjacent to the ventricular system (most commonly the lateral or third ventricles), characterized by evenly spaced, round, uniform nuclei and often islands of neuropil.  Gangliogliomas is a rare, slow-growing bening primary central nervous system (CNS) tumor which most frequently occurs in the temporal lobes of children and young adults. tumors with a mixture of glial elements, usually a low-grade astrocytoma, and matureappearing neurons. Most of these tumors are slow-growing, but the glial component occasionally becomes frankly anaplastic, and the disease then progresses rapidly.  Dysembryoplastic neuroepithelial tumor Benign mixed glioneuronal neoplasm of children and young adults it often manifests as a seizure disorder. It typically is located in the superficial temporal lobe and consists of small round neuronal cells arranged in columns and around central cores of processes. These typically form multiple discrete intracortical nodules that have a myxoid background. Also present are well-differentiated “floating” neurons within pools of mucopolysaccharide-rich myxoid fluid. Medulloblastoma:  Malignant tumor derived from granular cells of cerebellum (part of embryonal tumors all derive from neuro- ectodermal tissue with primitive small round neoplastic cells)  Predominantly arises in children and exclusively in the cerebellum.  Very malignant but also react well to radiation  Morphology: macro: in children – located in the midline in adult more lateral on surface of folia cerebellum as gray friable mass. micro: small, round blue cells, Homer- Wright rossets may be presnt. OTHER PARENCHYMAL TUMORS Primary central nervous system lymphoma  Primary CNS lymphoma, occurring mostly as diffuse large B cell lymphomas  It is the most common CNS neoplasm in immunosuppressed persons, in whom the tumors are nearly always positive for the oncogenic Epstein-Barr virus.  primary brain lymphoma is an aggressive disease with relatively poor response to chemotherapy  Lymphoma originating outside the CNS rarely spreads to the brain parenchyma; when it happens, tumor usually is also within the CSF or involvement of the meninges. By contrast primary brain lymphomas often involve deep gray structures, as well as the white matter and the cortex. Germ cell tumors  Primary brain germ cell tumors occur along the midline, most commonly in the pineal and the suprasellar regions. tumor of the young 90% occurring during the first 2 decades of life.  The most common primary CNS germ cell tumor is germinoma, a tumor that closely resembles testicular seminoma Secondary CNS involvement by metastatic gonadal germ cell tumors also occurs.

Answer 151

Meningioma:  Predominantly Benign tumor of meningioepithelial cells of the arachnoid membrane.  Most common in adults more in female (the tumor express astrogen receptors!)  Multiple meningioma, especially in association with 8th nerve schwannomas or glial tumor may indicate neruofibromatosis type 2. About half of meningiomas not associated with NF2 have acquired loss-of function mutations in the NF2 tumor suppressor gene on chromosome 22.  Imaging reveals a round mass attached to the dura. May present with seizures – due to pressure on the cortex  Morphology: macro: masses that attach dura and compress the brain but DO NOT invade it. micro: syncytial – whorled clusters of cells without cisible cell membranes, that sit in tight groups.  The cells will show a unique pattern: 1. maningiothelial cells in kind of onion skin whorled pattern. Some foci of dystrophic calcification create psammoma bodies. 2. Fibroblastic component elongated cells and abundant collagen deposition btw them. 3.hence denoting features of no. 1 and 2 it’s an transitional tumor which shares features of the syncytial and fibroblastic types  By Grading meningioma’s divide it into 3 categories: well differentiated benign slow growing tumor as described in morphology, atypical WHO grade II/IV also bening and recognized by the presence of certain histologic features increased cellularity higher mitotic rate and tend to recurred, anaplastic WHO grade III/IV the highly aggressive malignant variant. METASTATIC TUMORS  Mostly carcinomas; The most common primary sites are lung, breast, skin (melanoma), kidney, and gastrointestinal tract. Metastatic lesions, mostly carcinoma, account for quarter to half of intracranial tumors Carcinomas are more commonly metastatic to the nervous system than lymphoid malignancies. Sarcomas infrequently metastasize to the brain.  