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General Pathological Anatomy - Comprehensive Study Guide

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1. Circulatory Disorders - Classification. Plethora (Hyperemia). Arterial Plethora.

Classification of Circulatory Disorders

1. Hyperemia (arterial and venous)
2. Ischemia
3. Bleeding/hemorrhage
4. Stasis
5. Thrombosis
6. Embolism
7. Infarction
8. Shock
9. Edema

Hyperemia (Plethora) - General

Arterial Hyperemia (Active Hyperemia)

• Physiological: Working skeletal muscle, skin flushing, post-meal splanchnic engorgement, blush response
• Pathological: Sites of acute inflammation (due to mediators - histamine, prostaglandins causing arteriolar dilation)
• Reactive hyperemia: Hyperemia following a period of ischemia (post-ischemic reperfusion)
• Collateral hyperemia: Develops when a main artery is obstructed and collateral vessels dilate

• Affected tissues are bright red (erythema) due to increased delivery of oxygenated blood
• Microscopically: dilated arterioles and capillaries, engorged with red cells
• Tissue is warm to touch (increased blood flow)

• Usually beneficial - increases oxygen and nutrient delivery
• In inflammation, supports healing
• In pathological conditions (e.g., severe reactive hyperemia), may contribute to reperfusion injury through free radical generation

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2. Venous Hyperemia (Passive Congestion)

General Characteristics

Classification

• Systemic (general) vs. Local
• Acute vs. Chronic
• Systemic: cardiac failure (affects both pulmonary and systemic circulations)
• Local: isolated venous obstruction (e.g., DVT, portal hypertension)

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Venous Congestion in the Pulmonary (Small) Circulation

• Acute: Engorged alveolar capillaries; alveolar septal edema; focal intraalveolar hemorrhage
• Chronic:
  • Septal thickening and fibrosis
  • Alveoli contain hemosiderin-laden macrophages ("heart failure cells") derived from phagocytosed extravasated RBCs
  • Brown induration of the lung (gross appearance - stiff, brown lungs)
  • Diagnosed by Prussian blue stain for hemosiderin

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Venous Congestion in the Systemic (Large) Circulation

• Acute: Central veins and sinusoids distended; centrilobular hepatocytes may undergo ischemic necrosis (most distal from hepatic arterioles); periportal hepatocytes better oxygenated → only develop fatty change
• Chronic:
  • Gross: "Nutmeg liver" - centrilobular regions appear red-brown (congested) and depressed, surrounded by yellow-tan periportal zones (fatty change)
  • Micro: centrilobular congestion, hemorrhage, hemosiderin-laden macrophages, hepatocyte dropout and necrosis
  • Long-standing: cardiac cirrhosis (centrilobular fibrosis)

• Enlarged, tense, dark red
• Microscopically: dilated sinusoids, possible hemorrhagic infarcts

• Edema, stasis dermatitis, venous ulcers in chronic cases

• Edema (increased hydrostatic pressure)
• Ischemic injury and scarring
• Hemorrhagic foci from capillary rupture → hemosiderin deposits
• Fibrosis (cardiac cirrhosis in liver, brown induration in lung)

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Portal Hypertension (Venous Congestion in the Portal System)

1. Prehepatic: Portal vein thrombosis, splenomegaly
2. Intrahepatic (most common): Cirrhosis (alcohol, viral hepatitis, NASH) → regenerative nodules + fibrosis compress intrahepatic veins → increased resistance
3. Posthepatic: Budd-Chiari syndrome (hepatic vein occlusion), right heart failure

• Ascites: Increased hydrostatic pressure in portal capillaries + hypoalbuminemia (cirrhosis) + aldosterone excess → fluid accumulation in peritoneal cavity
• Esophageal and gastric varices: Portosystemic anastomoses dilate (left gastric vein → esophageal veins); risk of catastrophic hemorrhage
• Caput medusae: Dilated periumbilical veins (via paraumbilical veins)
• Hemorrhoids: Inferior mesenteric vein → superior hemorrhoidal plexus
• Splenomegaly (congestive): Can lead to hypersplenism (pancytopenia)
• Hepatic encephalopathy: Due to shunting of portal blood (ammonia) past liver

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3. Ischemia

• Arterial obstruction: atherosclerosis, thrombosis, embolism, vasospasm
• Hypotension/shock
• Venous outflow obstruction (venous ischemia)
• Reduced oxygen-carrying capacity (anemia, CO poisoning)

• Reduced oxygen → shift to anaerobic glycolysis → lactic acidosis, ATP depletion
• ATP depletion → failure of Na+/K+-ATPase → cellular swelling
• Calcium influx → activation of phospholipases, endonucleases, proteases
• Mitochondrial dysfunction → free radical generation (especially on reperfusion)
• If prolonged: irreversible injury → necrosis

• Gross: Pallor, swelling; later infarction (pale/red)
• Micro (early): Cytoplasmic eosinophilia, nuclear pyknosis, karyolysis, karyorrhexis; cell swelling
• Diagnostic methods: EM (mitochondrial swelling, membrane damage); immunohistochemistry (troponin in myocardium); LDH/AST/ALT enzymes in blood; TUNEL stain for DNA fragmentation

