Pathology Flashcards
Apoptosis
Programmed cell death; ATP required. Intrinsic or extrinsic pathway; both pathways lead to activation of cytosolic caspases that mediate cellular breakdown. No significant inflammation (unlike necrosis). Characterized by deeply eosinophilic cytoplasm, cell shrinkage, nuclear shrinkage (pyknosis) and basophilia, membrane blebbing, nuclear fragmentation (Karyorrhexis), and formation of apoptotic bodies, which are than phagocytosed. DNA laddering is a sensitive indicator of apoptosis; during karyorrhexis, endonucleases cleave at internucleosomal regions, yielding fragments in multiples in 180 bp. Radiation therapy causes apoptosis of tumors and surrounding tissue via free radical formation and dsDNA breakage. Rapidly dividing cells (eg skin, GI mucosa) are very susceptible to radiation therapy-induced apoptosis.
Intrinsic apoptotic pathway
Involved in tissue remodeling in embryogenesis. Occurs when a regulating factor is withdrawn from a proliferating cell population (eg a decrease in IL-2 after a completed immunologic reaction leading to apoptosis of proliferating effector cells). Also occurs after exposure to injurious stimuli (eg radiation, toxins, hypoxia). Changes in proportions of anti- and pro-apoptotic factors leading to an increase in mitochondrial permeability and cytochrome c release. BAX and BAK are proapoptotic proteins; Bcl-2 is antiapoptotic. Bcl-2 prevents cytochrome c release by binding to and inhibiting Apaf-1. Apaf-1 normally induces the activation of caspases. If Bcl-2 is overexpressed (eg follicular lymphoma), then Apaf-1 is overly inhibited, leading to a decrease caspase activation and tumorigenesis.
Extrinsic pathway
There are two pathways: ligand receptor interactions (FasL binding to Fas [CD95]) and immune cell (cytotoxic T-cell release of perforin and granzyme B). Fas-FasL interaction is necessary in thymic medullary negative selection. Mutations in Fas increases the number of circulating self- reacting lymphocytes due to failure of clonal deletion. After Fas crosslinks with FasL, multiple Fas molecules coalesce, forming a binding site for a death domain-containing adapter protein, FADD. FADD binds inactive caspases, activating them. Devective Fas-FasL interactions contribute to autoimmune disorders.
Necrosis
Enzymatic degradation and protein denaturation of cell due to exogenous injury, leading to leak of intracellular components. Inflammatory process (unlike apoptosis).
Coagulative necrosis
Seen in ischemia/infarcts in most tissue (except brain). It is due to ischemia or infarction; proteins denature, then enzymatic degradation. On histology, cell outlines are preserved; there is also an increase in cytoplasmic binding of acidophilic dyes.
Liquefactive necrosis
Seen in bacterial abscesses, brain infarcts (due to an increase in fat content). It is due to neutrophils releasing lysosomal enzymes that digest the tissue; enzymatic degradation first, then proteins denature.
Caseous necrosis
Seen in TB, systemic fungi (eg Histoplasma capsulatum), Nocardia. It is due to macrophages walling off the infecting microorganism, leading to granular debris. On histology, there are fragmented cells and debris surrounded by lymphocytes and macrophages.
Fat necrosis
Seen in enzymatic acute pancreatitis (saponification) and nonezymatic breast trauma. It is due to damaged cells release lipase, which breaks down fatty acids in cell membranes. On histology, there is an outlines of dead fat cells without peripheral nuclei; saponification of fat (combined with Ca) appears dark blue of H&E stain.
Fibrinoid necrosis
Seen in immune reactions in vessels. It is due to immune complexes combined with fibrin, leading to vessel wall damage. On histology, there are vessel walls that are thick and pink.
Gangrenous necrosis
Seen in distal extremity, after chronic ischemia. In dry gangrenous necrosis, it is due to ischemia (on histology, coagulation is seen). In wet gangrenous necrosis, it is due to superinfection (on histology, liquefaction is seen).
Cell injury reversible with O2
There is ATP depletion, cellular/mitochondrial swelling (a decrease in ATP leads to a decrease activity of Na/K pumps), nuclear chromatin clumping, a decrease in glycogen, fatty change, ribosomal/ polychromal clumping detachment (a decrease in protein synthesis), and membrane blebbing.