Metastases form sharply demarcated masses, often at the gray-white junction, and elicit edema. The boundary between tumor and brain parenchyma is sharp, with surrounding reactive gliosis.  Beside local direct effect on brain may see evolvement of Paraneoplastic syndrome may involve the peripheral and CNS, sometimes even preceding the clinical recognition of the malignant neoplasm. Many but not all patients with PNS have antibodies against tumor antigens.  Manifestation of paraneoplastic syndrome:  Subacute cerebellar degeneration  ataxia with destruction of purkinje cells, gliosis and mild inflammation infiltrate.  Limbic encephalitis = causing sub-acute dementia and perivascular inflammatory cuffs, Microglial nodules and some neuronal loss in the medial temporal lobe.  Subacute sensory neuropathy = altered pain sensation with loss of sensory neurons from dorsal root ganglia.  Syndrome of rapid onset psychosis, catatonia, epilepsy and coma – associated with ovarian teratoma and Ab against NMDA receptor

Answer 152

 Within the CNS, axons are tightly ensheathed by myelin, an electrical insulator that allows rapid propagation of neural impulses.  Myelin consists of multiple layers of specialized, plasma membranes that are assembled by oligodendrocytes.  Although myelinated axons are present in all areas of the brain, they are the dominant component in the white matter; therefore, most diseases of myelin are primarily white matter disorders.  The myelin in peripheral nerves is similar to the myelin in the CNS but has several important differences: (1) made by Schwann cells; (2) each Schwann cell in a peripheral nerve provides myelin for only one internode, while in the CNS, many internodes are created by processes coming from a single oligodendrocyte; and (3) the specialized proteins and lipids are also different; Therefore, most diseases of CNS myelin do not involve the peripheral nerves to any significant extent, and vice versa.  In general, diseases involving myelin are separated into two broad groups.  Demyelinating diseases -acquired conditions characterized by damage to previously normal myelin. The most common diseases in this group result from immunemediated injury, such as multiple sclerosis (MS); Other processes include viral infection of oligodendrocytes, and injury caused by drugs and other toxic agents.  Dysmyelinating diseases, myelin is not formed properly or has abnormal turnover kinetics. Associated with mutations that disrupt the function of proteins that are required for the formation of normal myelin sheaths. The other general term for these diseases is leukodystrophy MULTIPLE SCLEROSIS  An autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space.  It is the most common of the demyelinating disorders  The disease may become clinically apparent at any age, although onset in childhood or after age 50 is relatively rare. Women are more than men.  In most patients, the illness shows relapsing and remitting episodes of neurologic impairment.  Pathogenesis  Autoimmune diseases, caused by loss of tolerance to self proteins (myelin antigens).  A genetic risk factor is HLA-DR variants, the DR2 allele being the one that most significantly increases the risk for developing MS.  Other genetic causes are polymorphisms in the genes encoding receptors for the cytokines IL-2 and IL-7, which are known to control the activation and regulation of T cell–mediated immune responses. Immune-mediated myelin destruction is thought to have a central role in MS.  A central role for CD4+ T cells has been suggested, with an increase in TH17 and TH1 CD4+ cells thought to be a critical component of the injury to myelin.  There is also evidence for important contributions from CD8+ T cells and B cells.  Toxic effects of lymphocytes, macrophages, and their secreted molecules have been implicated in initiating the process of axonal injury, sometimes even leading to neuronal death.  Morphology  MS is primarily a white matter disease with affected areas showing multiple, wellcircumscribed, depressed, gray, irregularly shaped lesions termed plaques.  These commonly arise near the ventricles. They also are frequent in the optic nerves and chiasm, brain stem, ascending and descending fiber tracts, cerebellum, and spinal cord.  In an active plaque there is evidence of ongoing myelin breakdown with abundant macrophages containing myelin debris.  