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4. Bleeding and Hemorrhage

• Petechiae: Minute (1-2 mm) hemorrhages in skin/mucosa/serosal surfaces
• Purpura: Slightly larger (3 mm or more) hemorrhages
• Ecchymoses: Larger (1-2 cm) subcutaneous hematomas ("bruises"); color changes: red/blue → green (biliverdin) → yellow (bilirubin) → golden-brown (hemosiderin)
• Hematoma: Accumulation of blood in a tissue space
• Hemothorax, hemopericardium, hemoperitoneum, hemarthrosis: Blood in body cavities

1. Vessel wall rupture (hemorrhage per rhexin): Trauma, aneurysm rupture, erosion by tumor/inflammation
2. Diapedesis (hemorrhage per diapedesin): RBCs pass through intact vessel walls in severe congestion, inflammation, or vasculitis
3. Defects in primary hemostasis: Thrombocytopenia, platelet dysfunction, von Willebrand disease
4. Defects in secondary hemostasis: Coagulation factor deficiencies (hemophilias), anticoagulant drugs, DIC
5. Fragile vessels: Scurvy (collagen deficiency), amyloid, vasculitis

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5. Stasis

• Microthrombus formation: Slow flow allows coagulation factors to concentrate and platelets to aggregate
• Rouleaux formation: RBCs stack together, further impeding flow
• Hypoxic injury: Reduced oxygen delivery to tissues
• Leukocyte margination: White cells line up along vessel walls (important in inflammation)
• Viscosity increase: Polycythemia, dehydration, hyperviscosity syndromes
• Venous stasis: Promotes DVT (component of Virchow's triad)

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6. Thrombosis

Local and General Factors (Virchow's Triad)

Thrombus - Types and Morphological Characteristics

• Lines of Zahn: Alternating pale layers (platelets + fibrin) and dark layers (RBCs) - pathognomonic of antemortem thrombus; helps distinguish from postmortem clot
• Red (coagulation) thrombus: Forms in slow flow; rich in RBCs and fibrin
• White (platelet) thrombus: Forms in fast flow (arteries); pale, firm, adherent
• Mixed thrombus: Most common; has head (white, adherent), body (mixed), and tail (red, loosely attached)

• Mural thrombus: In heart chambers or aorta (on wall, non-occlusive)
• Occlusive thrombus: Completely fills vessel lumen (common in veins)
• Vegetations: On cardiac valves (infective endocarditis, non-bacterial thrombotic endocarditis)

Venous Thrombosis

• Most common site: deep veins of lower extremities (DVT) - popliteal, femoral, iliac veins
• Causes: stasis (immobilization, cardiac failure), hypercoagulable states, vessel injury
• Risk: pulmonary embolism (PE)
• Often occlusive, red/dark, may extend proximally

Arterial Thrombosis

• Usually at sites of atherosclerotic plaque disruption (turbulent flow, endothelial injury)
• Common in coronary, cerebral, and femoral arteries
• White/mixed; may be occlusive → acute MI, stroke, limb ischemia

Cardiac Thrombosis

• Atrial: Atrial fibrillation → stasis → clot in left atrial appendage → systemic emboli (stroke)
• Ventricular: Post-MI mural thrombus; akinetic wall segment → stasis
• Valvular: Endocarditis vegetations; non-bacterial thrombotic endocarditis (marantic) in debilitated patients

Outcomes of Thrombosis

1. Resolution/lysis: Fibrinolytic system dissolves small thrombi
2. Organization and recanalization: Fibroblasts and capillaries grow into thrombus; new channels form restoring partial flow (weeks)
3. Propagation: Thrombus enlarges
4. Embolization: Fragment detaches → embolus
5. Calcification: "Phleboliths" (venous calcified thrombi)

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7. Embolism

Types

1. Thromboembolism (most common - >95% of emboli)
2. Fat embolism
3. Air/gas embolism
4. Amniotic fluid embolism
5. Tumor embolism
6. Cholesterol embolism (atherosclerotic)
7. Bone marrow embolism
8. Septic embolism (infected thrombus fragments)

Pulmonary Embolism (PE)

• Over 95% originate from DVT proximal to the popliteal fossa
• Fragments travel through right heart → pulmonary arteries

• 60-80%: Small, clinically silent; undergo organization → incorporated into vessel wall (bridging fibrous webs)
• Large (saddle embolus): Sudden death, acute right heart failure (cor pulmonale), or cardiovascular collapse when >60% of pulmonary circulation is occluded
• Medium: Usually do NOT cause infarction (dual supply: pulmonary + bronchial arteries); but if bronchial circulation is compromised (left heart failure), pulmonary hemorrhage or infarction occurs
• Small end-arteriolar: Hemorrhage or infarction in periphery
• Recurrent/multiple: Pulmonary hypertension + right ventricular failure

Acute Pulmonary Heart Disease (Acute Cor Pulmonale)

• Sudden obstruction of major pulmonary arteries → acute rise in pulmonary vascular resistance → acute right ventricular dilation and failure
• ECG: S1Q3T3, right axis deviation, right bundle branch block
• Can be immediately fatal

Thromboembolic Syndrome

• Pattern of recurrent thromboemboli in the context of hypercoagulable states (Virchow's triad)
• DVT + PE is the classic presentation
• Associated with: immobility, surgery, malignancy (Trousseau syndrome - migratory thrombophlebitis), pregnancy, oral contraceptives, hereditary thrombophilias
• Morphologically: organizing thrombi in vessels at different stages; pulmonary hypertension in recurrent PE; potential for paradoxical embolism through patent foramen ovale

