Orris

Pneumonia, Bronchitis, Bronchiectasis, Asthma, Tuberculosis, Carcinoma of lungs, Occupational lung diseases 8. Cardiovascular Pathology -Congenital Heart diseases: Atrial septal defect, Ventricular septal defect, Fallot's tetralogy, Patent ductus arteriosu,. Endocarditis, Rheumatic Heart disease. - Vascular diseases: Atherosclerosis, Monckeberg's medial calcification. Ischemic heart Disease: Myocardial infarction. 9. Hepato Biliary Pathology Jaundice: Types, aetio-pathogenesis and diagnosis. 10. Musculoskeletal System - Osteomyelitis: acute, chronic, tuberculous, mycetoma Metabolic diseases: Rickets/ Osteomalacia, osteoporosis, Hyperparathyroidism, Paget's disease. Tumours Classification: Benign, Malignant, Metastatic and synovial sarcomaa. Arthritis: Suppurative, Rheumatoid. Osteoarthritis, Gout, Tuberculous. 11. Endocrine pathology -Non-neoplastic lesions of Thyroid: Thyrotoxicosis, myxedema, 12. Neuropathology -Inflammations and Infections: TB Meningitis, Pyogenic Meningitis, viral meningitis and Brain Abscess, Tuberculosis, Cysticercosis. 13. Dermatopathology: -Skin tumors: Squamos cell carcinoma, Basal cell carcinoma, Melanoma (brief idea) 14. Congenital Myopathy & mysthenia gravis

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Here are your detailed pathology study notes covering Topics 8-14.

PATHOLOGY STUDY NOTES: Topics 8-14

TOPIC 8: CARDIOVASCULAR PATHOLOGY

Congenital Heart Diseases (CHD)

Overview Congenital heart diseases are structural abnormalities of the heart or great vessels present from birth. They result from developmental errors during embryogenesis (weeks 3-8). The overall incidence is approximately 1% of live births. Clinically they are divided into:
  • Cyanotic (right-to-left shunts or mixing lesions): cause cyanosis from birth (e.g., Tetralogy of Fallot)
  • Acyanotic (left-to-right shunts): initially no cyanosis but can become cyanotic with Eisenmenger syndrome over time (e.g., ASD, VSD, PDA)
Atrial Septal Defect (ASD)
An ASD is an abnormal, fixed opening in the atrial septum that allows communication of blood between left and right atria. It must be distinguished from a patent foramen ovale (PFO), which is a failure to close a channel that is part of normal fetal development.
Embryology: The septum primum grows down between the atria; before it closes the ostium primum, a second hole (ostium secundum) forms in it. The septum secundum then grows to the right, partially covering the ostium secundum and creating the foramen ovale. At birth, with pulmonary expansion, left atrial pressure exceeds right atrial pressure and the foramen ovale closes. Failure of these processes leads to ASD.
Types (by location):
  • Secundum ASD (90%): Deficient septum secundum near the center of the atrial septum. Usually isolated, variable in size.
  • Primum ASD (5%): Adjacent to the AV valves; often associated with AV valve abnormalities and/or VSD.
  • Sinus venosus defect (5%): Near the entrance of the superior vena cava; may associate with anomalous pulmonary venous return.
Hemodynamics: ASD creates a left-to-right shunt because pulmonary vascular resistance is lower than systemic and the right ventricle is more compliant. Pulmonary flow may be 2-8 times normal.
Clinical features: Usually asymptomatic until adulthood (typically after age 30). Symptoms include exertional dyspnea, atrial arrhythmias, and paradoxical embolism. A soft systolic murmur from excessive pulmonary valve flow is typical, with wide fixed splitting of S2. ASDs are the most common congenital defect diagnosed in adults because they rarely close spontaneously. Irreversible pulmonary hypertension is less common than with VSD. Treatment: surgical or intravascular device closure to prevent heart failure, paradoxical embolism, and pulmonary vascular disease.
(Source: Robbins, Cotran & Kumar Pathologic Basis of Disease)
Ventricular Septal Defect (VSD)
VSD is incomplete closure of the interventricular septum, allowing free left-to-right communication; it is the most common congenital heart defect overall (see Fig. 12.3B in Robbins).
Types:
  • Membranous VSD (90%): In the region of the membranous interventricular septum, just proximal to the aortic valve; usually 2-3 cm.
  • Infundibular VSD: Below the pulmonary valve.
  • Muscular VSD: Within the muscular septum; may be multiple ("Swiss cheese").
Hemodynamics: Left-to-right shunt causing right ventricular volume overload and pulmonary hypertension. Large, unclosed VSDs lead to irreversible pulmonary vascular disease (Eisenmenger syndrome), with shunt reversal and late cyanosis.
Clinical features: Most pediatric VSDs are associated with other defects (e.g., Tetralogy of Fallot). Isolated VSDs are more common in adults. Small VSDs may close spontaneously (~50% of muscular VSDs). Large defects: harsh pansystolic murmur at left sternal border, early right ventricular hypertrophy, pulmonary hypertension. Management: close asymptomatic small VSDs conservatively; large VSDs require early surgical correction.
(Source: Robbins, Cotran & Kumar Pathologic Basis of Disease)
Fallot's Tetralogy (Tetralogy of Fallot - TOF)
TOF is the most common cyanotic congenital heart disease, accounting for about 5-8% of all CHDs. It results from an anterosuperior displacement of the infundibular septum during development.
The four components ("PROV"):
  1. Pulmonary stenosis (right ventricular outflow tract obstruction) - the dominant lesion
  2. Right ventricular hypertrophy (secondary to outflow obstruction)
  3. Overiding aorta (aorta straddles the VSD, receiving blood from both ventricles)
  4. Ventricular septal defect (large, sub-aortic)
Pathophysiology: The right ventricular outflow obstruction causes right ventricular hypertrophy and increases right-sided pressure. Blood is shunted right-to-left through the VSD into the overriding aorta, causing cyanosis. The degree of cyanosis depends on the severity of pulmonary stenosis.
Clinical features: Cyanosis from birth or early infancy. "Tet spells" (hypercyanotic episodes) occur when infundibular spasm worsens the shunt - child squats to relieve symptoms (squatting increases systemic vascular resistance, reducing right-to-left shunting). Clubbing and polycythemia develop over time. CXR shows "boot-shaped heart" (coeur en sabot) due to right ventricular hypertrophy and concave pulmonary artery segment. ECG: right axis deviation and right ventricular hypertrophy. Treatment: surgical correction (complete repair - patch VSD and relieve RVOT obstruction).
Patent Ductus Arteriosus (PDA)
The ductus arteriosus is a normal fetal vessel connecting the main pulmonary artery to the descending aorta (just distal to the origin of the left subclavian artery). It normally closes within hours of birth due to increased oxygen tension and decreased prostaglandin E2. PDA is its failure to close after birth.
Associations: Prematurity, congenital rubella infection, high altitude, respiratory distress syndrome in neonates.
Hemodynamics: Continuous left-to-right shunt (because aortic pressure exceeds pulmonary artery pressure throughout the cardiac cycle). Results in left ventricular volume overload and pulmonary hypertension over time.
Clinical features: Continuous "machinery" murmur under the left clavicle. Wide pulse pressure. Bounding peripheral pulses. Small PDAs may be asymptomatic; large ones cause heart failure, pulmonary hypertension, and eventual Eisenmenger syndrome. Treatment: in premature infants, indomethacin (prostaglandin inhibitor) promotes closure. Surgical ligation or transcatheter closure for persistent/symptomatic PDA.