Cell injury irreversible with O2
There is nuclear pyknosis, karyorrhexis (destructive fragmentation of the nucleus of a dying cell), karylolysis (the complete dissolution of the chromatin of a dying cell), plasma membrane damage (degradation of membrane phospholipid), lysosomal rupture, mitochondrial permeability/ vacuolization; phospholipid- containing amorphous densities within mitochondria (swelling alone is reversible).
Ischemia susceptible areas of the brain
They are located between the cortical territories of the anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA) boundary areas. Watershed areas (border zones) receive dual blood supply from most distal branches of 2 arteries, which protects these areas from single-vessel focal blockage. However, these areas are susceptible to ischemia from systemic hypoperfusion. Hypoxic ischemic encephalopathy (HIE) affects pyramidal cells of hippocampus and Purkinje cells of the cerebellum.
Ischemia susceptible areas of the heart
Subendocardium (left ventricle)
Ischemia susceptible areas of the kidney
Straight segment of the proximal tubule (medulla) and the thick ascending limb (medulla)
Ischemia susceptible areas of the liver
Area around central vein (zone III)
Ischemia susceptible areas of the colon
Splenic flexure and rectum. Watershed areas (border zones) receive dual blood supply from most distal branches of 2 arteries, which protects these areas from single-vessel focal blockage. However, these areas are susceptible to ischemia from systemic hypoperfusion.
Red infarcts
Red (hemorrhagic) infarcts occur in venous occlusion and tissue with multiple blood supplies, such as liver, lung, and intestine; reperfusion (eg after angioplasty). Reperfusion injury is due to damage by free radicals. Red=Reperfusion.
Pale infarcts
Pale (anemic) infarcts occur in solid organs with a single (end-arterial) blood supply, such as heart, kidney, and spleen.
Atropy
There is a reduction in the size and/or number of cells. Causes include: a decrease in endogenous hormones (eg post menopausal ovaries); an increase in exogenous hormones (eg factitious thyrotoxicosis, steroid use); a decrease in innervation (eg motor neuron damage); a decrease in blood flow/nutrients; a decrease in metabolic demand (eg prolonged hospitalization, paralysis); an increase in pressure (eg nephrolithiasis); occlusion of secretory ducts (eg cystic fibrosis, calculus/stone).
Inflammation
Characterized by rubor (redness), dolor (pain), calor (heat), tumor (swelling), and fanctio laesa (loss of function).
Vascular components of inflammation
an increase in vascular permeability, vasodilation, and endothelial injury.
Cellular components of inflammation
Neutrophils extravasate from circulation to injured tissue to participate in inflammation through phagocytosis, degranulation and inflammatory mediated release.
Acute inflammation
It is neutrophil, eosinophil, and antibody mediated. Acute inflammation has a rapid onset (seconds to minutes) and of short duration (minutes to days). Outcomes include complete resolution, abscess formation, or progression to chronic inflammation.
Chronic inflammation
It is mononuclear cell and fibroblast mediated. Characterized by persistent destruction and repair. It is associated with blood vessel proliferation, and fibrosis. There are granulomas, which are nodular collections of epithelioid macrophages and giant cells. Outcomes include scarring and amyloidosis.
Chromatolysis
A process involving the neuronal cell body following axonal injury. Changes reflect an increase in protein synthesis in effort to repair the damaged axon. It is characterized by round cellular swelling, displacement of the nucleus to the periphery, dispersion of Nissl substance (is a large granular body, found in neurons, of rough endoplasmic reticulum (RER) with rosettes of free ribosomes, and are the site of protein synthesis) throughout cytoplasm.
Dystrophic calcification
Ca deposition in abnormal tissue secondary to injury or necrosis. It tends to be localized (eg calcific aortic stenosis). It is seen in TB (lungs and pericardium), liquefactive necrosis of chronic abscesses, fat necrosis, infarcts, thrombi, schistosomiasis (a disease caused by infection with freshwater parasitic worms in certain tropical and subtropical countries), Monckeberg arteriolosclerosis ( calcium deposits are found in the muscular middle layer of the walls of arteries (the tunica media)), congenital CMV and toxoplasmosis, psammoma bodies. It is not directly associated with serum Ca levels (patients are usually normocalcemic). On histology, there can also be small bony tissue and thick fibrotic walls.