Small active lesions often are centered on small veins.  Active plaques fall into four classes Type I, which has macrophage infiltrates with sharp margins; Type II, which is similar to type I but also shows complement deposition (suggesting an antibody-mediated component); Type III, with less welldefined borders and oligodendrocyte apoptosis; Type IV, with nonapoptotic oligodendrocyte loss.  When plaques become quiescent (inactive plaques), the inflammation mostly disappears, leaving behind little to no myelin. Instead, astrocytic proliferation and gliosis are prominent.  Clinical features  The course of MS is variable, but commonly there are multiple relapses followed by episodes of remission;  As a consequence, over time there is usually a gradual accumulation of neurologic deficits.  Changes in cognitive function can be present, but are often much milder than the other deficits.  The CSF shows a mildly elevated protein level with an increased proportion of immunoglobulin; in one third of cases, there is moderate pleocytosis.  When the immunoglobulin is examined further, oligoclonal bands usually are identified. These antibodies are directed against a variety of antigenic targets and can be used as markers of disease activity. OTHER ACQUIRED DEMYELINATING DISEASES  Immune-mediated demyelination can occur after a number of systemic infectious illnesses, including relatively mild viral diseases.  It is believed that immune cells responding to pathogen-associated antigens are cross reactive against myelin antigens, resulting in myelin damage.  There are two general patterns of postinfectious autoimmune reactions to myelin; they are associated with acute-onset monophasic illnesses. In acute disseminated encephalomyelitis, symptoms typically develop a week or two after an antecedent infection and are nonlocalizing (headache, lethargy, and coma); Symptoms progress rapidly, and the illness is fatal in as many as 20% of cases Acute necrotizing hemorrhagic encephalomyelitis is a more devastating related disorder, which typically affects young adults and children.  Neuromyelitis optica (NMO) is an inflammatory demyelinating disease centered on the optic nerves and spinal Cord; Antibodies to the water channel aquaporin-4 are both diagnostic and pathogenic.  Central pontine myelinolysis is a nonimmune process characterized by loss of myelin involving the center of the pons, most often after rapid correction of hyponatremia. May be related to edema induced by sudden changes in osmotic pressure. It occurs in alcoholism and severe electrolyte or osmolar imbalance. Although the most characteristic lesion occurs in the pons, similar lesions can be found elsewhere in the brain. Because of the involvement of fibers in the pons carrying signals to motor neurons in the spinal cord, patients often present with rapidly evolving quadriplegia.  Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that occurs after reactivation of JC virus in immunosuppressed patients. LEUKODYSTROPHIES  Inherited dysmyelinating diseases in which the clinical symptoms derive from abnormal myelin synthesis or turnover.  Some of these disorders involve lysosomal enzymes, while others involve peroxisomal enzymes; a few are associated with mutations in myelin proteins.  Most are of autosomal recessive inheritance, although X-linked diseases also occur  Morphology  Most pathologic change are found in the white matter, which is diffusely abnormal in color (gray  and translucent) and volume (decreased).  Early in their course, some diseases may show patchy involvement, while others have a predilection for occipital lobe involvement; In the end, though, nearly all of the white matter usually is affected.  With the loss of white matter, the brain becomes atrophic, the ventricles enlarge, and secondary changes can be found in the gray matter.  Myelin loss leads to infiltration of macrophages, which often become stuffed with lipid. Some of these diseases also show specific inclusions created by the accumulation of particular lipids.  Clinical features  Affected children are normal at birth but begin to miss developmental milestones during infancy and childhood.  Diffuse involvement of white matter leads to deterioration in motor skills, spasticity, hypotonia, or ataxia.  In general, the earlier the age at onset, the more severe the deficiency and clinical course.