Other Emboli

• Fat embolism: After long bone fractures or soft tissue trauma; fat globules in vasculature. Fat embolism syndrome: pulmonary insufficiency, neurologic symptoms, anemia, thrombocytopenia, petechial rash; onset 1-3 days post-injury
• Air embolism: Iatrogenic (IV lines), decompression sickness (nitrogen bubbles); >100 mL air can cause fatal cardiac dysfunction; treat with hyperbaric oxygen
• Amniotic fluid embolism: Entry of amniotic fluid into maternal circulation during delivery; fetal squames and mucin in pulmonary vessels; presents as sudden dyspnea, cyanosis, DIC

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8. Shock

Types and Mechanisms

Stages of Shock

1. Compensated (non-progressive) stage: Reflex mechanisms maintain perfusion (catecholamines, renin-angiotensin, ADH); tachycardia, peripheral vasoconstriction, oliguria
2. Progressive (decompensated) stage: Perfusion falls despite compensation; metabolic acidosis, lactic acidosis; widespread cellular injury; may worsen tissue injury through reperfusion
3. Irreversible stage: Irreversible cell/organ damage; multi-organ dysfunction syndrome (MODS); death

Morphological Characteristics (in various organs)

• Brain: Hypoxic encephalopathy; "watershed" (boundary zone) infarcts
• Heart: Subendocardial hemorrhagic necrosis; coagulative necrosis (ischemic necrosis)
• Kidney: Acute tubular necrosis (ATN) - patchy tubular epithelial necrosis; shock kidney
• Adrenals: Lipid depletion from cortex (adrenal exhaustion)
• Liver: Central hemorrhagic necrosis; "shock liver"
• GI tract: Hemorrhagic/ischemic enteropathy; mucosal ulcers
• Lungs: Diffuse alveolar damage (ARDS - adult respiratory distress syndrome): hyaline membrane formation, interstitial and alveolar edema

Septic Shock Pathogenesis

• Bacterial components (LPS/endotoxin, peptidoglycan, lipoteichoic acid) activate macrophages and endothelium via TLRs
• Massive cytokine release (TNF, IL-1, IL-6, IL-12)
• Endothelial activation → coagulopathy (DIC), increased vascular permeability, vasodilation
• iNOS upregulation → nitric oxide → profound vasodilation

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9. Dystrophy - Definition, Mechanisms, Classification

Mechanisms of Development

1. Infiltration: Accumulation of substances from blood/extracellular space into cells
2. Perversion (perverse synthesis): Abnormal substances produced within cells
3. Transformation: Normal metabolites converted into abnormal products
4. Decomposition (phanerosis): Breakdown of normal organelle-associated lipoproteins releasing visible lipid or protein droplets

Classification

• Protein dystrophies (dysproteinoses)
• Lipid dystrophies (lipidoses)
• Carbohydrate dystrophies
• Mineral dystrophies (calcification, gout)

• Parenchymatous (intracellular): In parenchymal cells of organs
• Stromal-vascular (extracellular/mesenchymal): In connective tissue stroma and vessel walls
• Mixed

• General (systemic)
• Local (focal)

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10. Parenchymatous Protein Dystrophies (Dysproteinoses)

Types

• Most common; reversible
• Cause: any cellular injury (hypoxia, toxins, fever, infections)
• Pathogenesis: cell membrane injury → Na+ influx → cellular swelling; ER swells; protein denaturation
• Gross: organs enlarged, pale, dull, "boiled" appearance; tissue crumbles on cutting
• Micro: cytoplasm filled with fine eosinophilic granules (swollen mitochondria and dilated ER); nuclear changes minimal
• Outcome: reversible if cause removed

• More severe; may be irreversible
• Cause: hypoxia, viral infections (hepatitis), hypokalemia, toxic damage
• Pathogenesis: severe Na+/K+-ATPase failure → massive water influx → large cytoplasmic vacuoles
• Gross: enlarged, pale, flabby organs
• Micro: large clear cytoplasmic vacuoles ("balloon cells"); nucleus pushed to periphery
• Outcome: can progress to coagulative necrosis

• Protein droplets appear as eosinophilic, homogeneous intracellular inclusions
• Seen in: renal tubular cells (reabsorption of proteins - nephrotic syndrome); liver cells (Mallory-Denk bodies in alcoholic hepatitis - aggregates of keratin intermediate filaments)
• Diagnostic: PAS stain (pink droplets in tubular cells); hematoxylin-eosin shows bright pink droplets
• Outcome: cell death if severe

• Accumulation of keratinous material in epithelium

• H&E staining (eosinophilic granules/droplets)
• PAS stain (glycoproteins)
• Oil Red O/Sudan III (excludes lipid)
• Electron microscopy (ultrastructural changes)

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11. Stromal-Vascular Dysproteinoses

Stages of Stromal Disorganization (Connective Tissue Disorganization)

• Ground substance imbibes water → reversible; collagen fibers spread apart
• Metachromasia with toluidine blue (accumulation of glycosaminoglycans)
• Seen early in rheumatic diseases, hypertension

• Collagen fibers undergo fibrinoid transformation (lose cross-striations, become homogeneous, deeply eosinophilic, resembling fibrin)
• Fibrinogen + gamma-globulins infiltrate from plasma
• MSB stain (Masson): fibrinoid stains red; PAS-positive
• Irreversible; progression from mucoid swelling

