Rest Of Pathology

Question 1

Breast Tumours

Answer 1

Fibroadenoma is the most common benign tumor of the female breast with both stromal and epithelial components. It is commonly seen in women 15–35 years of age. It is 1 cm to 10 cm in size, firm in consistency, well-circumscribed, painless, and mobile. A rapidly increasing mass is a concern for malignancy. An example of a painful breast lesion is fibrocystic change.

Phyllodes tumour is a benign breast tumour seen mostly in post-menopausal women. On biopsy, this tumour shows “leaf-like” projections. Giant cells are seen in fat necrosis, papillae are seen in intraductal papilloma, calcifications are seen in malignancy, frequently DCIS and cells in “single-file” strands are seen in invasive lobular carcinoma.

Phyllodes tumour is a benign breast tumour seen mostly in post-menopausal women. On biopsy, this tumour shows “leaf-like” projections. Giant cells are seen in fat necrosis, papillae are seen in intraductal papilloma, calcifications are seen in malignancy, frequently DCIS and cells in “single-file” strands are seen in invasive lobular carcinoma.

The BRCA genes (BRCA1 and BRCA2) are tumour suppressor genes. Many mutations exist, some of which result in the familial breast and ovarian cancer syndromes. 50%–65% of women with the BRCA1 mutation will develop breast cancer by age 70.

Prolonged estrogen exposure (due to early menarche, late menopause, and/or nulliparity) also increases the risk for breast cancer, though not to such a great extent as presence of a BRCA mutation.

Most cancers carry a better prognosis if the cells are well- rather than poorly-differentiated. Similarly, a higher proliferative rate confers a poorer prognosis. Increasing tumour size and ductal subtype are both worse prognostic indicators.

Fat necrosis in the breast can present as a small and painful mass. Women with fat necrosis will almost always report a history of trauma to the breast. On histological evaluation, the mass will have a necrotic center surrounded by leukocytes. Infection, tumor, dyslipidemia, and ischemia do not lead to fat necrosis.

The following factors increase the risk of breast cancer:

• Age >30 years
• Early menarche
• Late menopause
• History of breast cancer in first-degree relative
• Nulliparity
• History of benign breast disease
• Use of exogenous estrogens
• Alcohol consumption
• Cigarette smoking

Breast cancer TNM staging is quite complex. The exact intricacies are probably not necessary to know, but the major stages are as follows:

Tumour Stage

• T1 = Tumour less than 20 mm
• T2 = 20–50 mm
• T3 = >50 mm
• T4 = Tumour invades skin or chest wall (any size)

Clinical Nodal Stage (pathological stage is slightly different)

• N0 = no nodal involvement
• N1 = mobile Level I or II axillary nodes
• N2 = fixed or matted Level I or II axillary nodes
• N3 = ipsilateral infraclavicular nodes with or without axillary nodes, OR internal mammary and axillary nodes, OR ipsilateral supraclavicular nodes with or without axillary nodes

Metastasis Stage

• M0 = no metastases
• M1 = proven distant metastases

BRCA1/BRCA2 gene mutations are present in one-third of inherited breast cancers. Features of inherited breast cancers include early age of onset, bilateral disease, and presence of disease in multiple first-degree relatives. Other mutations seen in breast cancer include mutated HER2/NEU, TP53, Rb, and amplification of RAS and MYC.

Fibrosis and cystic changes along with apocrine metaplasia have minimal or no risk of malignant transformation. Sclerosing adenosis and hyperplasia without atypia confer a slightly increased risk of breast cancer. However, hyperplasia with atypia in any location of the breast tissue has a significantly higher risk (five-fold increase) of malignant transformation.

The following features are associated with a poor prognosis of breast cancer:

• Size >2 cm
• Involvement of lymph nodes
• Presence of distant metastasis
• Poorly-differentiated on histopathology
• Absence of ER/PR receptors
• Overexpression of HER2/NEU
• Inflammatory breast cancer

S. aureus is the most common causative agent of acute mastitis. Acute mastitis presents with pain, redness, and swelling of the affected breast tissue. E. coli is a common cause of urinary tract infections, P. aeruginosa is a common cause of nosocomial infections, S. pyogenes is a common cause of pharyngitis and skin infections, and Group B streptococcus is a common cause of neonatal sepsis.

Paget’s disease of the nipple is an eczematous skin lesion of the nipple which is almost always associated with an underlying breast cancer. Fibrocystic changes are cyclic breast changes which occur normally during the menstrual cycle. A galactocele is a benign milk-retention cyst. A fibroadenoma is a benign tumour composed of stromal and glandular breast tissue. An intraductal papilloma is a benign papillary tumour seen in breast ducts.

Question 2

Vascular

Answer 2

Systemic thromboemboli, that is, distant embolisation by thrombus formed elsewhere in the body, most commonly originate in the heart. Atrial fibrillation is the most common underlying reason for this. These thrombi may travel through the systemic circulation to lodge in various sites, the most common being the lower limbs, usually the femoral artery.

Hageman factor (Factor XII) and prekallikrein complex on exposed subendothelial collagen intiate the first step in the intrinsic pathway of coagulation.

The coagulation cascade has been divided into extrinsic and intrinsic pathways. Tissue factor is the major initiator of coagulation in the extrinsic pathway, whereas Hageman factor and the prekallikrein complex initiate the intrinsic pathway.