Answer 153

CLASSIFICATION OF MUSCLE DISEASES A motor unit is made up of a motor neuron and the skeletal muscle fibers innervated by that motor neuron's axonal terminals hence muscle diseases may araise as : Peripheral nerves consist of fascicles that contain myelinated and unmyelinated axons. .Myelin is a spiral sheet of cell membrane wrapped around the axon. Unmyelinated axons are covered by Schwann cell cytoplasm, but there is no spiraling.  Axonal neuropathies direct injury to the axon. The entire distal portion of an affected axon degenerates atrophy of myofibers. The axon breaks down and secondary degrade of the myelin (Wallerian degeneration).The morphological hallmark is decrease in the density of the axons, which will lead to decrease in the strength of amplitude of nerve impulse. Causes are may be diabetes or vascular disease…  Demyelinating neuropathies Schwann cell injury or myelin damage = slow nerve conduction. Segmental demyelination –in individual myelin internodes* Remyelination may occur (with shorter internodes & thin myelin) if repetitive process see "Onion bulb" formations are concentric layers of Schwann cell processes and collagen around an axon .later secondary axonal degeneration may also occur. May result from inflammatory diseases like in topic or some tumors NFB schwannoma Causes neuropathies include inflammatory neuropathies from SLE till 2 disease I talk about these topic, metabolic disorder e.g. Diabetic (poly)neuropathy chronic axonal neuropathy with some segmental demyelination, hereditary Charcot Mari tooth neuropathy, vascular such as vasculitis One of the commonest and amyloid neuropathy, infectious-leprosy, neoplastic invasion of peripheral nerves, toxin alcohol lead exogenous glucocorticoids etc. … Patterns of peripheral neuropathies  Polyneuropathies usually affect peripheral nerves in a symmetric way Axonal loss is typically diffuse and more pronounced in the distal segments of the longest nerves. Patients commonly present with loss of sensation.  multiplex, in which the damage randomly affects portions of individual nerves, resulting in a right radial nerve palsy and wrist drop together with loss of sensation in the left foot  A simple mononeuropathy involving only a single nerve most commonly is the result of traumatic injury or entrapment (e.g., carpal tunnel syndrome). DISORDERS ASSOCIATED WITH PERIPHERAL NERVE INJURY Guillain-Barre syndrome  Acute autoimmune demyelinating peripheral neuropathy, It is a rapidly progressive disorder affecting motor axons that results in ascending weakness that may lead to death from failure of respiratory muscles over a period of only several days- One of the most common life threatening diseases of the peripheral nervous system  It appears to be triggered by an infection or a vaccine that breaks down self-tolerance, thereby leading to an autoimmune response. Associated infectious agents include Campylobacter jejuni, Epstein-Barr virus, cytomegalovirus, and human immunodeficiency virus.  Antibodies and activated T-lymphocytes, reacting with antigens present on peripheral nerves, elicit an inflammatory and macrophage reaction that destroys myelin and axons. The strongest evidence of a humoral immune reaction in these neuropathies is that plasma exchange results in significant clinical improvement. Peripheral nerves show mononuclear cell infiltrates rich in macrophages. , demyelination (myelin proteins are the source of elevated CSF protein).. Axonal damage, which accounts for the permanent deficits, is variable and may be severe. The pathology is most severe in nerve roots and proximal nerve segments and less pronounced in more distal nerves. In the phase of recovery, the nerve contains thin myelin sheaths, indicating myelin regeneration.  Treatments include plasmapheresis (to remove offending antibodies), intravenous immunoglobulin infusions and supportive care, such as ventilator support. Chronic inflammatory demyelinating polyneuropathy (CIDP) Typically manifests as a symmetric demyelinating disease. With similar immune pathomechanism as GBS but unlike it CIDP follows a chronic, relapsing-remitting or progressive course. occurs at increased frequency in patients with other immune disorders, such as systemic lupus erythematosus and HIV infection.  The peripheral nerves show segments of demyelination and remyelination In long-standing cases, chronically regenerating Schwann cells may concentrically wrap around axons in multiple layers in an onion-skin pattern.  Both motor and sensory abnormalities are common, such as difficulty in walking, weakness, numbness, and pain or tingling sensations. Some patients recover completely, but more often recurrent bouts of symptomatic disease lead to permanent loss of nerve function.  Treatment includes plasmapheresis and administration of immunosuppressive agents.