Endocarditis

Endocarditis is inflammation of the endocardium, most commonly involving the heart valves.
Infective (Bacterial) Endocarditis
Pathogenesis: Organisms seed the valve surfaces during bacteremia. Damaged or abnormal valves (rheumatic disease, prosthetic valves, congenital defects, IV drug use) are predisposed. Organisms adhere to valve surfaces, trigger fibrin-platelet deposition, and form "vegetations" - irregular, friable masses containing bacteria embedded in fibrin-platelet thrombus.
Acute Infective Endocarditis (AIE): Caused by virulent organisms (especially Staphylococcus aureus). Affects previously normal valves. Rapid onset, high fever, severe systemic illness. Vegetations are large, destructive, and may perforate valve leaflets. Emboli can cause abscesses in brain, kidneys, spleen.
Subacute Infective Endocarditis (SIE): Caused by less virulent organisms (especially Streptococcus viridans, enterococci). Affects previously abnormal valves. Insidious onset over weeks-months. Vegetations are smaller, non-destructive. Classical signs include: Osler nodes (painful nodules on fingertips/toes), Janeway lesions (painless hemorrhagic macules on palms/soles), Roth spots (retinal hemorrhages), splinter hemorrhages under nails, fever, and new or changed murmur.
Duke criteria are used for diagnosis (major criteria: positive blood cultures, echocardiographic evidence; minor criteria: fever, predisposing heart disease, immunologic phenomena, etc.).
Non-Bacterial Thrombotic (Marantic) Endocarditis (NBTE)
Sterile vegetations on previously normal valves. Associated with chronic debilitating illnesses (cancer, sepsis, SLE - Libman-Sacks endocarditis in SLE). Vegetations are small, flat, along the line of valve closure. Clinically important as a source of emboli.

Rheumatic Heart Disease

Pathogenesis: Rheumatic fever is a systemic inflammatory disease following pharyngeal infection with Group A beta-hemolytic Streptococcus pyogenes. It is caused by molecular mimicry - antibodies formed against streptococcal antigens (M protein) cross-react with cardiac proteins (specifically the valve endothelium and myocardium). This is a Type II hypersensitivity reaction.
Rheumatic Fever - Jones Criteria:
  • Major: Carditis, polyarthritis, chorea (Sydenham's), erythema marginatum, subcutaneous nodules
  • Minor: Fever, elevated ESR/CRP, prolonged PR interval
  • Diagnosis requires: 2 major, or 1 major + 2 minor + evidence of prior streptococcal infection
Cardiac pathology (pancarditis):
  • Pericarditis: Fibrinous "bread and butter" pericarditis
  • Myocarditis: Aschoff bodies - pathognomonic granulomatous lesions containing Anitschkow cells (caterpillar cells with owl-eye nuclei) and Aschoff giant cells
  • Endocarditis: Warty vegetations along the line of valve closure (especially mitral valve). Repeated attacks cause valve thickening, fusion of commissures, and fibrosis.
Chronic Rheumatic Heart Disease: The most common outcome is mitral stenosis (due to repeated episodes causing leaflet thickening, commissural fusion, chordal shortening - "fish-mouth" or "buttonhole" appearance). Can also cause mitral regurgitation, aortic stenosis/regurgitation. Complications: atrial fibrillation, left atrial thrombus, pulmonary hypertension.

Vascular Diseases

Atherosclerosis
Atherosclerosis is a chronic inflammatory disease of the intima of large and medium arteries characterized by the formation of atheromatous plaques (atheromas). It is the leading cause of cardiovascular morbidity and mortality worldwide.
Risk factors: Major modifiable: hypertension, dyslipidemia (elevated LDL, low HDL), smoking, diabetes mellitus. Non-modifiable: age, male sex, family history.
Pathogenesis (Response-to-Injury hypothesis):
  1. Endothelial injury/dysfunction: Due to hypertension, smoking, dyslipidemia, toxins. Results in increased permeability, leukocyte adhesion, and altered gene expression.
  2. Lipoprotein accumulation: LDL enters the intima and undergoes oxidation. Oxidized LDL is inflammatory and chemotactic.
  3. Monocyte recruitment: Monocytes adhere to dysfunctional endothelium (via VCAM-1, ICAM-1, selectins), migrate into the intima, and differentiate into macrophages.
  4. Foam cell formation: Macrophages engulf oxidized LDL via scavenger receptors, becoming lipid-laden "foam cells." Foam cells aggregate to form the fatty streak - the earliest visible lesion.
  5. Smooth muscle migration: Growth factors (PDGF from platelets and macrophages) stimulate smooth muscle cell migration from the media to the intima, where they proliferate and produce extracellular matrix.
  6. Plaque formation: The fibrous plaque has a fibrous cap (smooth muscle cells, collagen, foam cells) overlying a necrotic lipid core (extracellular lipid, cholesterol crystals, dead cells).
Complications of plaques:
  • Stable angina: Plaques reducing lumen by >70% during exertion
  • Plaque rupture/fissuring: Most dangerous complication. Exposes the thrombogenic lipid core, triggering platelet aggregation and thrombosis - cause of acute coronary syndromes
  • Ulceration and thromboembolism
  • Calcification
  • Aneurysm formation (in aorta)
Histology: Earliest lesion - fatty streak (lipid-laden foam cells in intima). Mature plaque - fibrous cap + lipid core + calcification.
Monckeberg's Medial Calcification (Medial Sclerosis)
Monckeberg's arteriosclerosis is characterized by calcification of the tunica media of muscular arteries, without narrowing of the lumen and without inflammatory reaction. It commonly affects the femoral, tibial, radial, and ulnar arteries.
It is distinct from atherosclerosis (which affects the intima with plaque formation and causes luminal narrowing) and hyaline arteriosclerosis (associated with hypertension/diabetes, affecting arterioles).
Features:
  • Affects medium-sized muscular arteries
  • Calcification is in the media (smooth muscle layer) - produces "pipestem" or "eggshell" calcification on X-ray
  • Does NOT narrow the lumen initially; therefore does NOT cause ischemia by itself
  • Commonly seen in elderly patients and those with diabetes mellitus and chronic kidney disease
  • Often found as an incidental X-ray finding ("railroad track" calcification in leg vessels)
  • Elevates ABI (ankle-brachial index) falsely, making peripheral vascular disease assessment difficult

Ischemic Heart Disease (IHD)

Myocardial Infarction (MI)
MI is coagulative necrosis of the myocardium due to prolonged ischemia, almost always caused by rupture of an atherosclerotic plaque with superimposed thrombosis.
Classification:
  • STEMI (ST-elevation MI): Total occlusion; transmural infarction typical
  • NSTEMI (Non-ST-elevation MI): Partial occlusion; subendocardial infarction typical
  • Transmural MI: Full thickness of ventricular wall; associated with Q waves on ECG
  • Subendocardial MI: Inner 1/3 to 1/2 of ventricular wall (most vulnerable zone - farthest from epicardial supply)
Most common site: Left anterior descending artery (LAD) occlusion → anterior wall + interventricular septum (most common, ~40-50%). Right coronary artery → inferior/posterior wall. Left circumflex → lateral wall.
Sequence of pathological changes:
TimeGross ChangesMicroscopic Changes
0-6 hoursNil visibleNil (electron microscopy: wavy fibers, contraction bands)
6-12 hoursSubtle pallorEarly coagulative necrosis, edema
12-24 hoursPale/mottledCoagulative necrosis, neutrophil infiltration begins
1-3 daysPale yellowProminent neutrophils, pyknosis, karyolysis
3-7 daysYellow, softMacrophage infiltration begins, myocyte "ghosts"
1-2 weeksHyperemic rim, yellow centerGranulation tissue (macrophages, fibroblasts, new vessels)
2-8 weeksGray-white scarProgressive fibrosis
>2 monthsDense white scarDense collagen scar
Biochemical markers:
  • Troponin I and T: Most sensitive and specific; rise at 4-6 hours, peak 24-48 hours, remain elevated 7-14 days. Gold standard.
  • CK-MB: Rises 4-8 hours, peaks at 24 hours, returns to normal by 48-72 hours - useful for detecting reinfarction.
  • LDH (LDH1 > LDH2): Rises late (24-48 hrs), remains elevated 7-10 days - historically used for late presentation.
  • Myoglobin: First to rise (1-4 hrs) but not cardiac-specific.
Complications:
  • Arrhythmias (first 24 hours, most common cause of early death - ventricular fibrillation)
  • Cardiogenic shock (large infarction, >40% of LV)
  • Left ventricular failure / pulmonary edema
  • Cardiac rupture (day 3-7 when necrosis is maximal and before scar formation): Free wall rupture (hemopericardium, tamponade), VSD, papillary muscle rupture (acute mitral regurgitation)
  • Pericarditis (fibrinous, days 2-3)
  • Mural thrombus (on akinetic wall segments)
  • Ventricular aneurysm (late complication, weeks-months)
  • Dressler's syndrome (autoimmune pericarditis, 2-10 weeks post-MI)

TOPIC 9: HEPATOBILIARY PATHOLOGY - JAUNDICE

Definition: Jaundice (icterus) is yellow discoloration of skin, sclerae, and mucous membranes due to accumulation of bilirubin. It becomes clinically visible when serum bilirubin exceeds approximately 2-3 mg/dL (normal: 0.3-1.0 mg/dL total).