The factors involved in the extrinsic pathway are factors III (tissue factor and VII. The factors involved in the intrinsic pathway are factors XII, XI, IX, and VIII. The common pathway factors are X, II (thrombin), I (fibrin) and XIII (fibrin stabilising factor).

Remember that tissue factor is number 3, and 3+7 = 10, so the extrinsic pathway is factors 3 and 7, which then catalyse conversion of 10 to 10a.

Whereas the intrinsic pathway is all the factors 12 - 8 EXCEPT 10 - which is part of the COMMON pathway. So the intrinsic pathway is factors 12, 11, 9 and 8.

Purpura are caused by the bursting of blood vessels that cause discolouration under the skin or mucous membrane. The discolourations are purple in colour and are 3–10 mm in size. This can be seen in certain circumstances, such as platelet and coagulation disorders. Ecchymoses are larger in size. Petechiae are smaller than purpura.

Fibrin degradation products can be identified in the blood following widespread activation of coagulation. Many inflammatory states may cause this, including the above. The most commonly used test is the D-dimer assay.

Question 3

Necrosis

Answer 3

Infarction results in a coagulative necrosis, except in the brain, where the picture is of liquefactive necrosis. In coagulative necrosis, tissue architecture is initially preserved. Dead cells may persist as the proteolytic enzymes required to digest them are also denatured. Liquefactive necrosis forms a liquid mass of dead cells due to digestion by enzymes released from leukocytes. This liquid mass is commonly called “pus”.

Caseous necrosis is characterised by granuloma formation—a mass of dead cells and debris surrounded by an inflammatory border. It is commonly seen in TB infection.

“Suppurative necrosis” is not a recognised term, but “suppuration” refers to the formation of pus.

Fibrinoid necrosis is common to vasculitides. Antigen–antibody complexes are found within blood vessel walls.

Question 4

SIRS

Answer 4

The term “systemic inflammatory response syndrome” (“SIRS”) is starting to fall out of favour but still sees some usage. It is defined as two or more of the following criteria:

• Heart rate greater than 90
• Respiratory rate greater than 20
• Temperature lower than 36 or greater than 38
• White cell count lower than 4 x 10^9 or greater than 12 x 10^9 per cubic millimetre

SIRS with an obvious infective source is regarded as sepsis.

Question 5

Head and Neck

Answer 5

Nasopharyngeal carcinomas:
These are usually squamous cell or anaplastic carcinomas. They are often radiosensitive, particularly the poorly-differentiated or anaplastic lesions.

Squamous cell carcinomas are the most common oral cancers. They have a strong association with smoking and also infection with human papillomavirus (HPV) (HPV is strongest risk factor for SCC)

Cancer of the oral cavity arises from either exposure to carcinogenic factors or certain oncogenic infections. Carcinogenic factors include chronic alcohol consumption, tobacco use, and chewing betel quid and paan. Exposure to high-risk strains of human papillomavirus (HPV) increases the risk of oropharyngeal cancer, especially squamous cell carcinoma. Erythroplakia and leukoplakia are two oral conditions that are associated with increased risk of malignant transformation.

The most common malignant tumour of the salivary glands is mucoepidermoid carcinoma, constituting approximately 15% of all malignant tumours. This is followed by adenocarcinomas, constituting approximately 10%.

Pleomorphic Adenoma - most common salivary gland tumour type not usually malignant, present as a painless mass

Pleomorphic adenoma is the most common benign salivary gland tumour. It represents approximately 50% of all salivary gland tumours. Pleomorphic adenomas consist of both epithelial and myoepithelial cells. Approximately 60% of pleomorphic adenomas occur in the parotid gland, and they rarely arise from small sublingual salivary glands. They are slowly-growing, painless, discrete, and mobile masses. The incidence of malignant transformation is very low (2%) during the first 5 years. Most common of salivary gland benign (Warthin are next most common)

Medullary thyroid tumour part of MENII originating from parafollicular C cells

Laryngeal carcinoma risk factors - predominantly smoking, alcohol next highest

Carotid body tumours - commonly recur or metastasise, part of MENII

Though there are more than 30 types of salivary gland tumour, a minority of them account for >90% of identified cases. Approximately 80% of them arise from the parotid gland. Most parotid gland tumours are benign. The larger the gland size, the lower the likelihood the tumour is malignant, i.e. the parotid gland has the lowest likelihood to have malignant tumours, whereas the sublingual glands have the highest likelihood for malignancy. Salivary gland tumours are more common in females.

Otitis media is inflammation of the middle ear, and is most common in children. It is commonly caused by staphylococci and pseudomonas; fungi are another cause of chronic otitis media. Chronicity (glue ear) is an important cause of deafness and developmental delay in children. In severe cases, otitis media can progress to mastoiditis, or spread into the cranial vault.

Squamous cell carcinoma is the most common cancer of the oral and oropharyngeal region (90-95%), others include salivary gland carcinomas, lymphomas and melanomas. Whilst it has been commonly associated with alcohol and tobacco use, the human papillomavirus (HPV) has more recently been found to be a causative agent. Anatomically the oral cavity includes the oral tongue, floor of mouth, lower and upper alveolus, hard palate and buccal mucosa. The oropharynx includes the base of the tongue, soft palate, palatine tonsil and posterior pharyngeal space.