• Complete destruction of collagen architecture; necrosis of connective tissue cells
• Seen in: arterial walls in hypertension, rheumatic nodules, immune complex vasculitis

• Organization of necrotic material → fibrosis → hyalinosis

Types of Fibrinoid

1. Coagulative fibrinoid - with fibrin (fibrinogen from plasma)
2. Metachromatic fibrinoid - with glycosaminoglycans
3. Collagenolytic fibrinoid - destruction of own collagen

Role in Disease Morphogenesis

• Rheumatic diseases (SLE, rheumatoid arthritis, etc.): Immune complex deposition in vessel walls and connective tissue → complement activation → fibrinoid necrosis → vasculitis; Aschoff bodies in rheumatic fever (granulomatous foci with fibrinoid necrosis)
• Glomerulonephritis: Immune complexes deposited in mesangium and basement membrane → fibrinoid necrosis of glomerular capillary walls → crescentic GN
• Gastric/duodenal ulcers: Fibrinoid necrosis at ulcer base; perpetuates ulceration
• Arterial hypertension: Hyaline arteriolosclerosis (benign); fibrinoid necrosis of arterioles (malignant hypertension)

Hyalinosis (Hyaline Dystrophy)

• Vascular hyalinosis: Hyaline arteriolosclerosis (benign hypertension, DM) - homogeneous pink material replaces vessel wall; lumen narrows
• Connective tissue hyalinosis: Old scars, keloids, cardiac valve thickening
• Intracellular hyaline: Russell bodies (immunoglobulin in plasma cells), Mallory-Denk bodies

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12. Parenchymatous Lipidoses (Fatty Degeneration)

Causes and Pathogenesis

• Causes: severe anemia, hypoxia (e.g., diphtheria toxin - blocks beta-oxidation), alcoholism, myocarditis
• Two patterns:
  • "Tigroid heart" (tabby cat pattern): Alternating yellow (fat-laden) and red-brown (normal) streaks under endocardium, due to patchy hypoxia; groups of myocytes with lipid droplets alternating with normal cells
  • Diffuse: Uniform fatty change in all myocytes; yellow, flabby heart
• Micro: small lipid vacuoles (Sudan III/Oil Red O positive, cleared in H&E) in myocyte cytoplasm; nuclei usually intact

• Most common cause: alcohol (inhibits beta-oxidation, increases fatty acid synthesis, impairs VLDL export)
• Other causes: obesity, DM type 2, malnutrition (kwashiorkor), toxins (CCl4), drugs (corticosteroids, methotrexate), pregnancy
• Pathogenesis: imbalance between fat delivery/synthesis and export/oxidation - excess triglycerides accumulate
• Gross: enlarged (up to 3-4x normal weight), yellow, greasy, soft
• Micro: Large clear cytoplasmic vacuoles displacing nucleus to periphery (macrovesicular) or multiple small droplets (microvesicular); H&E shows cleared vacuoles; Oil Red O/Sudan confirms fat
• Outcome: Reversible if cause removed. Can progress: steatohepatitis → fibrosis → cirrhosis

• Causes: nephrotic syndrome (lipid reabsorption by tubular cells), DM, severe anemia, toxins
• Proximal tubular epithelium most affected
• "Lipoid nephrosis" - tubules filled with lipid droplets
• Gross: pale, yellowish cortex
• Micro: vacuolated tubular cells (cleared on H&E); Sudan III/Oil Red O positive
• Also: lipid casts in tubular lumens and collecting ducts

• Oil Red O / Sudan III/IV: Stain neutral fats red/orange in frozen sections
• Osmic acid: Stains lipids black
• Sudan Black B: Stains phospholipids
• H&E alone: lipids dissolved during processing - leaves clear vacuoles

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13. Obesity

• By BMI: Grade I (30-34.9), Grade II (35-39.9), Grade III / morbid obesity (>40)
• By fat distribution:
  • Android (central/visceral): Intra-abdominal fat; "apple shape"; higher cardiovascular/metabolic risk (waist circumference: >102 cm men, >88 cm women)
  • Gynoid (peripheral/subcutaneous): Gluteofemoral fat; "pear shape"; lower metabolic risk
• By etiology:
  • Primary (dietary excess, sedentary lifestyle, genetic predisposition)
  • Secondary (Cushing syndrome, hypothyroidism, insulinoma, hypothalamic damage)

• Adipose tissue: Hypertrophy and hyperplasia of adipocytes; macrophage infiltration in visceral fat; chronic low-grade inflammation (adipokine dysregulation - increased TNF, IL-6, leptin resistance; decreased adiponectin)
• Liver: Steatosis/NASH (non-alcoholic steatohepatitis)
• Cardiovascular: Left ventricular hypertrophy; epicardial fat infiltration; cardiomegaly; atherosclerosis
• Lungs: Obesity hypoventilation syndrome; sleep apnea (pharyngeal fat compresses airway)
• Joints: Osteoarthritis (weight-bearing joints)
• Pancreas: Islet hyperplasia → insulin resistance → T2DM; lipotoxicity to beta cells

• Type 2 diabetes mellitus, metabolic syndrome, cardiovascular disease (MI, stroke), NASH/cirrhosis, obstructive sleep apnea, certain cancers (endometrial, breast, colon), osteoarthritis, venous thromboembolism

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14. Pigment (Chromoprotein) Metabolism Disorders