Metastatic calcification
Widespread (ie diffuse, metastatic) deposition of Ca in normal tissue secondary to hypercalcemia (eg primary hyperparathyroidism, sarcoidosis, hypervitaminosis D) or high calcium- phosphate product levels (eg chronic renal failure with secondary hyperparathyroidism, long-term dialysis, calciphylaxis ( a syndrome of vascular calcification, thrombosis and skin necrosis), and warfarin). Ca deposits predominantly in interstitial tissues of kidney, lung, and gastric mucosa (these tissues lose acid quickly; an increase in pH favors deposition). Patients are usually not normocalcemic. Metastatic calcification can be seen in alveolar walls in acute pneumonitis.
Leukocyte extravasation
Extravasation predominantly occurs at postcapillary venules. WBCs exit from blood vessels at sites of tissue injury and inflammation in 4 steps: 1. Margination and rolling. 2. Tight-binding. 3. Diapedesis. 4. Migration.
Migration and rolling of leukocytes along vessels
This is defective in leukocyte adhesion deficiency type 2, which is due to a decrease of Sialyl-LewisX (a tetrasaccharide carbohydrate that is usually attached to O-glycans on the surface of cells and plays a vital role in cell-to-cell recognition processes). Components of the vasculature/ stroma responsible for binding PMNs in this step includes E-selectin (which binds Sialyl-LewisX), P-selectin (which binds Sialyl-LewisX), GlyCAM-1 (which binds L-selectin), CD34 (which binds L-selectin).
Tight-binding of leukocytes to vessels
This is defective in leukocyte adhesion deficiency type 1, which is due to a decrease in CD18 integrin subunit. Components of the vasculature/ stroma responsible for binding PMNs in this step includes ICAM-1 (CD54), which binds CD11/18 integrins (LFA-1 and MAC-1) of PMNs, and VCAM-1 (CD106), which binds VLA-4 integrin.
Diapedesis of leukocytes
The movement or passage of white blood cells, especially white blood cells, through intact capillary walls into surrounding body tissue. Components of the vasculature/ stroma responsible for binding PMNs in this step includes PECAM-1 (CD31), which binds PECAM-1 (CD31) of leukocytes.
Migration of leukocytes through interstitium
WBCs travel to site of injury or infection guided by chemotactic signals. Chemotactic products released in response to bacteria includes C5a, IL-8, LTB4, kallikrein, and platelet-activating factor.
Free radical injury
Free radicals damage cells via membrane lipid peroxidation, protein modification, and DNA breakage. Initiated via radiation exposure (eg cancer therapy), metabolism of drugs (phase I), redox reactions, nitric oxide, transition metals, WBC (eg neutrophils, macrophages) oxidative burst. Free radicals can be eliminated by scavenging enzymes (eg catalase, superoxide dismutase, glutathione peroxidase), spontaneous decay, antioxidants (eg vitamins A, C, E) and certain metal carrier proteins (eg transferrin and ceruloplasmin).
Pathologies of free radical injury
Retinopathy of prematurity is a disease of the eye affecting prematurely-born babies generally having received intensive neonatal care, in which oxygen therapy is used on them due to the premature development of their lungs. It is thought to be caused by disorganized growth of retinal blood vessels which may result in scarring and retinal detachment. Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that affects newborns (mostly premature) and infants. It results from damage to the lungs caused by mechanical ventilation (respirator) and long-term use of oxygen. Carbon tetrachloridewas formerly widely used in fire extinguishers, as a precursor to refrigerants, and as a cleaning agent and leads to liver necrosis (fatty change); acetaminophen overdose. Acetaminophen overdose leads to fulminant and renal papillary necrosis. Iron overload due to hemochromatosis. Reperfusion injury, especially after thrombolytic therapy, results in inflammation and oxidative damage (eg superoxide) through the induction of oxidative stress rather than restoration of normal function.
Inhalation injury and sequelae
Pulmonary complication associated with smoke and fire. It is caused by heat, particulates (less than 1 micrometer diameter), or irritants (eg NH3) leads to chemical tracheobronchitis, edema, and pneumonia, and ARDS. Many patients present secondary to burns, CO inhalation, or arsenic poisoning. Bronchoscopy can show severe edema, congestion of bronchus, and carbon soot deposition 18 hours after inhalation injury and can largely resolve within weeks of the injury.
Scar formation
70-80% of tensile strength regained at 3 months, little additional tensile strength will be regained afterword.
Hypertrophic scars
There is an increase in collagen synthesis. Collagen is arranged in parallel. The scar’s borders are confined to the original wound. It infrequently recur following resection.
Keloid scars
There is a significant increase in collagen synthesis. The collagen arrangement is disorganized. The scar’s borders extend beyond the borders of the original wound. It will frequently recur following resection. There is a higher incidence in African Americans. The scar often has a characteristic “claw-like” projections.