Answer 154

#anatomical component of the eye:  Orbit  Eyelid  Conjunctiva  Cornea  Uvea (iris, ciliary body, choroid)  Lens  Vitreous body  Retina  Optic Nerve INFLAMMATION OF THE EYE &EYELID Panophthalmitisan inflammation of the entire eye, usually caused by virulent pyogenic organisms, such as strains of meningococci, pneumococci, streptococci, anthrax bacilli, and clostridia. Initial symptoms are pain, fever, headache, drowsiness, edema, and swelling. As the infection progresses, the iris appears muddy and gray, the aqueous humor becomes turbid, and precipitates form on the posterior surface of the cornea. The conjunctiva: #The conjunctiva, as well as other parts of the eye, may also become infected by hematogenous spread. # Bacterial conjunctivitis is an extremely common eye disease, characterized by hyperemic conjunctival blood vessels (pink eye). The inflammatory exudate that accumulates in the conjunctival sac commonly crusts, causing the eyelids to stick together in the morning. The conjunctival discharge may be purulent, fibrinous, serous or hemorrhagic. # trachoma- a chronic, contagious conjunctivitis caused by Chlamydia trachomatis. Chlamydia is responsible for a purulent conjunctivitis (inclusion blennorrhea) that develops in newborns who become infected during passage through the birth canal. #ophthalmia neonatorum- severe, acute conjunctivitis with a purulent discharge, especially in the newborn, caused by Neisseria gonorrhoeae The cornea: #keratitis- inflammation of the cornea. The condition is often marked by moderate to intense pain and usually involves impaired eyesight. It may cause feelings of itchiness each time the individual blinks. Types: o Superficial keratitis: involves the superficial layers (i.e. the epithelium) of the cornea. After healing, this form of keratitis does not generally leave a scar. o Deep keratitis: involves deeper layers of the cornea (i.e. The epithelium, Bowman's Membrane and often stroma), and the natural course leaves a scar upon healing that impairs vision if on or near the visual axis. Causes:  herpes simplex virus –cause corneal ulcerations. HSV has a predilection for corneal epithelium, where it causes keratitis, but it can invade corneal stroma and occasionally other ocular tissues. From the trigeminal ganglion, HSV may pass down the nerves and reactivate the infection.  Amoebic infection of the cornea is the most serious corneal infection, usually affecting contact lens wearers.  Bacterial keratitis- S. Aureus, P. aeruginosa  Fungal keratitis  photokeratitis (UV keratitis) # Fuchs (endothelial) dystrophy - ‘guttata’ – bullous protrusions downward from Descemet membrane. - major reason for corneal transplantation -primary problem: endothelial damage The lens # Cataracts- are opacifications in the crystalline lens that are a major cause of visual impairment and blindness. Congenital cataracts are a major cause of reversible blindness in children. pathogenesis: The most common cataract is associated with aging. Cataracts can also be caused by systemic diseases (diabetes mellitus, atopic dermatitis); drugs (steroids); radiation; trauma; or by deficiencies in riboflavin or tryptophan. A wide range of cataracts are inherited. The eyelid # Chalazion- A cyst in the eyelid that is caused by inflammation of a blocked meibomian gland (special kind of sebaceous gland responsible for the supply of meibum, an oily substance that prevents evaporation of the eye's tear film) usually on the upper eyelid. Chalazia differ from styes (hordeola) in that they are subacute and usually painless nodules. They may become acutely inflamed but, unlike a stye, chalazia usually point inside the lid rather than on the lid margin. Signs & symptoms:  Swelling on the eyelid  Eyelid tenderness  Sensitivity to light  Increased tearing  Heaviness of the eyelid #Stye (hordeola) שעורה -an infection of the sebaceous glands of Zeisat the base of the eyelashes, or an infection of the apocrine sweat glands of Moll. o External styes form on the outside of the lids and can be seen as small red bumps. o Internal styes are infections of the meibomian sebaceous glands lining the inside of the eyelids. They also cause a red bump underneath the lid with only generalized redness and swelling visible on the outside. o They contain water and pus and the bacteria will spread if the stye is forcefully ruptured. Styes are characterized by an acute onset and usually short in duration (7–10 days without treatment) compared to chalazia that are chronic and usually do not resolve without intervention. o Styes are usually caused by the