Bilirubin Metabolism (Normal)

Red blood cells are broken down by reticuloendothelial cells (spleen, liver, bone marrow). Haemoglobin → haem → biliverdin → unconjugated (indirect) bilirubin. Unconjugated bilirubin is:
  • Lipid-soluble, water-insoluble
  • Bound to albumin in plasma
  • NOT filtered by kidneys (not in urine)
  • Toxic to brain (kernicterus in neonates)
In the liver, hepatocytes take up unconjugated bilirubin (facilitated by ligandin/Y protein), conjugate it with glucuronic acid via UDP-glucuronosyltransferase (UGT) → conjugated (direct) bilirubin. Conjugated bilirubin is:
  • Water-soluble
  • Excreted into bile canaliculi
  • In gut, reduced by bacteria to urobilinogen → stercobilin (gives stool brown color); some urobilinogen reabsorbed (enterohepatic circulation) → excreted in urine as urobilin (gives urine yellow color).

Types/Classification of Jaundice

1. Pre-hepatic (Haemolytic) Jaundice
Cause: Excessive destruction of RBCs overwhelms the liver's ability to conjugate bilirubin. Bilirubin type: Predominantly unconjugated (indirect) hyperbilirubinaemia. Causes: Hereditary haemolytic anemias (sickle cell, spherocytosis, G6PD deficiency), immune haemolysis (transfusion reactions, autoimmune), malaria, severe infections. Lab findings: ↑ unconjugated bilirubin, normal LFTs (AST/ALT normal), ↑ urinary urobilinogen, NO bilirubinuria (no conjugated bilirubin in urine), ↑ stercobilinogen (dark stools), ↑ LDH, ↓ haptoglobin, peripheral blood smear shows features of haemolysis.
2. Hepatic (Hepatocellular) Jaundice
Cause: Liver cell damage impairs uptake, conjugation, and/or excretion of bilirubin. Bilirubin type: Mixed - both unconjugated and conjugated elevated. Causes: Viral hepatitis (A, B, C, E), alcoholic liver disease, cirrhosis, drug-induced liver injury (paracetamol, INH), sepsis, Wilson's disease, autoimmune hepatitis. Lab findings: ↑ both conjugated and unconjugated bilirubin, markedly elevated ALT/AST (hepatocellular pattern), ↑ urinary urobilinogen (early) but may decrease in severe disease, bilirubinuria present, PT prolonged.
Specific hepatocellular causes:
  • Gilbert's syndrome: Benign, autosomal recessive deficiency of UGT1A1; impaired conjugation; mild unconjugated hyperbilirubinaemia, aggravated by fasting/illness; no other liver abnormality.
  • Crigler-Najjar syndrome: Type I (complete UGT absence, severe - kernicterus, fatal without liver transplant); Type II (partial UGT deficiency, responds to phenobarbitone).
  • Dubin-Johnson syndrome / Rotor syndrome: Impaired excretion of conjugated bilirubin. Conjugated hyperbilirubinaemia. DJS shows black liver on gross; benign.
3. Post-hepatic (Obstructive/Cholestatic) Jaundice
Cause: Obstruction to bile flow at any level from bile canaliculi to the duodenum. Conjugated bilirubin regurgitates back into blood. Bilirubin type: Predominantly conjugated (direct) hyperbilirubinaemia.
Causes:
  • Intrahepatic cholestasis: primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), drug-induced (OCP, chlorpromazine), intrahepatic cholestasis of pregnancy
  • Extrahepatic obstruction: choledocholithiasis (gallstones in common bile duct), carcinoma of head of pancreas (most common malignant cause), cholangiocarcinoma, strictures, pancreatitis, enlarged lymph nodes at porta hepatis.
Lab findings: ↑ conjugated bilirubin (>50% of total), ↑ ALP and GGT (cholestatic markers), mildly elevated AST/ALT, dark urine (bilirubinuria), pale/clay-coloured stools (no stercobilin), NO urinary urobilinogen (no bile reaching gut), ↑ serum cholesterol and bile salts (pruritus).

Diagnostic Approach to Jaundice

  • History + clinical exam: Duration, associated symptoms (fever, pain, weight loss, dark urine, pale stools, pruritus), alcohol use, medications, travel, transfusions.
  • Urine: Bilirubin (present = conjugated hyperbilirubinaemia), urobilinogen.
  • LFTs: Bilirubin fractions (direct/indirect), AST, ALT, ALP, GGT, albumin, PT.
  • CBC + peripheral smear: Haemolytic workup if unconjugated jaundice.
  • Imaging: Ultrasound (first-line for obstruction - shows dilated bile ducts, gallstones, liver parenchyma), CT, MRCP (non-invasive bile duct evaluation), ERCP (diagnostic + therapeutic for biliary obstruction).
  • Liver biopsy: If hepatocellular cause not established.
  • Viral serology, autoimmune markers, ceruloplasmin as indicated.

TOPIC 10: MUSCULOSKELETAL SYSTEM

Osteomyelitis

Osteomyelitis is infection of bone, classified by cause, acuity, and clinical setting.
Acute Haematogenous Osteomyelitis
Most common in children (metaphysis of long bones - distal femur, proximal tibia, proximal humerus), because the blood supply in this region is sluggish (capillary loops near the growth plate). Most common organism: Staphylococcus aureus (in all age groups). In neonates: S. aureus, Group B Streptococcus. In sickle cell disease: Salmonella is classically associated.
Pathogenesis: Bacteremia seeds the bone metaphysis → acute suppurative (pus-forming) infection → Vascular thrombosis → Bone necrosis → Formation of sequestrum (necrotic bone separated from living bone) → Reactive new bone formation from periosteum (involucrum) → Pus may break through cortex into periosteum and soft tissue (subperiosteal abscess), or through skin (sinus tract).
Clinical features: Acute onset fever, local pain, swelling, redness, and tenderness over affected bone. Systemic sepsis in severe cases. Child refuses to use the limb.
Investigations: Raised WBC, ESR, CRP. Blood cultures (positive in ~50%). X-ray changes appear late (7-10 days) - periosteal reaction, lytic lesion. MRI is the gold standard for early diagnosis. Bone scan sensitive in early disease.
Treatment: Prolonged IV antibiotics (4-6 weeks); surgical drainage if abscess formed or no response to antibiotics.
Chronic Osteomyelitis
Develops from inadequately treated acute osteomyelitis, or de novo in debilitated/immunocompromised patients. Characterized by:
  • Sequestrum: Dead necrotic bone fragment (avascular, acts as a nidus for persistent infection)
  • Involucrum: Sheath of new periosteal bone surrounding the sequestrum
  • Cloaca: Opening in the involucrum through which pus drains
  • Sinus tract: Persistently discharging opening to skin surface
Chronic osteomyelitis is difficult to eradicate; requires surgical debridement (sequestrectomy) + prolonged antibiotics. Complications: pathological fracture, squamous cell carcinoma of sinus tract (Marjolin's ulcer), amyloidosis.
Tuberculous Osteomyelitis
Pathogenesis: Haematogenous spread of Mycobacterium tuberculosis to bone. Most commonly affects the spine (Pott's disease - >50% of skeletal TB), followed by hip and knee.
Spinal TB (Pott's disease): Typically affects the thoracic and lumbar vertebrae. Begins in the vertebral body at the disc margin. The disc space is destroyed early (unlike pyogenic osteomyelitis, where disc involvement is variable). "Cold abscess" (psoas abscess) - caseous pus tracks down along the psoas muscle sheath to the groin (psoas sign). Vertebral collapse can cause kyphosis ("Pott's kyphosis" / gibbus deformity). Spinal cord compression is a serious complication (Pott's paraplegia).
Histology: Caseating granulomas with Langhans giant cells, epithelioid cells, and central caseation. No pus (or very little).
Treatment: Standard anti-TB regimen (isoniazid, rifampicin, pyrazinamide, ethambutol x 2 months, then isoniazid + rifampicin x 4-7 months). Surgery for abscess, instability, or neurological compromise.
Mycetoma (Madura Foot)
Mycetoma is a chronic, slowly progressive, locally destructive granulomatous infection of the subcutaneous tissues and bone, characterized by a triad of: painless swelling, multiple sinus tracts, and discharge containing "grains" (compact colonies of the organism).
Causes:
  • Eumycetoma: True fungi (Madurella mycetomatis most common)
  • Actinomycetoma: Actinomycetes bacteria (Nocardia, Actinomadura, Streptomyces)
Pathology: Grains embedded in suppurative granulomatous inflammation. Progressive destruction of soft tissue and bone.
Treatment: Actinomycetoma responds well to long-term antibiotics/co-trimoxazole. Eumycetoma requires antifungal therapy (voriconazole, itraconazole) ± surgical debridement. Amputation in severe cases.