The most common sites of squamous cell carcinoma are the ventral tongue surface, the soft palate, gingiva and the lower lip. Histologically, the pattern ranges from well-differentiated to anaplastic tumours, but the degree of differentiation does not correlate with the tumour’s biological behaviour. Squamous cell carcinomata typically spread by local invasion before distant metastasis (to cervical and mediastinal lymph nodes, then lungs and liver).

Odontogenic keratocysts are common tumours of the jaw that are typically located within the posterior mandible. They have a male preponderance and can occur at any age between 10 and 40 years. Odontogenic keratocysts are characterised by high recurrence rate (up to 60%) and a locally invasive nature. Histologically, they are lined by ortho- or parakeratinized stratified epithelium with a prominent basal cell layer and a corrugated luminal epithelial surface.

Common benign salivary gland tumors include pleomorphic adenoma (50%), Warthin tumor (5%), oncocytoma (2%), cystadenoma (2%) and basal cell adenoma (2%). Common malignant tumors include mucoepidermoid carcinoma (15%), acinic cell carcinoma (6%), adenocarcinoma not otherwise specified (NOS) (6%), adenoid cystic carcinoma (4%) and malignant mixed tumor (3%).

Singer’s nodules are by convention bilateral. Nodules are polypoid lesions located on the true vocal cords. They almost never progress to cancerous lesions.

Radiation exposure and Hashimoto thyroiditis are the most common causes of papillary carcinoma of the thyroid. Pre-existing multinodular goitre may lead to follicular carcinoma. The risk factors for anaplastic carcinoma include age greater than 65, history of radiation exposure to the chest or neck, or a long-standing goitre. Primary thyroid lymphomas are usually non-Hodgkin lymphomas. Radiation exposure is not linked to thyroid lymphoma and medullary carcinoma. Medullary carcinoma is a tumour of neuroendocrine origin.

Question 6

Renewal and repair

Answer 6

Quiescent tissues normally have a low level of replication. However, cells from these tissues can undergo rapid division in response to stimuli and are thus capable of reconstituting the tissue of origin. In this category are the parenchymal cells of the liver, kidneys, and pancreas; mesenchymal cells such as fibroblasts and smooth muscle; vascular endothelial cells; and lymphocytes and other leukocytes. Although mature skeletal muscle cells do not divide, skeletal muscle does have regenerative capacity, through the differentiation of the satellite cells that are attached to the endomysial sheaths. The lining mucosa of salivary glands contains continuously-proliferating cells.

Osteopontin, Laminin, E-cadherin, Fibronectin are cell adhesion molecules

Matrix metalloproteinases are a large family of enzymes produced by macrophages, neutrophils, fibroblasts and epithelial cells. They include collagenases, gelatinases and stromelysins. Secretion is stimulated by growth factors and cytokines, such as IL-1, TNF and PDGF, and inhibited by TGF-beta and steroids.

Growth factors act on specific receptors. When a growth factor stimulates the specific cell membrane receptor, the signal is communicated by signal transduction. This causes altered gene expression.

VEGFs are a family of proteins that promote formation of new vessels in utero and in adulthood. They are stimulated by multiple factors, including PDGF, TGF-beta, TGF-alpha, as well as tissue hypoxia. Bevacizumab (Avastin) is a monoclonal antibody that blocks the effects of VEGF.

Cyclins and cyclin-dependent kinases mediate progression through the cell cycle. All the others listed are involved in the inflammatory response.

Stem cells are undifferentiated cells that multiply by cell division to replenish dying cells and heal damaged tissues. There are many types of stem cells. Hematopoietic stem cells that are found in the bone marrow may differentiate into various blood cells. Limbal stem cells, also known as “corneal epithelial stem cells”, are located on the corneal limbus and their main function is to replenish cornea cells that are damaged. Neural stem cells in the brain have a role in neurogenesis, the process of producing new neurons. Epidermal stem cells are responsible for the everyday regeneration of the different layers of the epidermis. These stem cells are found in the basal layer of the epidermis. Heart stem cells or progenitor cells are multipotent cells residing in the adult mammalian heart that are capable of self-renewing and generating coronary vessels and heart muscle cells, called the “cardiomyocytes”. Other stem cells include intestinal stem cells, mammary stem cells, and endothelial stem cells, among others.

Genetic defects in collagen production cause many inherited syndromes, including various forms of Ehlers–Danlos syndrome, Alport syndrome, and osteogenesis imperfecta. Alport syndrome is due to genetic defects in the basement membrane collagens. Osteogenesis imperfecta and Ehlers–Danlos syndrome are caused by defects in the fibrillar collagens. The von Hippel–Lindau (VHL) syndrome is an autosomal dominant disorder caused by deletions or mutations in a tumor suppressor gene on human chromosome 3p25. It is characterized clinically by vascular tumors including benign hemangioblastomas of the cerebellum, spine, brain stem, and retina.

Oral epithelial cells are damaged every time the oral phase of digestion takes place. Epithelial stem cells in the oral epithelium will continuously replenish damaged cells with new epithelial cells. Hematopoietic stem cells that are found in the bone marrow continuously differentiate into various blood cells in order to maintain the blood cells in the plasma.