Platelet-derived growth factor (PDGF)
A wound healing tissue mediator. It is secreted by activated platelets and macrophages. It induces vascular remodeling and smooth muscle cell migration. It also stimulates fibroblast growth for collagen synthesis.
Fibroblastic growth factor (FGF)
A wound healing tissue mediator. It stimulates angiogenesis.
Epithelial growth factor (EGF)
A wound healing tissue mediator. It stimulates cell growth via tyrosine kinases (eg EGFR as expressed by ERBB2).
Transforming growth factor beta (TGF-β)
A wound healing tissue mediator. It induces angiogenesis, fibrosis, cell cycle arrest.
Metalloproteinases
A wound healing tissue mediator. It induces tissue remodeling.
Vascular endothelial growth factor (VEGF)
A wound healing tissue mediator. It stimulates angiogenesis.
Phases of wound healing
Inflammatory (up to 3 days after a wound), proliferative (from day 3 to weeks after a wound), and remodeling (from 1 week to over 6 months after a wound).
Inflammatory phase of wound healing
Occurs up to three days after an injury. Mediators include platelets, neutrophils, and macrophages. Characteristics include clot formation, increase vessel permeability and neutrophil migration into tissue. Macrophages clear debris two days later.
Proliferative phase of wound healing
Occurs from three days to weeks after a wound. Mediators include fibroblasts, myofibroblasts, endothelial cells, keratinocytes, and macrophages. Characteristics include deposition of granulation tissue and collagen, angiogenesis, epithelial cell proliferation, dissolution of clot, and wound contraction (mediated by myofibroblasts).
Remodeling phase of wound healing
Occurs from 1 week to over 6 months. Mediators include fibroblasts. Characteristics include type III collagen replaced by type I collagen and an increase in the strength of tissue.
Granulomatous diseases
Includes Baronella henselae (cat scratch disease), Berylliosis, eiosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), Crohn disease (noncaseating granuloma), foreign bodies, Francisella tularensis (causes tularemia), fungal infections (caseous necrosis), granulomatosis with polyangiitis (wegener), Listeria monocytogenes (granulomatosis infantiseptica-pyogenic granulomas distributed over the whole body), M. leprae (leprosy; Hansen disease), M. tuberculosis (caseous necrosis), Treponema pallidum (tertiary syphilis), sarcoidosis (noncaseating granuloma), Schistosomiasis.
Formation of a granuloma
Th1 cells secrete IFN-gamma, activating macrophages. TNF-alpha from macrophages induces and maintains granuloma formation. Anti-TNF drugs can, as a side effect, cause sequestering granulomas to break down, leading to disseminated disease. Always test for latent TB before starting anti-TNF therapy.
Exudate
Think thick. It is composed of cells, it is protein rich with a specific gravity greater than 1.020. It occurs due to lymphatic obstruction, inflammation/infection, and malignancy.
Transudate
Think thin. It is hypocellular, protein-poor with a specific gravity less than 1.012. It occurs due to an increase in hydrostatic pressure (eg HF), a decrease in oncotic pressure (eg cirrhosis, nephrotic syndrome), and Na retention.
Erythrocyte sedimentation rate
Products of inflammation (eg fibrinogen) coat RBCs and cause aggregation. The denser RBC aggregates fall at a faster rate within a pipette tube. Often co-tested with CRP.
An increase in ESR
Can be due to most anemias, infections, inflammation, cancer, pregnancy, and autoimmune disorders.
An decrease in ESR
Can be due to sickle cell anemia (altered shape), polycythemia (an increase in RBCs dilute aggregation factors), heart failure, microcytosis, hypofibrinogenemia.
Amyloidosis
Abnormal aggregation of proteins (or their fragments) into beta pleated sheets, which causes damage and apoptosis. Congo red stain shows amyloid deposits, which appear apple green birefringence under polarized light.
AL amyloidosis
It is considered primary and is due to deposition of proteins from Ig Light chains. It can occur as a plasma cell disorder or associated with multiple myeloma. It often affects multiple organ systems, including renal (nephrotic syndrome), cardiac (restrictive cardiomyopathy and arrhythmia), hematologic (easy bruising and splenomegaly), GI (hepatomegaly), and neurologic (neuropathy).
AA amyloidosis
It is considered secondary and is seen with chronic inflammatory conditions such as rheumatoid arthritis, IMD spondyloarthropathy, protracted infection. Fibrils are composed of serum Amyloid A. It often involves multiple systems like AL amyloidosis.