Metabolic Bone Diseases

Rickets / Osteomalacia
Rickets (children) and osteomalacia (adults) result from defective mineralization of newly formed osteoid, due to vitamin D deficiency (most common) or hypophosphataemia.
Causes: Dietary deficiency of vitamin D, inadequate sunlight exposure, malabsorption (coeliac disease, Crohn's, post-gastrectomy), chronic kidney disease (impaired 1-alpha-hydroxylation), liver disease (impaired 25-hydroxylation), hereditary forms (vitamin D-resistant rickets/X-linked hypophosphataemia).
Pathophysiology: Vitamin D → promotes calcium and phosphate absorption from gut + renal calcium reabsorption. Without vitamin D, serum calcium falls → secondary hyperparathyroidism → phosphaturia → hypophosphataemia → impaired bone mineralization. Osteoid accumulates unmineralized.
Rickets (children - before epiphyseal fusion):
  • Skeletal deformities: Bow legs (genu varum), knock knees (genu valgum), frontal bossing of skull, craniotabes (soft skull bones), rachitic rosary (beading of costochondral junctions), Harrison's sulcus (horizontal groove at diaphragm insertion), pigeon chest.
  • Widened, irregular, fraying of metaphyses on X-ray ("paintbrush" appearance); cupped, frayed growth plates; Looser's zones in severe cases.
  • Delayed fontanelle closure, delayed tooth eruption, muscle hypotonia.
Osteomalacia (adults):
  • Diffuse bone pain and tenderness, muscle weakness (proximal myopathy), pathological fractures.
  • Looser's zones (pseudofractures): Radiolucent bands perpendicular to cortex (at femoral neck, pubic rami, ribs) - pathognomonic of osteomalacia.
  • Lab: ↓ Ca²⁺, ↓ PO₄³⁻, ↑ ALP, ↑ PTH, ↓ 25-OH vitamin D.
Treatment: Vitamin D (ergocalciferol or cholecalciferol) + calcium supplementation; underlying cause addressed.
Osteoporosis
Osteoporosis is a metabolic bone disease defined as reduced bone mass (quantity) with normal mineralization (unlike osteomalacia), leading to increased fracture risk. Defined by WHO as bone mineral density (BMD) T-score ≤ -2.5.
Types:
  • Primary Type I (Postmenopausal): Estrogen deficiency → increased osteoclast activity → primarily trabecular bone loss → vertebral compression fractures and Colles' fractures.
  • Primary Type II (Senile): Age-related → affects both cortical and trabecular bone → femoral neck and vertebral fractures.
  • Secondary: Corticosteroid use (most common cause of secondary osteoporosis), hypogonadism, hyperparathyroidism, multiple myeloma, malabsorption, hyperthyroidism.
Pathophysiology: Imbalance between bone formation (osteoblasts) and bone resorption (osteoclasts) - net bone loss. Estrogen normally inhibits osteoclast activity; its loss accelerates resorption.
Histology: Thin, atrophied trabecular bone; wide resorption lacunae (Howship's lacunae); however, the bone that is present is normally mineralized (unlike osteomalacia).
Complications: Vertebral compression fractures (loss of height, kyphosis - "dowager's hump"), hip fractures (femoral neck - significant morbidity/mortality in elderly), Colles' fractures (distal radius).
Treatment: Calcium + Vitamin D supplementation; bisphosphonates (alendronate, risedronate - inhibit osteoclast activity); RANKL inhibitor (denosumab); HRT in postmenopausal women; weight-bearing exercise.
Hyperparathyroidism (Osteitis Fibrosa Cystica)
Excess PTH causes:
  • Increased osteoclast activity → bone resorption
  • Subperiosteal bone resorption (most specific radiological finding - radial border of middle phalanx of 2nd finger)
  • Brown tumors: Foci of fibroblastic proliferation + hemosiderin-laden macrophages + osteoclast giant cells replacing resorbed bone. NOT true tumors; resolve with treatment.
  • "Salt and pepper" skull: Multiple small lytic lesions on skull X-ray.
  • Osteitis fibrosa cystica: Severe hyperparathyroidism causing widespread fibrous replacement of marrow + cystic spaces ("von Recklinghausen disease of bone" in primary hyperparathyroidism).
  • Soft tissue calcification (metastatic calcification), nephrolithiasis.
Paget's Disease of Bone (Osteitis Deformans)
A chronic disorder of bone remodeling characterized by disorganized and excessive bone turnover. Affects adults >50 years; common bones: skull, spine (L3-L5), pelvis, femur, tibia.
Pathogenesis: Uncertain; paramyxovirus involvement (measles, RSV) proposed. Characterized by 3 phases:
  1. Osteolytic phase: Excessive osteoclast activity destroying bone.
  2. Mixed phase: Simultaneous osteoclast and osteoblast activity.
  3. Osteosclerotic/burnt-out phase: Osteoblastic activity predominates → dense but structurally weak bone.
Histology (pathognomonic): "Mosaic pattern" / "jigsaw puzzle" pattern - irregular cement lines representing many cycles of resorption and redeposition, giving bone an irregular mosaic appearance.
Clinical features: Often asymptomatic (discovered incidentally by elevated ALP). When symptomatic: bone pain, deformity (bowing of tibia - "sabre tibia"), skull enlargement (hat size increases), deafness (8th nerve compression), pathological fractures. Skull involvement may cause cranial nerve palsies.
Labs: Markedly elevated serum ALP (reflects osteoblast activity); serum calcium and phosphate usually normal; elevated urinary hydroxyproline (reflects bone resorption).
Complication: Sarcomatous transformation (~1% of polyostotic Paget's) to osteosarcoma, fibrosarcoma, or chondrosarcoma - presents as sudden worsening of pain.
Treatment: Bisphosphonates (first-line); calcitonin. NSAIDs for pain.