Macrophages are the main source of growth factors that drive wound healing and are stimulated by tissue injury. Endothelial cells release growth factors but are not the main source.

TGF-b is a potent fibrogenic agent that stimulates fibroblast chemotaxis and enhances the production of collagen, fibronectin, and proteoglycans. It inhibits collagen degradation by decreasing matrix proteases and increasing protease inhibitor activities. TGF-b is involved in the development of fibrosis in a variety of chronic inflammatory conditions, particularly in the lungs, kidneys, and liver. FGFs contribute to wound healing responses, hematopoiesis, angiogenesis, and other processes through several functions. PDGF causes migration and proliferation of fibroblasts, smooth muscle cells, and monocytes to areas of inflammation and healing skin wounds. TNF is a cytokine that participates in wound healing.

S. Both down- and up-regulation of TGF-b can be associated with neoplasia because R. TGF-b is normally inhibitory to the growth of many epithelial cells but stimulatory to the growth of other cell lines.

Vitamin C acts as a cofactor during the formation of collagen from procollagen by hydroxylation of proline and lysine. This collagen is necessary in wound healing and scar formation.

The capacity for regeneration of whole tissues and organs has been lost in mammals. The Wnt/β-catenin pathway is a highly conserved pathway that participates in regeneration. In humans, Wnt/β-catenin modulates stem cell functions in the intestinal epithelium, bone marrow, and muscle; participates in liver regeneration after partial hepatectomy; and stimulates oval cell proliferation after liver injury.

Hypertrophic scars may be ugly, broad, or hyperpigmented, but they do not show overgrowth of scar tissue beyond the original wound edges. Keloid scarring is classically seen in black skin and can be a very exaggerated response to a minor scarring stimulus, e.g. ear piercing. It can be very troublesome to treat.

Wound healing proceeds in several predictable stages. These can be classified as inflammation, proliferation, and maturation.

In the inflammatory phase, bleeding into the wound results in formation of a clot and platelet activation. Fibrin within the clot forms a scaffold for cells to migrate into the area, including neutrophils, and release of multiple growth factors promotes this process. This starts occurring from 0–24 hours after injury.

From 24–72 hours, fibroblasts proliferate in the wound, forming granulation tissue. This commences the proliferative phase, with epithelial cells starting to migrate out from the edges of the wound from 24–48 hours after injury. Collagen is laid down by fibroblasts and begins to cross the wound.

Question 7

Paediatric

Answer 7

Congenital malformations are primary intrinsic errors of morphogenesis that are usually multifactorial rather than the result of a single gene or chromosomal defect. Unlike congenital malformations, disruptions and deformations arise from extrinsic disturbances of development. A sequence refers to multiple congenital anomalies that result from secondary effects of a single localized aberration in organogenesis. Oligohydramnios is a typical example of a sequence that results from maternal, placental, or fetal abnormalities.

Osteogenesis imperfecta is characterised by brittle bones, blue sclerae, short stature, hypermobility and hearing loss. It results from a lack of type 1 collagen, most often from a mutation in the COL1A1 or COL1A2 genes.

Achondroplasia arises from a mutation in the FGFR3 fibroblast growth factor receptor gene. It causes dwarfism.

Neurofibromatosis has two types: type 1 arising from a mutation for the gene coding for the neurofibromin protein on chromosome 17. It has multiple features, including cafe-au-lait spots, neurofibromas, Lisch nodules (brown spots in the iris), and scoliosis. Neurofibromatosis type 2 is caused by an inactivating mutation in the NF2 gene on chromosome 22. It leads to the formation of benign brain and spinal cord tumours including schwannomas, meningiomas and ependymomas.

Hereditary haemochromatosis is iron overload arising most commonly from a mutation in the HFE gene.

Cystic fibrosis is a defect in a membrane sodium transporter protein with a spectrum of effects, including severe chest infections and bronchiectasis, chronic pancreatitis and pancreatic insufficiency, malabsorption, diabetes, and infertility. It is caused by one of many different possible mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Wilms’ tumor is the most common tumor of the kidneys in children. It arises from primitive tissues like blastema, stroma, and epithelium, a triphasic tissue combination also responsible for the embryologic development of the kidney. It usually manifests as a large abdominal mass that is readily palpable. Wilms’ tumor is more common in certain syndromes of congenital malformations like Denys–Drash, Beckwith–Wiedemann, and WAGR syndrome (i.e. Wilms’ tumor, aniridia, genital abnormalities, and mental retardation). Wilms’ tumor usually manifests as a well-circumscribed focal mass but 10% of cases can be multifocal. Sometimes it can present with fever, abdominal pain, and hematuria.

X-linked agammaglobulinemia is an immunodeficient disorder which occurs due to a defective Bruton tyrosine kinase gene. This causes defective maturation of B cells, eventually leading to a decreased number of immunoglobulins. Adenosine deaminase deficiency is one of the causes of severe combined immunodeficiency (SCID). NADPH oxidase is defective in chronic granulomatous disease. A mutated WAS gene is present in Wiskott–Aldrich syndrome and a mutated ATM gene is present in ataxia-telangiectasia.