Staphylococcus aureus bacterium. Optic Nerve #Glaucoma- a collection of disorders that feature an optic neuropathy accompanied by a characteristic excavation of the optic nerve head and progressive loss of visual field sensitivity. # most common cause of preventable blindness # In most cases, glaucoma is produced by increased intraocular pressure (ocular hypertension); however, increased intraocular pressure does not necessarily cause glaucoma. #After being produced by the ciliary body, the aqueous humor enters the posterior chamber before passing through the pupil to the anterior chamber. From that site, it drains into veins by way of the trabecular meshwork and Schlemm canal. A delicate balance between the production and drainage of the aqueous humor maintains intraocular pressure within its physiologic range. In certain pathologic states, aqueous humor accumulates within the eye, and intraocular pressure increases . #Glaucoma can be classified into several different types o Congenital glaucoma o Adult onset primary glaucoma o Primary open angle glaucoma NEOPLASTIC DISORDERS OF THE EYE & EYELID # Eye cancers can be primary or metastatic cancer. The two most common cancers that spread to the eye from another organ are breast cancer and lung cancer # Tumors in the eye and orbit can be benign like dermoid cysts, or malignant like rhabdomyosarcoma and retinoblastoma. # Orbital dermoid cysts are benign choristomas which are typically found at the junction of sutures, most commonly at the fronto-zygomatic suture. Large deep orbital dermoid cysts can cause pressure effects on the muscles and optic nerve, leading to diplopia and loss of vision. # eyelid tumors: The most common is called basal cell carcinoma. This tumor can grow around the eye but rarely spreads to other parts of the body. Other types of common eyelid cancers include: -squamous carcinoma -sebaceous carcinoma -malignant melanoma. #in adults: The most common malignant primary intraocular tumor is uveal melanoma. These tumors can occur in the choroid, iris and ciliary body. The latter are sometimes called iris or ciliary body melanoma. The next most common is primary intraocular lymphoma (PIOL) which is usually nonHodgkin’s, large cell lymphoma of the B-cell type. #in children: The most common malignant intraocular tumor in children is retinoblastoma. The second most common is medulloepithelioma which can occur in the ciliary body and the uvea of the eye Retinal detachment #Separation between retinal pigment epithelium and photoreceptor layers #pathogenesis: Factors predisposing to retinal detachment include: o retinal defects & tears (rhegmatogenous RD) o vitreous traction, diminished pressure on the retina o weakening of retinal fixation. The photoreceptors and retinal pigment epithelium normally function as a unit. After they separate in a retinal detachment, oxygen and nutrients that normally reach the outer retina from the choroid must diffuse across a greater distance. This situation causes the photoreceptors to degenerate, after which cyst-like extracellular spaces appear within the retina. #Causes: o Malignant hypertesnsion o Trauma (boxing, karate, motor racing, skiing) o Diabetic retinopathy o Eclampsia o Tumor o Local inflammation o Increased pressure (weightlifting) o Genetic: photoreceptor degeneratuon o AIDS Retinopathia of prematurity (ROP) -(retrolental fibroplasia) #disease that affects prematurely‐born babies with low birth weight who have received intensive neonatal care with high‐pressure oxygenation #free radical (oxygen radicals) toxicity is important in pathogenesis # it is thought to be caused by disorganized growth of retinal blood vessels which may result in scarring and retinal detachment. #may resolve spontaneously or may lead to blindness Hypertensive retinopathy # damage to the retina and retinal circulation due to high blood pressure # The changes in hypertensive retinopathy result from damage and adaptive changes in the arterial and arteriolar circulation in response to the high blood pressure. # pathology : In the eye, arteriolosclerosis accompanies long-standing hypertension and commonly affects the retinal and choroidal vessels. Lumina of the thickened retinal arterioles become narrowed, increasingly tortuous and of irregular caliber. Diabetic retinopathy # retinopathy (damage to the retina) caused by complications of diabetes, which can eventually lead to blindness. #pathogenesis: Diabetic retinopathy is the result of microvascular retinal changes. Hyperglycemia-induced intramural pericyte death and thickening of the basement membrane lead