Bone Tumors - Classification

Benign Bone Tumors:
  • Osteoma: Dense bone projection on membranous bones (skull, sinuses). Associated with Gardner syndrome (multiple osteomas + intestinal polyps + soft tissue tumors).
  • Osteoid osteoma: Young adults; long bones (femur, tibia); nocturnal pain relieved by aspirin; central nidus of osteoid surrounded by sclerotic bone.
  • Osteoblastoma: Similar to osteoid osteoma but larger (>2cm); spine; not relieved by aspirin.
  • Enchondroma: Cartilaginous tumor within medullary cavity; small bones of hand/foot.
  • Osteochondroma (exostosis): Most common benign bone tumor; bony projection with cartilaginous cap arising from metaphysis; stops growing at skeletal maturity.
  • Giant cell tumor (osteoclastoma): Benign but locally aggressive; epiphysis of long bones (distal femur, proximal tibia) in skeletally mature adults; "soap bubble" appearance on X-ray; contains osteoclast-like giant cells. Risk of malignant transformation (~1-2%).
Malignant Bone Tumors:
  • Osteosarcoma: Most common primary malignant bone tumor in young people (10-20 years); distal femur/proximal tibia metaphysis. "Sunburst" periosteal reaction + Codman's triangle (elevation of periosteum). Produces osteoid. Highly aggressive.
  • Chondrosarcoma: Malignant cartilaginous tumor; middle-aged/older adults; pelvis, femur, ribs. Slower-growing.
  • Ewing's sarcoma: Aggressive tumor of small, round cells; children/adolescents; diaphysis of long bones + flat bones. "Onion-skin" periosteal reaction on X-ray. t(11;22) translocation (EWS-FLI1 fusion). Small, round blue cell tumor.
  • Multiple myeloma: Most common primary malignant bone tumor overall (in adults >40 years); involves axial skeleton; "punched-out" lytic lesions; Bence-Jones protein; monoclonal gammopathy.
Metastatic Bone Disease: The most common malignant bone tumor overall. Breast, prostate, lung, kidney, and thyroid primaries most commonly metastasize to bone. Typical sites: vertebrae, ribs, pelvis, femur, skull. Breast and prostate = mixed lytic/blastic or blastic; lung, kidney, thyroid = lytic. Pathological fractures common.
Synovial Sarcoma: A malignant tumor arising from mesenchymal cells near (but not from) synovium, usually around large joints (knee most common) in young adults (15-40 years). NOT derived from synoviocytes despite the name. Contains characteristic biphasic pattern: epithelial-like glands surrounded by spindle cells. Cytogenetics: t(X;18) translocation (SYT-SSX fusion). Highly aggressive with high metastatic potential. Treatment: wide surgical excision + radiotherapy + chemotherapy.

Arthritis

Suppurative (Septic) Arthritis
Bacterial infection of a joint, usually via haematogenous spread. Most common organism: S. aureus (all ages). In sexually active young adults: Neisseria gonorrhoeae. In children: S. aureus, Streptococcus. Most commonly affects large joints (knee, hip, shoulder).
Pathology: Joint space fills with pus. Polymorphonuclear cells dominate synovial fluid. Cartilage destruction occurs rapidly due to proteolytic enzymes. If untreated, fibrous ankylosis or osteomyelitis follows.
Clinical features: Acute severe joint pain, swelling, redness, heat. Patient refuses to move the joint (guarding). Fever, leukocytosis. Joint aspiration: turbid fluid, WBC >50,000/mm³ (>90% neutrophils), positive Gram stain and culture, low glucose, high LDH.
Treatment: Emergency joint drainage (aspiration or arthroscopic washout) + IV antibiotics. Delay causes permanent joint damage.
Rheumatoid Arthritis (RA)
A chronic, systemic, autoimmune inflammatory disease predominantly affecting the synovial joints. Peak onset: 35-55 years, female predominance (3:1).
Pathogenesis: Autoimmune attack on synovium triggered by unknown antigen in genetically susceptible individuals (HLA-DR4/DR1 association). CD4+ T cells activate macrophages and B cells → release of cytokines (TNF-α, IL-1, IL-6) → chronic synovitis → pannus formation → cartilage and bone destruction.
Pathology:
  • Synovitis: Synovium becomes hyperplastic and inflamed; villous hypertrophy.
  • Pannus: Granulation tissue (activated synoviocytes, inflammatory cells, fibroblasts) that grows over and erodes cartilage and subchondral bone.
  • Subluxation and deformity: Destruction of supporting structures.
  • Rheumatoid nodules: Subcutaneous nodules with central fibrinoid necrosis surrounded by palisading macrophages (histiocytes) - found in ~20-30% over pressure points.
Clinical features: Symmetric, deforming polyarthritis. Hands: MCP and PIP involvement (DIP spared), ulnar deviation, swan-neck deformity (PIP hyperextension + DIP flexion), Boutonniere deformity (PIP flexion + DIP hyperextension), Z-thumb deformity. Morning stiffness >1 hour. Systemic: fever, malaise, weight loss. Extra-articular: rheumatoid nodules, episcleritis, pleural effusion, interstitial lung disease, vasculitis, Felty syndrome (RA + splenomegaly + neutropenia).
Labs: Rheumatoid factor (RF) positive in ~70-80% (IgM anti-IgG). Anti-CCP (anti-cyclic citrullinated peptide) antibody - more specific. Elevated ESR, CRP.
Treatment: NSAIDs, corticosteroids (short-term), DMARDs (methotrexate first-line), biologics (anti-TNF: etanercept, infliximab, adalimumab; anti-IL-6: tocilizumab; rituximab).
Osteoarthritis (OA, Degenerative Joint Disease)
The most common joint disease; a non-inflammatory (primarily mechanical/degenerative) arthritis due to degradation of cartilage.
Risk factors: Age (most important), obesity, repetitive joint stress, previous injury, female sex (after menopause), genetic predisposition.
Pathology:
  • Progressive erosion and fragmentation of articular cartilage
  • Cartilage becomes irregular, fibrillated, and ulcerated down to bone
  • Subchondral sclerosis (eburnation - polished, ivory-like bone)
  • Osteophytes (spurs of new bone at joint margins from fibrocartilage metaplasia)
  • Subchondral cysts (synovial fluid forced into subchondral bone through cartilage defects)
  • Synovial membrane shows mild secondary inflammation only
Clinical features: Deep aching pain worsened by use, relieved by rest (opposite of RA). Morning stiffness <30 minutes. No significant systemic symptoms. Weight-bearing joints most affected: knees, hips, lumbar/cervical spine. Hands: DIP joints (Heberden's nodes = osteophytes at DIP), PIP joints (Bouchard's nodes). Joint line tenderness, crepitus, bony enlargement.
X-ray: JOSS - Joint space narrowing, Osteophytes, Subchondral Sclerosis, Subchondral cysts.
Treatment: Weight loss, physiotherapy, analgesics (paracetamol, NSAIDs), intra-articular corticosteroids, joint replacement (arthroplasty) for severe disease.
Gout
Gout is a disorder of purine metabolism resulting in hyperuricaemia and deposition of monosodium urate (MSU) crystals in joints and soft tissues.
Pathophysiology: Uric acid is the end product of purine metabolism (via xanthine oxidase). Hyperuricaemia occurs due to: overproduction (high cell turnover - leukaemia, psoriasis, high-purine diet) or underexcretion (chronic kidney disease, diuretics - especially thiazides). MSU crystals precipitate in joints (usually at lower temperature of peripheral joints) → phagocytosed by neutrophils → release of lysosomal enzymes + IL-1β → intense acute inflammatory arthritis.
Clinical features:
  • Acute gout: Sudden onset of excruciating pain, swelling, redness, warmth. First MTP joint (big toe - podagra) most classic (>50%). Also knee, ankle. Precipitated by alcohol, rich foods, dehydration, diuretics, minor trauma.
  • Interval/intercritical gout: Asymptomatic between attacks.
  • Chronic tophaceous gout: Recurrent attacks → tophi (deposits of MSU crystals surrounded by giant cell reaction) in soft tissues (ear helix, olecranon bursa, Achilles tendon, joints, kidneys).
Histology: Needle-shaped, negatively birefringent crystals (yellow when parallel to slow ray of polarized light).
Lab: Synovial fluid analysis (gold standard): needle-shaped negatively birefringent MSU crystals under polarized light microscopy, WBC elevated. Serum uric acid elevated (though may be normal during acute attack).
Treatment: Acute: NSAIDs (first-line), colchicine, corticosteroids. Prevention: allopurinol (xanthine oxidase inhibitor), uricosuric agents (probenecid). Avoid precipitants.
Tuberculous Arthritis
Haematogenous or direct spread of TB to joints. Usually monoarticular. Most commonly affects large joints: hip (most common joint TB in India) and knee. Insidious onset. "Cold" (non-hot, non-red) joint with progressive pain and stiffness. X-ray shows Phemister's triad: juxta-articular osteoporosis, peripheral erosions, and gradual joint space narrowing (vs. septic arthritis which destroys rapidly; vs. RA which causes symmetric involvement). Synovial biopsy: caseating granulomas with Langhans giant cells. Treatment: anti-TB regimen ± surgery.