Accumulation of edema fluid in the fetus during intrauterine growth is called “fetal hydrops”. It can occur due to multiple conditions. Previously hemolytic disease of the newborn due to a mismatch between maternal and fetal blood types was the most common cause of fetal hydrops. Fetal macrosomia describes a newborn who weighs more than 8 pounds (4,000 grams), regardless of gestational age. Fetal gigantism is a rare disorder (Perlman syndrome). A localized fluid collection in the posterior neck area is called “cystic hygroma”.

cute lymphocytic leukaemia is the most common of the listed cancers in childhood, followed by neuroblastomas (which typically arise from the sympathetic ganglia and adrenal medulla).

Neuroblastomas metastasise early and widely. They often produce catecholamines.

Wilms’ tumours arise from renal nephrons. 95% are seen before age 10, and 5%–10% are bilateral. They are often associated with genetic syndromes, including WAGR and Denys–Drash syndromes.

Hodgkin lymphomas are characterised by the presence of Reed–Sternberg cells. They are often localised to one lymphatic region of the body. Prognosis is related to stage, which describes the extent of spread of the lymphoma in relation to the diaphragm. They are seen in children and adults and generally have a better prognosis than non-Hodgkin lymphomas.

Osteosarcomas are seen in older children (10–14 years of age).

Papillary thyroid cancers are seen in children and adults. In children they are frequently associated with previous radiation exposure, e.g. for haematological malignancies earlier in life.

Bronchiolitis is a respiratory infection caused by the respiratory syncytial virus (RSV). It causes both upper and lower respiratory tract infections in children <2 years of age and is very severe in children <6 months of age. It can be prevented by the use of the antibody palivizumab. The treatment of RSV is supportive.

Congenital syphilis is caused by infection due to Treponema pallidum. Neonates affected by syphilis can develop fever, nasal discharge, haemolytic anemia, maculopapular rash, saddle nose, saber shins, Hutchinson’s teeth, and osteochondritis. Patent ductus arteriosus is a feature of congenital rubella infection. Intracranial calcifications are a feature of congenital toxoplasmosis.

Phenylketonuria is a common inborn error of metabolism. It is caused by a deficiency in phenylalanine hydroxylase or tetrahydrobiopterin cofactor which normally converts phenylalanine into tyrosine. Tyrosine becomes an essential amino acid. Galactosemia, Niemann–Pick disease, McArdle disease, and albinism are caused by deficiencies of galactose-1-phosphate uridyltransferase, sphingomyelinase, muscle glycogen phosphorylase, and tyrosine, respectively.

Tay–Sachs disease is a lysosomal storage disease due to a deficiency in hexosaminidase A enzyme. Gaucher disease, Von Gierke disease, Pompe disease, and Fabry disease are due to deficiency in the enzymes glucocerebrosidase, glucose-6-phosphatase, lysosomal alpha (1,4)-glucosidase, and alpha galactosidase A, respectively.

Fetal hydrops is the abnormal collection of fluid in two fetal compartments. These may include the abdomen, pericardium pleura, etc. Parvovirus B19 is one of the common causes of fetal hydrops. It is transmitted hematogenously through the placenta from the mother to the fetus. When it reaches the fetus, it enters the normoblasts (erythroid precursors) where it replicates and destroys cells, leading to anaplastic anemia and, consequently, fetal hydrops. TORCH infections (i.e. toxoplasma, rubella, cytomegalovirus, herpes virus) result in mental retardation, growth restriction, cardiac anomalies, cataract, hepatosplenomegaly, encephalitis, chorioretinitis and myocarditis).

Intussusception is the telescoping of one portion of the bowel into an adjacent segment. It occurs primarily in children between the ages of 3 months and 3 years, and mainly involves the terminal ileum. Affected children present with colicky abdominal pain, partially relieved by knee flexion onto the chest, redcurrant jelly stool, and a sausage-shaped abdominal mass palpable in the abdomen. The stool-guaiac test will be positive due to the presence of blood in the stool.

Fetal neural tube defects occur due to failure of the neural tube to fuse. They are commonly associated with folic acid deficiency in the mother. Examples of neural tube defects include spina bifida and anencephaly. Gastroschisis and omphalocele are ventral body wall defects. Gastroschisis occurs due to failure of the ventral body folds to fuse, and omphalocele occurs due to failure of the midgut to herniate back into the body cavity during development.

Haemangiomas (capillary and cavernous) are the most common benign tumours in children and infants, and they particularly affect the skin. Lymphangiomas are the lymphatic counterparts of haemangiomas which occur in deeper tissues such as in the neck, axilla, mediastinum, and retroperitoneum. Mature teratomas are benign, well-differentiated teratomas that are common at the sacrococcygeal region. Neuroblastoma is a common malignant tumour of the sympathetic chain and the suprarenal gland.

Retinoblastomas are the most common tumors arising in the eyes of young children. They cause poor vision, strabismus, a white pupil, and eye pain. Their cells of origin are primitive neuronal cells. Approximately 40% of cases are familial and arise due to germline mutations in the RB1 gene (a tumor suppressor gene). The remaining 60% of the tumors develop sporadically due to somatic mutations in the RB1 gene. Most sporadic tumors are unifocal and unilateral but familial tumors can be bilateral/multifocal. Patients with familial retinoblastoma also have an increased risk of developing osteosarcoma and other soft tissue tumors. Retinoblastomas are malignant tumors that are fatal if left untreated. However, they have a good prognosis after treatment with enucleation (removal of the eye), chemotherapy, and radiotherapy.