to incompetence of the vascular walls. These damages change the formation of the blood-retinal barrier and also make the retinal blood vessels become more permeable. Small blood vessels – such as those in the eye – are especially vulnerable to poor blood sugar (blood glucose) control. # After many years, diabetic retinopathy becomes proliferative. Delicate new blood vessels grow along with fibrous and glial tissue toward the vitreous body. Neovascularization of the retina is a prominent feature of diabetic retinopathy. # Blindness in diabetic retinopathy results when the macula is involved, but it also follows vitreous hemorrhage, retinal detachment and glaucoma. Age‐related macular degeneration (ARMD) # affects older adults and results in a loss of vision in the center of the visual field (the macula) because of damage to the retina. #It occurs in "dry" and "wet" forms. # In the dry (nonexudative) form, cellular debris called drusen accumulates between the retina and the choroid, and the retina can become detached. In the wet (exudative) form, which is more severe, blood vessels grow up from the choroid behind the retina, and the retina can also become detached. #It is a major cause of blindness and visual impairment in older adults (>50 years). TUMORS OF THE RETINA Retinoblastoma # Rapidly developing cancer that develops from the immature cells of a retina (neuronal‐cell derived tumor. #Most common primary intraocular malignancy in children # There are two forms of the disease: 1. heritable form 2. non-heritable form All cancers are considered genetic in that mutations of the genome are required for their development, but this does not imply that they are heritable, or transmitted to offspring. Approximately 55% of children with Rb have the non-heritable form. # Bilateral RB are commonly heritable, while unilateral RB are commonly nonheritable # In children with the heritable genetic form of retinoblastoma there is a mutation on chromosome 13, called theRB1 gene. #symptoms: o The most common an abnormal appearance of the pupil as white -leukocoria. o Light entering the eye commonly reflects a yellowish color similar to that from the tapetum of a cat (cat’s eye reflex). o deterioration of vision o red and irritated eye with glaucoma o delayed development. #Histology: small blue cell tumour; Flexner‐Wintersteiner rosettes; necrosis; calcification #Therapy: Bulbus enucleation vs Chemoth + laser or cryotreatment Melanoma # Malignant melanoma is the most common primary intraocular malignancy. It may arise from melanocytes in any part of the eye, and the choroid (uvea) is the most common site. # may be metastatic to the orbit & the liver. # pathology: Choroidal melanomas are mostly circumscribed and invade the Bruch membrane, causing a mushroom-shaped mass. By contrast, some tumors are fl at (diffuse melanoma) and cause a gradual deterioration of vision over many years. Some do not even become apparent until extraocular dissemination has occurred. #Microscopically, uveal melanomas are composed: (1) variable numbers of spindle-shaped cells without nucleoli (spindle A cells) (2) spindle-shaped cells with prominent nucleoli (spindle B cells) (3) polygonal cells with distinct cell borders and prominent nucleoli # The usual treatment for most uveal melanomas is enucleation of the eye (the removal of the eye that leaves the eye muscles and remaining orbital contents intact. )

Answer 155

Muscle fiber types: 1. Slow twich, aerobic = type I 2. fast twich, anaerobic = type II Normal distribution of muscle fibers- checkboard pattern. Muscle atrophy: abnormally small myofibers due to variety of disorders, for example immobilization, exogenous glucocorticoids, Cushing syndrome. Neurogenic atrophy: Atrophy of muscle that results from damage to the nerve that stimulates the muscle. E.g: diabetic neuropathy, spinal cord injuries and syndromes that cause nerve impingement. Reminder: loss of a single neuron will affect all muscle fibers in a motor unit, then the adjacent intact neurons send out sprouts to engage the NMJ which is injured. = now these fibers will have the same innervating neuron. This process is called fiber type grouping. Symptoms of neurogenic atrophy:  Stooped posture  Limited neck movement  Leg contractions  Heart failure (sometimes) Disorders in the NMJ: Produce functional abnormalities due to the disruption in the transmission of signals across the NMJ- resulting in muscle weakness. Most common NMJ disorders: 1. Myestenia gravis. 2. Lambert – eaton syndrome (Picture) Therapy myestenia gravis: 1. anti-choline esterase inhibitors. 