TOPIC 11: ENDOCRINE PATHOLOGY - NON-NEOPLASTIC THYROID LESIONS

Thyrotoxicosis (Hyperthyroidism)

Thyrotoxicosis is the clinical syndrome resulting from excess thyroid hormone (T3/T4) acting on peripheral tissues. Hyperthyroidism specifically refers to overproduction of thyroid hormone by the thyroid gland.
Causes:
  • Graves' disease (most common cause overall, 70-80%): Autoimmune - IgG autoantibodies (TSI - thyroid-stimulating immunoglobulins) bind and activate TSH receptors → continuous thyroid stimulation and growth.
  • Toxic multinodular goitre (Plummer's disease): Autonomous hyperfunction of multiple nodules.
  • Toxic adenoma (solitary toxic nodule): Single autonomous hyperfunctioning nodule.
  • Thyroiditis: Subacute (de Quervain's), postpartum thyroiditis - transient thyrotoxicosis due to release of preformed hormone from damaged thyroid.
  • Factitious thyrotoxicosis: Exogenous T4 ingestion.
  • TSH-secreting pituitary adenoma (rare).
  • Struma ovarii, choriocarcinoma (HCG-driven, rare).
Pathology of Graves' disease:
  • Diffusely enlarged, hyperemic thyroid gland.
  • Histology: Marked follicular cell hyperplasia; tall columnar cells; scanty, pale, vacuolated colloid with "scalloping" at periphery; lymphocytic infiltration in stroma; papillary infoldings.
Clinical features: Tachycardia, palpitations, atrial fibrillation, heat intolerance, excessive sweating, weight loss despite increased appetite, tremor, anxiety, irritability, diarrhea, proximal muscle weakness. Specific to Graves' disease: pretibial myxedema (thickening of skin of lower legs), exophthalmos/proptosis (due to retroorbital inflammation, glycosaminoglycan deposition, and muscle swelling - can occur independently of thyroid function), thyroid acropachy (periosteal new bone + finger clubbing).
Thyroid storm: Life-threatening exacerbation - hyperpyrexia, tachyarrhythmia, delirium, vomiting, diarrhea, cardiovascular collapse. Precipitated by surgery, infection, stress.
Investigations: ↓ TSH (suppressed), ↑ free T4/T3, positive anti-TSH receptor antibodies (Graves'), high radioiodine uptake (Graves'/toxic nodule) vs. low uptake (thyroiditis/factitious).
Treatment: Antithyroid drugs (carbimazole/methimazole, propylthiouracil); radioactive iodine (I-131); thyroidectomy. Beta-blockers for symptomatic control.

Myxedema (Hypothyroidism)

Myxedema is the clinical syndrome resulting from deficiency of thyroid hormone. "Myxedema" refers to the non-pitting edema from glycosaminoglycan accumulation in skin and other tissues characteristic of severe hypothyroidism.
Causes:
  • Hashimoto's thyroiditis (most common cause in iodine-sufficient areas): Autoimmune destruction of thyroid by cytotoxic T cells + anti-thyroid antibodies (anti-TPO, anti-thyroglobulin). Histology: lymphocytic infiltration, germinal center formation, Hürthle cell (oxyphilic) metaplasia, progressive follicle destruction and fibrosis.
  • Primary atrophic hypothyroidism (myxedema): End-stage autoimmune thyroiditis with a small, atrophied gland.
  • Iodine deficiency (most common worldwide cause of hypothyroidism/goitre).
  • Iatrogenic: Post-thyroidectomy, post-radioiodine, anti-thyroid drugs, amiodarone, lithium.
  • Congenital hypothyroidism (cretinism): Thyroid agenesis or dyshormonogenesis; presents in neonates. Untreated leads to irreversible intellectual disability and dwarfism.
  • Secondary/Central: TSH deficiency (pituitary disease) or TRH deficiency (hypothalamic disease).
Pathology of Hashimoto's:
  • Thyroid may initially be enlarged (goitre) then atrophies.
  • Histology: diffuse lymphocytic and plasma cell infiltration with germinal centre formation; Hürthle cell (oxyphilic/eosinophilic) metaplasia of follicular cells (characteristic); fibrosis.
Clinical features: Fatigue, lethargy, cold intolerance, weight gain, constipation, bradycardia, dry coarse skin, hair loss, hoarse voice (laryngeal myxedema), macroglossia, periorbital puffiness, ankle edema, carpal tunnel syndrome, menorrhagia in women, delayed relaxation of deep tendon reflexes (hung-up reflexes - hallmark sign), depression, cognitive slowing.
Myxedema coma: Extreme, life-threatening hypothyroidism - hypothermia, bradycardia, hypotension, hypoventilation, coma. Precipitated by cold, infection, or drugs (sedatives).
Investigations: ↑ TSH (in primary hypothyroidism), ↓ free T4, positive anti-TPO and anti-thyroglobulin antibodies (Hashimoto's), hyperlipidaemia, elevated CK, anaemia.
Treatment: Levothyroxine (T4) replacement. Start low, increase gradually. Myxedema coma: IV T3/T4, corticosteroids (often co-existent adrenal insufficiency).