Hyperbilirubinemia manifests clinically as jaundice. It can be broadly classified into two types: unconjugated hyperbilirubinemia and conjugated hyperbilirubinemia. Causes of unconjugated hyperbilirubinemia include Gilbert syndrome and Crigler–Najjar syndrome. Causes of conjugated hyperbilirubinemia include Dubin–Johnson and Rotor syndrome.

Respiratory distress syndrome is more common among male infants. It results from the underproduction of surfactant in the lungs. Pulmonary surfactant is a mixture of natural lipids and proteins which lowers the surface tension at the air/liquid interface within the alveoli. It is formed towards the end of the gestational period as the pneumocytes mature and production is enhanced by corticosteroids. The most common risk factor for underproduction is premature birth at lower gestational age. Other factors that can lead to surfactant underproduction are maternal diabetes and cesarean delivery. On the other hand, factors that lead to fetal stress like growth restriction and vaginal delivery produce corticosteroids and are associated with less risk of surfactant deficiency.

Duodenal atresia is a congenital disease in which a portion of the duodenum does not canalize, leading to obstruction. On ultrasound, it shows a “double-bubble” sign. It is associated with Down’s syndrome. In pyloric stenosis, hypertrophied pylorus is seen on ultrasound. A “triple-bubble” sign is seen in the case of jejunal atresia. An NG tube is seen coiled in the oesophagus on chest X-ray in a tracheoesophageal fistula. In meconium ileus, dilated loops of bowel are seen on radiography.

Perinatal infections transmit from the mother to the fetus either through ascending from the cervix to the uterus (transcervical transmission) or through the placenta (transplacental transmission). Examples of transcervical transmission are alpha-hemolytic streptococci and herpes simplex virus, whilst TORCH infections are examples of transplacentally-transmitted infections (toxoplasma [T], rubella virus [R], cytomegalovirus [C], herpesvirus [H], and any of a number of other [O] microbes such as Treponema pallidum).

Edward’s syndrome is a genetic disease caused by trisomy 18. Trisomy 13 causes Patau syndrome and trisomy 21 causes Down’s syndrome. Some examples of diseases due to trinucleotide repeat expansion include fragile X syndrome, Huntington disease, and myotonic dystrophy. Prader–Willi syndrome and Angelman syndrome are caused by deletions in chromosome 15.

Neuroblastoma is a common malignant tumor in children that affects the adrenal glands and the sympathetic chain. Histologically, the Homer–Wright pseudorosettes characterize it. Flexner–Wintersteiner rosettes, on the other hand, are characteristic of retinoblastomas. Wilms’ malignant tumor of the kidney is characterized by the triphasic combination of stromal, blastemal, and epithelial cell types as well as nephrogenic crests.

Sacrococcygeal teratomas are a type of germ cell tumor. They arise from the germ cells located in multiple places inside the body due to aberrant cellular migration during development. They are the most common type of germ cell tumor in children. Approximately 10% of sacrococcygeal teratomas are associated with some kind of congenital anomaly. Primarily, defects of the hindgut or cloacal region and midline defects like meningocele or spina bifida are the most commonly associated congenital defects. Most of the tumors are histologically mature and have a benign course. A few tumors can be malignant and they are often composed of immature cellular architecture (undifferentiated). Benign teratomas are common in infants before the age of 4 months, whereas children with malignant lesions are usually older.

Respiratory distress syndrome (RDS) is the most common cause of respiratory distress in newborns and is common in infants born at less than 28 weeks of gestation because of inability of the lungs to synthetize sufficient surfactant, which is essential for lung inflation. The lungs in infants with this syndrome are usually of normal size but heavy and relatively airless. Hormones play a role in the regulation of surfactant synthesis. For example, corticosteroids stimulate its synthesis, whilst insulin suppresses it. Thus, infants subjected to intrauterine stress and increased corticosteroid release are at lower risk of RDS, whereas infants to diabetic mothers are at higher risk.

Morphogenesis refers to the process of formation of an organ. When errors occur during the process of morphogenesis, the resultant defect is called a “malformation”. They occur due to multiple factors that disrupt the intrinsic developmental process. An atrial septal defect is a congenital heart malformation where a septum fails to form between two atria. When an organ undergoes successful primary formation but some secondary factor causes its destruction, the process is called “disruption” (amniotic band syndrome).

Neuroblastomas are a type of neuroblastic tumor. Neuroblastic tumors are cancers that originate in organs/tissues derived from neural crest cells. The adrenal medulla and sympathetic ganglia throughout the body develop from neural crest cells. Roughly 40% of neuroblastomas arise in the adrenal medulla and 60% occur in sympathetic ganglia especially in regions like the paravertebral region (25%) and posterior mediastinum (15%). 90% of neuroblastomas produce catecholamines but hypertension is uncommon. Typically, neuroblastomas are a result of a mutation that occurs sporadically. Some cases are familial and occur due to an inherited gain-of-function mutation in the anaplastic lymphoma kinase (ALK) gene. Prognosis is better among children under 18 months of age and becomes less favorable thereafter.