Lipofuscin Disorders

• Morphology: Fine, golden-brown granular cytoplasmic deposits, particularly perinuclear
• Brown atrophy: Organ atrophy (particularly heart) with prominent lipofuscin accumulation in old age or cachexia
• Significance: Marker of oxidative stress and aging; generally not harmful itself
• Stains: PAS-positive, autofluorescent, Ziehl-Neelsen weakly positive

Melanin Disorders

• Hyperpigmentation:
  • Addison disease (adrenal insufficiency): elevated ACTH/MSH → diffuse hyperpigmentation of skin and mucosae
  • Cafe-au-lait spots (neurofibromatosis); freckles; nevi; melanoma
  • Chloasma (melasma): pregnancy/oral contraceptives
• Hypopigmentation:
  • Vitiligo: autoimmune destruction of melanocytes → patches of depigmentation
  • Albinism: absence of tyrosinase → no melanin synthesis; photosensitivity, risk of skin cancer

Hemoglobin Metabolism Disorders

• Localized accumulation at sites of prior hemorrhage
• Old bruise, pulmonary congestion ("heart failure cells"), hepatic congestion
• Consequence of local RBC breakdown and iron storage in macrophages

• Widespread hemosiderin deposits throughout the reticuloendothelial system (liver, spleen, bone marrow, lymph nodes)
• Causes: hemolytic anemias, multiple transfusions, increased iron absorption
• Iron stored mainly in macrophages; parenchymal cells relatively spared
• Usually does NOT cause organ dysfunction (unlike hemochromatosis)

• Severe systemic iron overload with iron accumulation in parenchymal cells (hepatocytes, pancreatic acini, myocardium, joints, skin, pituitary)
• Primary (hereditary): HFE gene mutations (most common: C282Y homozygous); impaired hepcidin regulation → excessive duodenal iron absorption
• Secondary: Multiple transfusions, ineffective erythropoiesis (beta-thalassemia)
• Morphology: liver - hemosiderin deposits; cirrhosis; pancreas - fibrosis (diabetes); myocardium - cardiomyopathy; skin - bronze pigmentation (melanin + hemosiderin); joints - arthropathy; pituitary - hypogonadism
• "Bronze diabetes" = classic triad of cirrhosis + DM + bronze skin
• Outcome: cirrhosis, hepatocellular carcinoma, cardiomyopathy, diabetes
• Diagnosis: serum ferritin, transferrin saturation, liver biopsy (Prussian blue), HFE genotyping

• Pre-hepatic (hemolytic): excess unconjugated bilirubin
• Hepatic (hepatocellular): both fractions elevated
• Post-hepatic (obstructive/cholestatic): conjugated bilirubin elevated

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15. Pathological Calcification (Calcinosis)

Types

• Definition: Calcium deposition in dead or dying tissues with normal serum calcium levels
• Mechanism: Cell death → release of phospholipids from membranes → precipitation of calcium phosphate; cellular debris acts as a nidus; alkaline phosphatase activity; mitochondrial calcium accumulation
• Sites: Atherosclerotic plaques (calcified vessels), old caseous necrosis (tuberculosis - "Ghon complex"), fat necrosis, dead parasites (cysticercosis), old infarcts, thrombi (phleboliths), aging cardiac valves ("porcelain" lesions)
• Gross: Hard, gritty, chalk-white deposits
• Micro: Initially, granular basophilic deposits; later, dense acellular masses; bone may even form (heterotopic ossification)
• Significance: Can cause valve dysfunction (aortic stenosis), vessel rigidity

• Definition: Calcium deposition in normal living tissues due to hypercalcemia
• Mechanism: Elevated Ca2+ or phosphate overwhelms normal tissue buffering
• Causes of hypercalcemia:
  • Hyperparathyroidism (primary, secondary in renal failure)
  • Destruction of bone (metastases, multiple myeloma)
  • Hypervitaminosis D
  • Milk-alkali syndrome
  • Sarcoidosis (ectopic 1α-hydroxylase)
• Sites: Interstitial tissues of kidney (nephrocalcinosis), stomach, lungs, arterial walls, cornea - tissues that excrete acid (interstitial pH is relatively alkaline)
• Significance: Can impair organ function; nephrocalcinosis → renal failure

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16. Necrosis - Causes, Mechanisms, Macro/Micro Characteristics

Causes

• Hypoxia/ischemia (most common)
• Physical agents (radiation, trauma, temperature extremes)
• Chemical toxins and drugs
• Infectious agents (bacteria, viruses, fungi, parasites)
• Immune reactions (complement, cytotoxic T cells)
• Nutritional deficiencies

Mechanisms

1. ATP depletion → Na+/K+-ATPase failure → cell swelling, Ca2+ influx
2. Ca2+ overload → activation of:
   • Phospholipases → membrane breakdown
   • Proteases (calpains) → cytoskeletal disruption
   • Endonucleases → DNA fragmentation
   • ATPases → further energy depletion
3. Free radical injury: ROS from reperfusion, mitochondria; lipid peroxidation; protein oxidation; DNA oxidation
4. Lysosomal rupture: Autolytic enzymes released → self-digestion

Macroscopic Characteristics (by type - see below)

• Coagulative necrosis: firm, pale
• Liquefactive: soft, liquified, cavity
• Caseous: cheesy, white-gray
• Fat: chalky white
• Gangrenous: black, wet or dry