TOPIC 12: NEUROPATHOLOGY - INFLAMMATIONS AND INFECTIONS

Meningitis

Meningitis is inflammation of the meninges (arachnoid and pia mater - leptomeningitis). Classified by:
  • Causative agent: Bacterial (pyogenic), viral (aseptic), tuberculous, fungal
  • CSF analysis: Critical for diagnosis (obtained by lumbar puncture)
FeaturePyogenicTuberculousViral
AppearanceTurbid/purulentClear/fibrinous (cobweb)Clear
CellsPMN (>1000)Lymphocytes (100-500)Lymphocytes (<500)
ProteinMarkedly ↑Moderately ↑Mildly ↑
GlucoseVery ↓ (<45 mg/dL)LowNormal
OrganismsBacteria on Gram stainZN stain (paucibacillary)PCR
Tuberculous (TB) Meningitis
The most common CNS manifestation of extrapulmonary TB. Caused by Mycobacterium tuberculosis - haematogenous spread from a primary focus.
Pathogenesis: Small subependymal tuberculous foci (Rich foci) develop during haematogenous dissemination. Rupture of a Rich focus into the subarachnoid space → TB meningitis. More common in children and immunocompromised.
Pathology:
  • Thick gelatinous exudate predominantly at the base of the brain (basal meningitis) - characteristic feature.
  • Granulomatous inflammation: epithelioid cells, Langhans giant cells, caseation.
  • Arteritis (affects vessels in subarachnoid space) → thrombosis → infarction.
  • Communicating hydrocephalus (CSF flow obstruction by exudate at basal cisterns).
  • Cranial nerve palsies (especially CN III, IV, VI - from basal exudate).
Clinical features: Subacute/chronic onset over days-weeks. Fever, headache, neck stiffness (meningism), photophobia. Signs of raised intracranial pressure. Cranial nerve palsies. Altered consciousness.
CSF: Clear/xanthochromic, lymphocytic pleocytosis (100-500 cells), protein raised (100-500 mg/dL), glucose low (<45 mg/dL, CSF:serum glucose <0.5), ZN stain (positive in only ~30% - paucibacillary). ADA (adenosine deaminase) elevated. Culture gold standard but takes 6-8 weeks.
Treatment: Standard anti-TB regimen (2HRZE/10HR - longer than pulmonary TB). Dexamethasone adjunctive therapy reduces mortality and neurological complications.
Pyogenic (Bacterial) Meningitis
Acute suppurative inflammation of the meninges due to bacterial infection.
Common causative organisms (age-related):
  • Neonates: E. coli, Group B Streptococcus, Listeria monocytogenes
  • Children/young adults: Neisseria meningitidis (meningococcus) - most common cause of epidemic meningitis; associated with petechial/purpuric rash (meningococcaemia)
  • Adults: Streptococcus pneumoniae (pneumococcus) - most common in adults and elderly; associated with pneumonia, sinusitis, otitis media, CSF leak
  • Elderly/immunocompromised: Listeria monocytogenes
  • Post-trauma/post-surgical: Staphylococcus, Gram-negative organisms
Pathology:
  • Subarachnoid space filled with creamy-purulent exudate (PMNs, fibrin, bacteria).
  • Congestion and edema of brain.
  • Convexity of brain surface and cisterns involved (vs. TB meningitis which is predominantly basal).
  • Complications: Ventriculitis, cerebritis, subdural empyema, venous sinus thrombosis, obstructive hydrocephalus.
Clinical features: Rapid onset fever, severe headache, neck stiffness (Kernig's sign, Brudzinski's sign), photophobia, phonophobia. Petechial rash in meningococcal meningitis. Altered sensorium progressing to coma. In neonates: bulging fontanelle, poor feeding, seizures, high-pitched cry.
CSF: Turbid, markedly elevated neutrophilic pleocytosis (>1000 cells/mm³), protein markedly elevated, glucose very low, bacteria on Gram stain/culture.
Treatment: Medical emergency - empirical IV antibiotics immediately (ceftriaxone ± ampicillin ± dexamethasone). Do not delay treatment for imaging unless papilloedema/focal signs.
Viral (Aseptic) Meningitis
The most common form of meningitis overall. Usually self-limiting.
Common causes: Enteroviruses (most common - Echovirus, Coxsackievirus), Herpes simplex virus (HSV-2), mumps, HIV (seroconversion illness), EBV, VZV, CMV, arboviruses.
Pathology: Predominantly lymphocytic infiltration of meninges. Less exudate. Brain parenchyma relatively spared (unlike encephalitis).
Clinical features: Fever, headache, neck stiffness, photophobia, but generally less severe than bacterial meningitis. No altered consciousness (if altered - consider encephalitis). Generally self-resolving in 7-10 days.
CSF: Clear, lymphocytic pleocytosis (usually <500 cells/mm³), protein mildly elevated, glucose normal, no organisms on Gram stain.
Treatment: Supportive. Acyclovir for HSV meningitis/encephalitis.
Brain Abscess
A focal collection of pus within the brain parenchyma.
Etiology: Direct spread (from sinusitis, otitis media, mastoiditis - most common routes), haematogenous spread (from endocarditis, pulmonary infections, dental procedures), post-traumatic/post-surgical.
Location: Related to source - frontal lobe (frontal sinusitis), temporal lobe or cerebellum (otitis media/mastoiditis).
Common organisms: Polymicrobial (mixed streptococci, anaerobes, Bacteroides). Immunocompromised: Toxoplasma gondii (most common CNS lesion in HIV/AIDS), Aspergillus, Cryptococcus, Nocardia.
Pathology (stages):
  1. Early cerebritis: Focal area of cerebritis, edema, and necrosis with PMN infiltration (days 1-3).
  2. Late cerebritis: Central necrosis expands; lymphocytes, macrophages appear; early vascular proliferation (days 4-9).
  3. Early capsule formation: Capsule of fibroblasts and granulation tissue forms around necrotic center (days 10-13).
  4. Late capsule: Well-formed thick fibrous capsule; the wall is thinner on the medial (ventricular) side → prone to rupture into ventricle.
Clinical features: Headache, focal neurological deficits, fever (may be absent or low-grade), seizures, signs of raised ICP.
MRI: Ring-enhancing lesion with surrounding edema. DWI: diffusion restriction within the pus (helps differentiate from necrotic tumor).
Treatment: IV antibiotics (ceftriaxone + metronidazole ± vancomycin) for 6-8 weeks. Surgical drainage for large accessible abscesses. Dexamethasone to reduce cerebral edema. Treat underlying source.
Neurocysticercosis
Infection of the CNS by the larval stage (cysticercus) of the tapeworm Taenia solium. The most common CNS parasitic infection and the most common cause of acquired epilepsy in the developing world.
Life cycle: Humans are the definitive host for T. solium (pork tapeworm). Cysticercosis occurs when humans accidentally ingest the eggs (from contaminated food/water/autoinfection in tapeworm carriers) → larvae hatch in gut → penetrate intestinal wall → disseminate haematogenously → settle in brain, muscle, subcutaneous tissue, eye.
CNS locations: Parenchymal (most common), intraventricular (most dangerous - obstructive hydrocephalus), subarachnoid (racemose form - most aggressive), spinal.
Pathology:
  • Vesicular stage (viable cyst): Scolex visible inside cyst; minimal host reaction; cyst fluid is clear.
  • Colloidal vesicular stage (degenerating): Scolex degenerates, cyst fluid becomes turbid; intense surrounding inflammation.
  • Granular nodular stage: Cyst shrinks; granulomatous reaction; fibrosis.
  • Calcified nodular stage: Calcified granuloma; no further inflammation.
Clinical features: Seizures (most common presentation). Headache, raised ICP (from hydrocephalus or edema). Focal neurological deficits. Symptoms appear when the cyst dies and triggers inflammation.
Investigations: CT/MRI showing ring-enhancing lesions, scolex ("hole with dot" sign - pathognomonic), calcifications, hydrocephalus. Serology (ELISA) for anticysticercal antibodies.
Treatment: Antiepileptics for seizures. Antiparasitic therapy with albendazole or praziquantel (with caution - treatment kills cysts, causing inflammatory response; pretreat with steroids). Dexamethasone for cerebral edema. VP shunt for hydrocephalus.

TOPIC 13: DERMATOPATHOLOGY - SKIN TUMORS

Squamous Cell Carcinoma (SCC) of Skin

SCC is a malignant tumor of keratinocytes (epidermal cells), the second most common skin cancer.
Risk factors: Prolonged UV radiation exposure (most important), fair skin (Fitzpatrick types I-II), HPV infection (especially HPV 16/18 for mucosal SCC), immunosuppression (organ transplant recipients have 65x higher risk), chronic ulcers (Marjolin's ulcer), radiation, chemicals (arsenic, tar), pre-existing lesions (Bowen's disease - SCC in situ, actinic keratosis, leukoplakia).
Precursor lesions:
  • Actinic (Solar) Keratosis: Pre-malignant lesion due to UV damage. Rough, scaly papules on sun-exposed skin. ~5-10% progress to SCC.
  • Bowen's Disease (SCC in situ): Full-thickness epidermal dysplasia that has not breached the basement membrane.
Pathology: Irregular nests and sheets of atypical squamous cells invading through the basement membrane into dermis and deeper structures. Well-differentiated SCC shows keratinization, keratin pearls (concentric whorls of squamous cells with central keratin), and intercellular bridges. Poorly differentiated SCC: pleomorphic cells, loss of squamous differentiation.
Clinical features: Indurated, scaly, ulcerated nodule/plaque on sun-exposed skin (face, dorsal hands, scalp). May arise in pre-existing actinic keratosis or chronic skin lesions. Bleeds easily.
Behaviour: Unlike BCC, SCC has significant metastatic potential (particularly lip and ear SCCs), usually to regional lymph nodes.
Treatment: Surgical excision (first-line), Mohs micrographic surgery (for high-risk areas), radiotherapy.

Basal Cell Carcinoma (BCC)

BCC is the most common skin cancer overall, arising from the basal layer of the epidermis (basal cells/hair follicle stem cells). Despite being "malignant," it is locally invasive but rarely metastasizes (<0.1%).
Risk factors: UV radiation (most important), fair skin, immunosuppression, nevoid BCC syndrome (Gorlin syndrome - multiple BCCs + jaw cysts + skeletal anomalies + calcified falx cerebri, due to PTCH1 mutation on Chr 9q).
Molecular basis: PTCH1 (patched) gene mutations → uncontrolled hedgehog signaling. UV-induced mutations in TP53.
Clinical types:
  • Nodular BCC (most common): Pearly, translucent papule/nodule with rolled telangiectatic borders and central ulceration ("rodent ulcer"). Face, especially nose and nasolabial fold.
  • Superficial BCC: Thin, erythematous plaques; trunk and limbs.
  • Morphoeic/sclerosing BCC: Firm, scar-like plaque; poorly defined margins; most aggressive subtype.
  • Pigmented BCC: May mimic melanoma.
Pathology: Basaloid cells in nests and lobules in the dermis with peripheral palisading (columnar arrangement of nuclei at the periphery of nests) and retraction artifact (cleft between tumor and stroma). No keratin pearls (distinguishes from SCC).
Treatment: Surgical excision (first-line), Mohs surgery for high-risk areas, topical imiquimod or 5-FU for superficial BCC, radiotherapy. Vismodegib (hedgehog pathway inhibitor) for advanced/metastatic BCC.