2. immunosuppression. 3. Plasmapheresis 4. Thymectomy (in patients with thymic lesion). Lambert – Eaton syndrome:  Antibodies against presynaptic Ca2+ channels at the NMJ.  Arises as a paraneoplastic syndrome, most commonly due to small cell carcinoma.  Leads to impaired Ach release.  Proximal muscle weakness which improve with use.  Eyes are usually spared. Muscular dystrophies: Muscle dystrophy = inherited disporders of degeneration of muscle tissue with associated muscle weakness and replacement of skeletal muscle by fibrofatty tissue. Muscle dystrophy is due to primary inherited disease ( a muscle disease itself) in contrast to muscle atrophy which is secondary due to loss of innervation, malnutrition etc. 1. X linked MD (Duchenne and Becker MD)  Dystrophinopathies = Duchenne and Becker muscular dystrophy.  Dystrophinopathies are the most common form of muscular dystrophy.  Duchenne (DMD) and Becker (BMD) are the 2 most common examples, linked to mutation in dystrophine gene. (DMD is more severe).  Both are X-linked MD associated with: 1. muscle wasting. 2. replacement of skeletal muscle by adipose tissue. 3. deletion of dystrophin (the mutation in the dystrophin gene is spontaneous!) Dystrophin: plays a role of a “linker” protein btw the myofibrilar cytoskeleton to the ECM.  Morphology: 1. Ongoing myofiber necrosis and regeneration. 2. replacement by fibrosis and fat. 3. micro level: in immunohistochemical method- complete absence of Membrane associated dystrophin. Pathogenesis : loss of function mutation in the dystrophin gene located on the short arm of X chromosome.  Clinical features: progress to involve distal muscles (begins in pelvic => shoulders). Calf pseudohypertrophy is characteristic finding, heart failure. 2. Autosomal MD: Several of the autosomal MD affect the proximal muscles (similar to X linked MD) and are called limb girdle muscular dystrophy. It can be recessive or dominant. 3. Myotonic Dystrophy: Myotonia = sustained involuntary contraction of a group of muscles. Inherited as autosomal dominant, CTG trinucleotide repeat expansion on chromosome 19, which will affect the synthesis of the intracellular protein kinase. The disease will be present at late childhood with gait abnormalities, hands, wrist and facial muscles weakness. Myopathy:  Myopathy = muscle disease. (such as the muscle dystrophy).  Primary myopathy should be distinguished from secondary neuropathic changes caused by disorders that disrupt muscle innervation (even though both are associated with altered muscle function but due to different reasons).  Myopathic condition are often associated with segmental necrosis and regeneration of individual muscle fibers. Inflammatory infiltrate and intracellular inclusions may also be present. Congenital myopathies: 1. ion channel myopathies: characterize by myotonia, relapsing episodes of hypotonic paralysis, or both. Hyperkalemic periodic paralysis results from mutations in the gene for the skeletal muscle sodium channel protein. 2.myopathies due to inborn errors of metabolism: disorders of glycogen synthesis and degradation, lipid handling, carnitine transport. 3. mitochondrial myopathies: mutations in mitochondrial or nuclear DNA that encodes mitochondrial constituents. (will shoe maternal inheritance). These disorders will be present at young adulthood with proximal muscle weakness and ocular musculature. The most important pathological finding in skeletal muscle are irregular muscle fibers and aggregates of abnormal mitochondria. Acquires myopathies: 1.Toxic muscle injury: for example thyroxine myopathy: (intrinsic exposure). Either acute or chronic proximal muscle weakness. The findings will include myofiber necrosis, regeneration and interstitial lymphocytes. Examples for extrinsic exposure: ethanol, chloroquine. 2. Inflammatory myopathies:  Dermatomyositis: Inflammatory disorders of the skin and skeletal muscle. Unknown etiology, some cases are associated with carcinoma => paraneoplastic syndrome. Clinical features: bilateral proximal weakness, distal involvement can develop, rush of upper eyelids (helioptrope rash), malar rash, red papules on the elbows. Micro: perivascular mononuclear cells infiltrate, myofiber damage, inflammation at the perimysium => perifascicular atrophy (it helps to differentiate it from polymyositis which shows endomysial inflammation)  Polymyositis: autoimmune disorder with increased expression of MHC I on myofibers. Resemble dermatomyositis but skin is NOT involved. Endomysial inflammation (CD8+) with necrotic muscle fibers. 3. muscle infraction in the setting of diabetes.