Microscopic Characteristics

• Pyknosis: Nuclear shrinkage and increased basophilia (chromatin condensation)
• Karyorrhexis: Fragmentation of pyknotic nucleus
• Karyolysis: Fading of nucleus (DNase activity)

• Increased eosinophilia (protein denaturation, loss of RNA)
• Cell outlines may persist (coagulative) or be lost (liquefactive)
• "Ghost cells" - cell shapes visible but no organelle detail

• Loss of tissue architecture
• Inflammatory infiltrate (neutrophils first, then macrophages)

Necrosis vs. Apoptosis - Morphological Differences

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17. Clinical and Morphological Forms of Necrosis

1. Coagulative Necrosis

• Most common form; architecture preserved ("ghost outlines")
• Pathogenesis: Protein denaturation predominates over enzymatic digestion; acidic pH inactivates lysosomal enzymes
• Causes: Ischemia (virtually all organs except brain), toxins
• Morphology: Firm, pale, opaque area; cell outlines preserved microscopically for days/weeks; nuclei disappear
• Classic example: Renal infarct, myocardial infarction (first days)

2. Liquefactive Necrosis

• Enzymatic digestion dominates → liquid mass
• Pathogenesis: Rich in lysosomal enzymes (brain has little connective tissue framework); neutrophil enzymes (bacterial infections)
• Causes: Brain infarct (ischemia/stroke); bacterial abscesses (pyogenic bacteria release powerful enzymes)
• Morphology: Soft, yellow-gray, viscous; cystic cavity in brain; pus (neutrophils + dead cells + fluid) in abscess
• Examples: Cerebral infarct, lung abscess

3. Caseous Necrosis

• "Cheesy" appearance; specific to granulomatous infections
• Pathogenesis: Mixture of coagulative and liquefactive necrosis + immune-mediated injury; waxy lipid coat of mycobacteria contributes
• Morphology: Gross - white, soft, crumbly ("cottage cheese"); Micro - amorphous, structureless, eosinophilic granular debris; NO preserved cell outlines (unlike coagulative); surrounded by granulomatous reaction
• Examples: Tuberculosis (classic), fungal infections (histoplasmosis)

4. Fat Necrosis

• Specific to adipose tissue
• Pathogenesis: Release of pancreatic lipases (acute pancreatitis) → enzymatic saponification of fat; fatty acids released react with calcium → calcium soaps
• Morphology: Gross - chalky white deposits in adipose tissue (peritoneal, omental fat); Micro - necrotic fat cells (shadowy outlines), basophilic calcium deposits, surrounding inflammation
• Example: Acute pancreatitis, breast trauma (traumatic fat necrosis)

5. Fibrinoid Necrosis

• In blood vessel walls
• Pathogenesis: Immune complex deposition + complement activation → destruction of vessel wall; deposits of plasma proteins (fibrin, immunoglobulins)
• Morphology: Hyper-eosinophilic, smudgy deposits in vessel walls; MSB stain: deep red
• Examples: Malignant hypertension, polyarteritis nodosa, immune complex vasculitis, rheumatic diseases

6. Gangrenous Necrosis

• Not a specific type - usually coagulative necrosis with secondary bacterial infection
• Dry gangrene: Coagulative necrosis predominates; no bacterial infection; limb becomes dry, black, mummified; sharp demarcation
• Wet gangrene: Liquefactive superimposed; secondary bacterial infection; putrefaction; foul odor; no clear border; spreads rapidly
• Gas gangrene: Clostridium perfringens infection; gas bubbles in tissue

Outcomes of Necrosis

1. Organization: Granulation tissue replaces necrotic area → scar (fibrosis)
2. Regeneration: If parenchymal cells regenerate (liver, tubular epithelium)
3. Encapsulation/calcification: Dystrophic calcification
4. Cavity formation: Liquefaction (brain cyst, abscess)
5. Sequestration: Dead tissue separates (bone sequestrum in osteomyelitis)
6. Ulceration: Necrotic surface tissue sloughs off
7. Mutations: Rarely, surviving cells near necrotic zone may undergo mutational changes

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18. Infarction

Morphological Characteristics by Type

• Occur in solid organs with end-arterial (non-collateral) supply
• Sites: Kidney, spleen, heart
• Mechanism: occlusion → ischemia; hemorrhage cannot fill compact solid tissue
• Morphology: wedge-shaped (base at surface, apex toward hilus), pale/white-yellow; surrounded by dark hyperemic zone; histologically: coagulative necrosis with preserved ghost outlines
• Myocardial infarction (MI):
  • Day 0-4: coagulative necrosis; hyperemic border; irreversible injury at 20-40 minutes of ischemia; histologically: eosinophilic "wavy fibers," loss of nuclei, contraction bands
  • Day 1-3: neutrophilic infiltrate
  • Day 5-10: macrophage infiltrate (phagocytosis)
  • 2-8 weeks: granulation tissue → fibrosis (scar)
  • Complications: arrhythmia, cardiogenic shock, rupture (day 3-7), mural thrombus, pericarditis, Dressler syndrome

• Occur in: (a) venous occlusions; (b) loose tissue (lung) where blood can re-enter; (c) tissues with dual blood supply; (d) reperfused areas
• Sites: Lung (arterial embolism + dual supply), intestine (venous occlusion), testis (torsion), brain (venous)
• Morphology: dark red, wedge-shaped; microscopically - coagulative or liquefactive necrosis with hemorrhage
• Pulmonary infarct: Wedge-shaped hemorrhagic area at pleural surface; firm, red-brown → yellow-white as infarct ages → scar