Dialysis related amyloidosis
Fibrils composed of beta-2-microglobulin (a component of MHC class I molecules) occur in patients with end-stage renal disease (ESRD) and/or on long term dialysis. It may present as carpal tunnel syndrome.
Heritable amyloidosis
This is a heterogeneous group of disorders, including familial amyloid polyneuropathies due to transthretin gene mutation.
Age related (senile) systemic amyloidosis
This occurs due to deposition of normal (wild-type) transthyretin in myocardium and other sites. There is slower progression of cardiac dysfunction relative to AL amyloidosis.
Organ specific amyloidosis
Amyloid deposition localized to a single organ. The most important form is amyloidosis in Alzheimer disease due to deposition of beta-amyloid protein cleaved from amyloid precursor protein (APP). Islet amyloid polypeptide (IAP) is commonly seen in diabetes mellitus type 2 and is caused by deposition of amylin in pancreatic islets.
Lipofuscin
A yellow brown wear and tear pigment associated with normal aging. Formed by oxidation and polymerization of autophagocytosed organellar membranes. Autopsy of elderly person will reveal deposits in heart, colon, liver, kidney, eye, and other organs.
Hallmarks of cancer
Evasion of apoptosis, growth signal self-sufficiency, anti-growth signal insensitivity, sustained angiogenesis, limitless replicative potential, tissue invasion, and metastasis.
Hyperplasia
cells increase in number. Distinct from hypertrophy (an increase in size of cells). Reversible
Dysplasia
Abnormal proliferation of cells with loss of size, shape, and orientation in comparison to normal tissue maturation; commonly preneoplastic. Reversible
Carcinoma in situ
It is preinvasive. Neoplastic cells have not invaded intact basement membrane. There is an increase in nuclear/cytoplasmic (N/C) ratio and clumped chromatin. Neoplastic cells encompass entire thickness.
Invasive carcinoma
Cells have invaded basement membrane using collagenases and hydrolases (metalloproteinases). Cell-cell contacts lost by inactivation of E-cadherin.
Metastasis
Spread to distant organ (eg metastatic cells in liver parenchyma). Seed and soil theory of metastasis: seed= tumor embolus, soil=target organ, which is often the first-encountered capillary bed (eg liver, lungs, bone, brain).
P-glycoprotein
Also known as multidrug resistance protein 1 (MDR1). Classically seen in adrenal cell carcinoma but also expressed by other cancer cells (eg colon and liver). Used to pump out toxins, including chemotherapeutic agents (one mechanism of a decrease responsiveness or resistance to chemotherapy over time).
Metaplasia
One adult cell type is replaced by another. Often secondary to irritation (eg Barrett esophagus) and/or environmental exposure (eg smoking induced tracheal/bronchial squamous metaplasia). Also occurs where two different epithelia meet (eg squamocolumnar junction of the uterine cervix). Reversible
Anaplasia
Loss of structural differentiation and function of cells, resembling primitive cells of same tissue; often equated with undifferentiated malignant neoplasms. May see giant cells with single large nucleus or several nuclei. Irreversible.
Neoplasia
An uncontrolled and excessive clonal proliferation of cells. Neoplasia may be benign or malignant. Irreversible.
Desmoplasia
Fibrous tissue formation in response to neoplasm (eg linitis plastica in diffuse stomach cancer). Irreversible.
Grade of tumor
Degree of cellular differentiation and mitotic activity on histology. Usually graded 1-4; 1=low grade, well differentiated; 4=high grade, poorly differentiated, anaplastic. State almost always has more prognostic value than grade.
Stage of tumor
Degree of localization/spread based on site and size of primary lesion, spread to regional lymph nodes, presence of metastases. Based on clinical (c) or pathology (p) findings. Example: cT3N1M0. TNM staging system (Stage=Spread): T=Tumor size, N=Node involvement, M=Metastases. Each TNM factor has independent prognostic value.
Tumor nomenclature
Carcinoma implies epithelial origin, whereas sarcoma denotes mesenchymal origin. Both terms imply malignancy. Most carcinomas spread via lymphatics; most sarcomas spread hematogenously. Terms for non-neoplastic malformations include hamartoma (disorganized overgrowth of tissues in their native location, eg Peutz-Jaghers polyps) choristoma (normal tissue in a foreign location, eg gastric tissue located in small bowel in Meckel diverticulum).