Question 8

Neurology

Answer 8

Neurofibromatosis type 2 (NF2) is an autosomal dominant inherited syndrome caused by mutations in the Merlin (or schwannomin) cytoskeletal gene on chromosome 22. Mutations in the Merlin gene cause tumour formation through disruption of cell shape, cell-matrix, and cell–cell communication or signalling functions attributed to actin–plasma membrane interactions. Individuals with NF2 develop brain tumours (schwannomas, meningiomas, ependymomas, astrocytomas and neurofibromas), peripheral neuropathy, ophthalmological lesions (cataracts, retinal hamartomas), and cutaneous lesions (skin tumours).

The macroscopic appearance of the brain after a non-hemorrhagic infarct evolves gradually. During the first 6 hours after the infarct, the microscopic picture of the brain is essentially normal. This occurs because cellular disruption is slow despite a rapid loss of cellular function in neurons. The brain tissue appears pale, soft and swollen after 48 hours, and changes to a gelatinous and friable consistency in 2–10 days. Within 3 weeks the tissue liquefies and gives rise to scarring over months.

Microcephaly is the most common type of brain malformation, and refers to a small brain and head size. It occurs due to inadequate generation of neurons in the forebrain. Risk factors are chromosomal abnormalities, fetal alcohol syndrome, and HIV-1 infection acquired in utero. Megalencephaly (large brain volume) is less common than microcephaly. Lissencephaly is characterized by the presence of a few gyri giving rise to a smooth-surfaced brain. Polymicrogyria refers to large number of irregularly formed gyri producing a cobblestone brain surface. Holoprosencephaly occurs when the brain fails to develop into two hemispheres properly.

Injury to neurons often leads to irreversible cell damage. Cell damage in neurons progresses as a sequential set of events. It involves shrinkage of the cell body, irreversible condensation of chromatin in the nucleus (pyknosis), disappearance of the nucleolus, loss of Nissl substance (RER with ribosomes that synthesise proteins), and eosinophilia of the cytoplasm. All these changes are visible on microscopy within 24 hours of injury and are collectively called “red neurons”. Axonal injury leads to a slightly different pattern of changes like cell body enlargement, displacement of the nucleus and Nissl substance to the periphery, and enlargement of the nucleolus.

Encephalitis is inflammation of the brain parenchyma. It is characterised by fevers, seizures or focal neurological signs, CSF pleocytosis, and EEG and neuroimaging findings suggestive of encephalitis. Encephalopathy, on the other hand, refers to disease of the brain. It can be acute or chronic. It is characterised by a steady deterioration in mental status persisting for longer than 24 hours, including cognitive decline, delirium, stupor, irritability, or a change in personality or behaviour. In patients with encephalopathy, an MRI scan is commonly normal.

Spontaneous intraparenchymal hemorrhages often occur in the elderly in the absence of brain trauma. Peak age of incidence is 60 years. Most of these cases result from rupture of small intraparenchymal vessels that become weak with age. Hypertension is often a precipitating factor in the rupture of these weak vessels, particularly in the basal ganglia, thalamus, pons, and cerebellum. Large intraparenchymal hemorrhages in sensitive brain areas can cause irreversible neurologic dysfunction or death. In some cases, they can be asymptomatic if the hemorrhage itself is small and affects a less sensitive brain area like the frontal lobe.

Although all brain herniations are associated with significant neurological complications, tonsillar herniation can be rapidly fatal due to compression of the brain stem. It occurs due to displacement of the cerebellar tonsils through the foramen magnum leading to compression of the lower brainstem and upper cervical spinal cord. Vital respiratory and cardiac centers in the medulla are compressed, leading to cardiopulmonary arrest and death. Hydrocephalus produces increased ICP leading to papilledema, nausea and headache, with herniation occurring in severe cases. Third nerve palsy causes dilated pupils and paralysis of extraocular muscles.

Falx cerebri is a dural extension at the top of the head between the two hemispheres of the brain. Subfalcine (cingulate) herniation occurs due to displacement of the cingulate gyrus (innermost part of the frontal lobe) under the edge of the falx. This can lead to compression of the anterior cerebral artery producing weakness in the contralateral leg. Herniation of the medial temporal lobe occurs through the tentorial gap and is called “transtentorial herniation”. Progression of transtentorial herniation can produce flame-shaped hemorrhages in the midbrain and pons called “Duret hemorrhages”.

In Alzheimer’s disease, neurofibrillary tangles and amyloid plaques are found. Senile plaques have a beta-amyloid core. Early-onset familial Alzheimer’s disease is inherited in an autosomal dominant fashion. Acetylcholinesterase inhibitors can slow (but not reverse) the progression of Alzheimer’s.

Hyaline arteriolar sclerosis is a condition characterised by deposition of hyaline material in the walls of the arterioles. These deposits stain pink with routine H/E staining. Some brain structures such as the basal ganglia and brainstem lie deep inside the brain matter. They are away from the brain surface where most of the brain blood vessels are located. These are supplied by small penetrating branches of main cerebral arteries. These penetrating branches are most susceptible to hyaline arteriolar sclerosis. Affected vessels’ walls are weak and less flexible which makes them vulnerable to rupture in settings of high blood pressure.