• Ischemic stroke: Most commonly from atherothrombosis or cardioembolism
• Initially: coagulative necrosis (first 12-24h); but brain undergoes liquefactive necrosis (rich in lipid, lacks connective tissue)
• Within days: neutrophils, then macrophages (foam cells)
• Weeks-months: cystic cavity lined by gliosis (astrocytic scarring)
• Reperfusion injury: Conversion to hemorrhagic (red) infarct common in embolic strokes

Factors Influencing Infarct Development

• Nature of blood supply (end-arterial vs. dual)
• Rate of occlusion (gradual → collateral development)
• Tissue vulnerability to hypoxia (neurons: 3-5 min; myocardium: 20-40 min; fibroblasts: hours)
• Oxygen-carrying capacity of blood
• Presence of underlying disease (prior vascular disease)

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19. Inflammation - Definition, Etiology, Phases, Classification

• Eliminates causative agent (phagocytosis, killing)
• Limits tissue damage
• Initiates repair
• BUT: may become harmful if excessive (ARDS, septic shock, chronic inflammatory diseases)

• Microbial infections (bacteria, viruses, fungi, parasites)
• Physical agents (trauma, heat, cold, radiation, foreign bodies)
• Chemical agents (toxins, acids, alkalis, drugs)
• Tissue necrosis (ischemic, traumatic)
• Immune reactions (hypersensitivity, autoimmunity)

Phases

• Primary alteration: direct damage by causative agent
• Secondary alteration: cellular and tissue changes; release of vasoactive amines (histamine from mast cells/platelets), prostaglandins, leukotrienes, cytokines

• Vascular changes: Transient vasoconstriction → sustained vasodilation (arterioles) → increased permeability → increased hydrostatic pressure → edema. Classic signs: rubor (redness), calor (heat), tumor (swelling), dolor (pain), functio laesa (loss of function)
• Cellular events:
  • Margination → pavementing → emigration (diapedesis) of leukocytes through vessel walls
  • Chemotaxis (directed migration to injury site)
  • Phagocytosis: recognition (opsonins - IgG, C3b), engulfment, killing (ROS, MPO, defensins)
  • Mediators: complement (C3a, C5a), cytokines (TNF, IL-1, IL-8/CXCL8), PAF, prostaglandins

• Removal of exudate and necrotic debris
• Parenchymal regeneration (if tissue retains regenerative capacity and stroma is intact)
• Connective tissue repair (granulation tissue → scar)

• By duration: Acute (days-weeks) vs. Chronic (weeks-months-years)
• By exudate type: Serous, fibrinous, purulent/suppurative, hemorrhagic, mixed
• By extent: Local vs. systemic
• Productive/Proliferative: Predominantly cellular proliferation

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20. Acute Inflammation - Exudative Forms

Types

• Exudate: watery, protein-poor fluid (transudate-like but from inflammation)
• Examples: Skin blisters (burns, vesicle virus), pleural/pericardial effusion in early inflammation, peritonitis (early)
• Micro: sparse leukocytes; diluted proteins
• Outcome: Usually resolves completely

• Exudate: rich in fibrinogen → precipitates as fibrin strands/meshwork
• Examples: Fibrinous pericarditis ("bread and butter" or "cor villosum"), fibrinous pleuritis (pneumonia), diphtheria (pseudomembranous laryngitis)
• Micro: pink fibrin network with leukocytes
• Outcome: Organization → fibrosis → adhesions/pericardial constriction; or resolution if fibrinolysis sufficient

• Exudate: pus - abundant neutrophils (dead and dying = pyocytes) + necrotic debris + fluid
• Caused by pyogenic bacteria (Staph., Strep., Pseudomonas, etc.)
• Abscess: Focal collection of pus in solid tissue; surrounded by pyogenic membrane (wall of granulation tissue)
• Phlegmon (cellulitis): Diffuse purulent inflammation spreading through tissue planes
• Empyema: Pus in preformed cavity (empyema thoracis, pyopericardium)
• Outcome: Abscess may rupture, drain, organize; chronic inflammation if unresolved

• Exudate: bloody; vessel walls severely damaged
• Examples: anthrax, plague, severe viral infections (hanta, Ebola), hemorrhagic pancreatitis
• Poor prognosis

• Mucous membranes: excessive mucus production
• Examples: common cold (rhinitis), catarrhal bronchitis, gastritis

• Fibrinopurulent exudate firmly adherent to mucosal surface
• Examples: Diphtheria (pharynx - gray pseudomembrane), pseudomembranous colitis (C. difficile)
• Removal of membrane leaves bleeding ulcerated surface

Outcomes of Acute Inflammation

1. Resolution: Complete return to normal (small exudate, no necrosis)
2. Healing by fibrosis/scarring: Significant tissue damage
3. Abscess formation: Contained purulent focus
4. Chronic inflammation: If cause persists or immune response is involved

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21. Chronic Inflammation and Productive Inflammation

• Persistent infections with organisms resistant to destruction (TB, leprosy, viral infections, parasites)
• Prolonged toxic agent exposure (silica → silicosis)
• Autoimmune diseases (rheumatoid arthritis, SLE, inflammatory bowel disease)
• Foreign bodies (implants, sutures)
• Failure to resolve acute inflammation