Melanoma (Brief Overview)

Melanoma is a malignant neoplasm of melanocytes (neural crest-derived pigment-producing cells). It accounts for <5% of skin cancers but causes the majority of skin cancer deaths due to its high metastatic potential.
Risk factors: UV radiation, fair skin, multiple naevi (especially dysplastic naevi), family history, personal history, immunosuppression. BRAF mutation (V600E) present in ~50% of cutaneous melanomas.
Types:
  • Superficial spreading melanoma (most common, ~70%): Radial growth phase before vertical invasion. Usually arises from pre-existing naevus.
  • Nodular melanoma (~15-30%): Immediate vertical growth; most aggressive; often amelanotic (lacks pigmentation); bluish-black nodule.
  • Lentigo maligna melanoma: In elderly, sun-damaged skin (face); slow radial growth over years.
  • Acral lentiginous melanoma: Palms, soles, subungual; most common type in dark-skinned individuals.
Pathology: Atypical melanocytes in nests and single units within the epidermis and dermis. Pagetoid spread (upward migration of melanocytes). Breslow thickness (vertical depth of invasion in mm) is the most important prognostic factor.
ABCDE rule for clinical recognition:
  • A - Asymmetry
  • B - Border irregularity
  • C - Colour variation (multiple shades)
  • D - Diameter >6mm
  • E - Evolving/changing over time
Treatment: Wide local excision (margin based on Breslow thickness), sentinel lymph node biopsy. Adjuvant therapy for advanced disease: BRAF inhibitors (vemurafenib, dabrafenib), MEK inhibitors, immune checkpoint inhibitors (pembrolizumab/anti-PD1, ipilimumab/anti-CTLA4).

TOPIC 14: CONGENITAL MYOPATHY & MYASTHENIA GRAVIS

Myasthenia Gravis (MG)

Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ) characterized by weakness and abnormal fatigability of skeletal muscles that worsens with activity and improves with rest. It is a postsynaptic disorder.
Pathogenesis: Autoantibodies (IgG) are formed against components of the postsynaptic NMJ:
  • Anti-AChR (acetylcholine receptor) antibodies (80-90% of generalized MG): Most common. Bind to AChR → complement-mediated destruction + internalization of receptors → reduced functional AChR at the motor end plate → impaired neuromuscular transmission.
  • Anti-MuSK (muscle-specific tyrosine kinase) antibodies (~5%): More prominent facial/bulbar weakness; negative for AChR antibodies.
  • Anti-LRP4 antibodies (~1-3%): Mild to moderate symptoms.
Thymus association:
  • Thymic hyperplasia (germinal center formation) in ~70% of AChR-positive MG patients - the thymus is thought to be the site of autosensitization.
  • Thymoma found in ~10% of MG patients; conversely, 30% of thymoma patients develop MG. Thymoma-related MG is almost always AChR-antibody positive.
Clinical features: Insidious onset of weakness and fatigability. Ptosis and diplopia occur in most patients (extraocular muscles affected earliest). Bulbar weakness: dysarthria, dysphagia, nasal regurgitation. Proximal limb weakness. Tendon reflexes and sensation are normal. "Fatigable weakness" - strength decreases with repeated testing.
Subtypes:
  • Ocular MG: Confined to extraocular/eyelid muscles in 15% of patients.
  • Generalized MG: Involves limb/bulbar/respiratory muscles.
  • Myasthenic crisis: Life-threatening respiratory failure requiring mechanical ventilation - precipitated by infection, surgery, medications (aminoglycosides, neuromuscular blockers, fluoroquinolones).
Diagnosis:
  • Edrophonium (Tensilon) test: Short-acting acetylcholinesterase inhibitor → brief improvement of ptosis/weakness - positive in MG.
  • Anti-AChR antibodies (serological diagnosis).
  • Electrophysiology: Repetitive nerve stimulation at 3 Hz → decremental response in compound muscle action potential (CMAP) - characteristic of MG.
  • Single fiber EMG (SF-EMG): Most sensitive test; shows increased "jitter" (variability in NMJ transmission time).
  • CT chest: to look for thymoma.
Treatment:
  • Symptomatic: Pyridostigmine (acetylcholinesterase inhibitor) - does not alter disease course but improves symptoms.
  • Immunomodulation: Plasma exchange (plasmapheresis) or IVIG - rapid short-term improvement (for crisis, pre-surgery).
  • Immunosuppression: Corticosteroids (first-line); azathioprine (steroid-sparing); mycophenolate mofetil, cyclosporine, methotrexate.
  • Thymectomy: Recommended for all thymomatous MG; also beneficial in non-thymomatous AChR-positive generalized MG (especially in patients <60 years).
  • Complement inhibitors: Eculizumab (anti-C5) for refractory AChR-positive MG.
(Source: Bradley and Daroff's Neurology in Clinical Practice)

Congenital Myopathies

Congenital myopathies are a heterogeneous group of inherited muscle disorders present from birth (or early infancy), characterized by structural abnormalities on muscle biopsy. They are distinct from muscular dystrophies (which show dystrophic changes - necrosis, regeneration, fibrosis) and metabolic myopathies.
General features: Onset at birth or early childhood. Generalized hypotonia ("floppy infant"), proximal > distal weakness, delayed motor milestones, respiratory muscle involvement, often non-progressive or slowly progressive. Creatine kinase levels may be normal or mildly elevated. EMG: myopathic pattern.
Major Types (by histological findings):
1. Central Core Disease (CCD)
  • Most common congenital myopathy.
  • Gene: RYR1 (ryanodine receptor gene) - autosomal dominant.
  • Histology: "Central cores" (areas devoid of mitochondria and oxidative enzyme activity) running longitudinally in the center of type I muscle fibers.
  • Clinical: Mild proximal weakness, hypotonia, delayed motor milestones, hip dislocation. Associated with malignant hyperthermia susceptibility (also RYR1 mutation).
2. Nemaline (Rod) Myopathy
  • Gene: NEB (nebulin), ACTA1 (skeletal muscle alpha-actin), and others.
  • Histology: Nemaline rods (accumulations of Z-disc material containing alpha-actinin) in muscle fibers, demonstrated by Gomori trichrome stain (rods appear red/purple).
  • Clinical: Variable severity - severe neonatal form (severe hypotonia, respiratory failure, death) to mild adult-onset. Facial, bulbar, and respiratory muscles commonly involved.
3. Centronuclear (Myotubular) Myopathy
  • Gene: MTM1 (X-linked myotubular myopathy, severe, males), DNM2, BIN1 (autosomal forms).
  • Histology: Central nuclei in the majority of muscle fibers (resembling fetal myotubes); small type I fibers.
  • Clinical: X-linked form: severe neonatal hypotonia, respiratory failure, ophthalmoplegia. Autosomal forms: milder, adult-onset.
4. Multicore (Minicore) Disease
  • Gene: SEPN1 (selenoprotein N), RYR1.
  • Histology: Multiple small, poorly demarcated cores in muscle fibers (shorter than central cores in CCD).
Diagnosis of Congenital Myopathies:
  • Muscle biopsy: Key investigation - histochemistry (ATPase, NADH-TR, Gomori trichrome) identifies specific structural abnormalities.
  • Genetic testing: Confirms the specific gene mutation.
  • EMG, nerve conduction studies: Myopathic pattern.
  • CK: Often normal or mildly elevated (unlike dystrophies where CK is very high).
Management: No disease-modifying therapy exists for most types. Supportive: physiotherapy, respiratory support (non-invasive ventilation/CPAP), nutritional support, orthopaedic management of scoliosis/hip dislocation. Genetic counselling.
Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease; Bradley and Daroff's Neurology in Clinical Practice; Goldman-Cecil Medicine International Edition; Pye's Surgical Handicraft 22nd Edition.
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