Acute hypertensive encephalopathy is characterized by global cerebral dysfunction (not focal as seen in stroke). This occurs with sudden and sustained increase in diastolic pressure above 130 mmHg. Increased blood pressure leads to increased intracranial pressure, manifesting as headache, confusion, and vomiting. Convulsions and coma can occur in severe cases. Rapid intervention is required to reduce blood pressure to prevent permanent neurological dysfunction.

Tentorium cerebelli is an extension of the dura that separates the cerebellum below from the temporal and occipital lobes above. The medial aspect of the temporal lobe lies above the margin of the tentorium and can become compressed or herniated due to increased pressure in the middle cranial fossa. Compression of the third cranial nerve is characteristic and produces paralysis of extraocular muscles (except superior oblique and lateral rectus), and dilated pupils. The posterior cerebral artery can also be compressed with resulting ischemia of the primary visual cortex, and blindness.

Sub-arachnoid hemorrhage can cause communicating hydrocephalus by impairing CSF reabsorption due to scarring of arachnoid granulations. Any mass obstructing the foramen of Monro or causing compression of the aqueduct of Sylvius can cause non-communicating hydrocephalus by obstructing ventricular outflow of CSF. Hydrocephalus ex vacuo can occur after loss of brain volume and can lead to non-communicating hydrocephalus. Chiari malformation also results in non-communicating hydrocephalus due to impairment of CSF outflow.

The blood–brain barrier (BBB) is a semipermeable border that separates circulating blood from the CSF and extracellular fluid in the CNS. Disruption of the BBB can lead to a shifting of fluid from the vasculature into the extracellular spaces of the brain, producing vasogenic cerebral oedema. Cytotoxic brain oedema occurs due to toxic or ischaemic injury to the neurons or glial cells. Hydrocephalus occurs due to blockage of CSF reabsorption or a blocked ventricular system. Although disruption of the BBB raises the risk of bacterial infection, it cannot be the sole cause of bacterial meningitis.

Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloidogenic proteins in the walls of small or medium vessels. The meningeal and cortical vessels in the lobes of the cerebral cortex are most commonly affected. This deposition makes the arteries rigid, structurally weak, and prone to rupture with hypertension, causing lobar hemorrhages. The amyloid deposits stain with Congo red dye. Silver staining is used to identify diffuse axonal injury.

The brain and spinal cord have an excellent blood supply with a degree of interconnection. Watershed areas are localized areas at the border zone between tissues supplied by different arteries. These areas at the distal portions of the arterial territories are particularly susceptible to ischemic insults. Cerebral infarcts occurring in these watershed areas are called “border zone” (“watershed”) infarcts.

Myasthenia gravis is caused by acetylcholine receptor antibody production which results in inhibition of ACh molecules and downregulation of ACh receptors. Muscle weakness becomes more pronounced with repeated use and worsens throughout the day.

During brain trauma, injury can occur at the site of impact or on the side opposite to the site of impact. Injuries occurring at the site of impact are called “coup injuries”, whilst contrecoup injuries occur on the opposite side to the site of traumatic impact. Both injuries cause brain contusions and have identical microscopic and gross features. The gyri are most vulnerable to coup or contrecoup injury as they lie close to the inner skull surface. This is particularly true where skull surface is uneven and rough.

Hydrocephalus ex-vacuo refers to increased CSF volume due to enlarged cerebral ventricles and subarachnoid spaces. This usually accompanies brain atrophy that occurs with old age, degenerative brain diseases, brain injuries, and some psychiatric disorders. The intracranial pressure usually remains normal as this increase in CSF is mainly compensatory to brain atrophy. Decreased absorption of CSF and blockade in the ventricular system cause communicating hydrocephalus and non-communicating hydrocephalus, respectively.

Oligodendrocytes are glial cells in the central nervous system (CNS). Oligodendrocytes have cytoplasmic processes that wrap around axons in the CNS, allowing CNS myelination and axonal support. Each oligodendrocyte is metabolically active and functionally interconnected with approximately 30 subjacent axons via cytoplasmic-rich myelinic channels. These channels facilitate the movement of macromolecules to and from the internodal periaxonal space under the myelin sheath.

Development of fluid-filled cavities in the inner portion of the spinal cord is called “syringomyelia” or “syrinx”. Their development is associated with spinal cord trauma and tumors arising in the spinal canal. Symptoms depend on the level of cord involved and the type of nerve fibres damaged. Encephalocele is a sac-like protrusion of the brain through openings in the skull. Dandy–Walker malformation and Chiari type I malformation are posterior skull fossa malformations. Myelomeningocele refers to a posteriorly open spinal canal with membranes and spinal nerves extending through this opening into a sac on the baby’s back.

Diffuse axonal injuries are widespread injuries to axons in the brain. The injury to axons occurs at the microscopic level and is often not visible with brain imaging. It can be demonstrated by axon-specific silver staining. Although not seen on imaging, they often cause significant neurological deficits. Angles of the lateral ventricles and in the brainstem are the most commonly involved regions because they house longer axons.

Ependymal cells line the ventricles and spinal cord. They are a class of glial cells that perform important functions related to cerebral fluid balance, toxin metabolism, and secretion. Satellite cells (also called “myosatellite cells”) are multipotent cells found in mature muscle. Schwann cells are nucleated cells located in the peripheral nervous system. Radial glial cells are specialised cells that emerge during the earliest development of neuroepithelium and are characterised by long radial processes.