• Macrophages central: activated by T lymphocytes (via IFN-γ) and other stimuli; secrete mediators that both injure tissue and promote repair
• Angiogenesis, fibrosis occur simultaneously with ongoing injury

Types

1. Interstitial (diffuse) productive inflammation: Diffuse infiltration by macrophages, lymphocytes, plasma cells in stroma of parenchymal organs (liver, kidney); leads to diffuse fibrosis (e.g., chronic hepatitis, chronic pyelonephritis)
2. Granulomatous inflammation: (See topic 23)
3. Hypertrophic (vegetative) inflammation: Hyperplasia of epithelium and stroma forming polyps or condylomas (chronic irritation of mucosae); e.g., nasal polyps, cervical polyps
4. Productive inflammation around parasites and foreign bodies: (See topic 22)

• Mononuclear infiltrate: macrophages, lymphocytes, plasma cells (vs. neutrophils in acute)
• Tissue destruction
• Repair: angiogenesis (capillary sprouting), fibroblast proliferation, collagen deposition
• Vascular proliferation (granulation tissue)

• Fibrosis/sclerosis
• Atrophy of affected organ
• Chronic organ dysfunction
• Transformation to malignancy (e.g., H. pylori gastritis → gastric carcinoma)

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22. Productive Inflammation Around Foreign Bodies and Parasites

Around Foreign Bodies

• Mechanism: Large foreign bodies (suture material, talc, silica, prosthetic material) cannot be phagocytosed by single macrophages
• Morphology: Macrophages surround the material; fuse to form multinucleate foreign body giant cells (nuclei randomly distributed throughout cytoplasm - differs from Langhans giant cells where nuclei are peripheral)
• The foreign body can often be seen within the giant cells, particularly under polarized light
• No necrosis, no specific immune response; fibrous capsule forms around the reaction

Opisthorchiasis

• Infection by Opisthorchis felineus (liver fluke - raw freshwater fish), common in Siberia/SE Asia
• Parasites inhabit bile ducts
• Morphology: Productive periductal fibrosis; bile duct epithelial hyperplasia; granuloma-like reactions with eosinophils; chronic inflammation with lymphocytes, macrophages; ductal dilatation
• Outcomes: Cholangitis, cholestasis, cirrhosis, and importantly - cholangiocarcinoma (the most feared complication)

Echinococcosis (Hydatid Disease)

• Caused by Echinococcus granulosus (dog tapeworm)
• Cyst formation in liver (most common), lung, brain
• Cyst structure:
  1. Inner germinal (endocyst) layer (parasite-derived, produces brood capsules and protoscolices)
  2. Laminated (ectocyst) membrane (acellular, laminated, characteristic PAS-positive layer)
  3. Pericyst (host-derived): Fibrous capsule of compressed host tissue with:
     • Eosinophil infiltration (eosinophilia hallmark of helminth infections)
     • Giant cell reaction at parasite-host interface
     • Chronic granulomatous-like inflammation
     • Progressive fibrosis and calcification
• Outcomes: Compression of adjacent structures; rupture → anaphylaxis + dissemination; secondary bacterial infection; calcification

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23. Granulomatous Inflammation

• Infections: TB, leprosy, syphilis, fungal (histoplasmosis, coccidioidomycosis, blastomycosis), schistosomiasis
• Unknown/immune-mediated: Sarcoidosis, Crohn disease, primary biliary cirrhosis
• Inorganic particles: silicosis, berylliosis
• Foreign bodies (non-immunogenic): talc, sutures

Mechanisms of Development

• Persistent antigen that cannot be cleared → sustained T-cell activation
• Th1 cells produce IFN-γ → activates macrophages → epithelioid cells
• Activated macrophages fuse → Langhans giant cells (nuclei arranged in horseshoe/peripheral pattern)
• Some responses involve Th2 cells and eosinophils (schistosomiasis)

Morphological Characteristics

• Center: Epithelioid macrophages (pink granular cytoplasm, "footprint" nuclei, indistinct cell borders); may have central caseous necrosis (in TB)
• Giant cells: Langhans type (nuclei peripheral/horseshoe); foreign body type (nuclei scattered)
• Surrounding: Collar of lymphocytes (mainly CD4+ T cells)
• Older granulomas: Rim of fibroblasts and connective tissue; eventual fibrosis

• H&E for basic granuloma architecture
• ZN stain (Ziehl-Neelsen) / Auramine-rhodamine for acid-fast bacilli (TB)
• GMS (Grocott) / PAS for fungi
• Culture and PCR for infectious agents
• ACE level, chest CT (sarcoidosis)
• Polarized light (birefringent foreign material)

• Fibrosis (most common fate of granulomas)
• Calcification (dystrophic)
• Resolution (if antigen cleared)
• Liquefaction of caseous material → cavity formation (TB)

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24. Granulomatous Diseases - Classification and Features

Classification by Etiology

• Sarcoidosis: Multi-system non-caseating granulomas; primarily lung, skin, lymph nodes, eyes; hypercalcemia; elevated serum ACE; Löfgren syndrome (acute: erythema nodosum + hilar adenopathy + polyarthritis); treat with corticosteroids
• Silicosis: Progressive massive fibrosis; upper lobe nodular shadows; increased susceptibility to TB; no treatment except supportive

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25. Tuberculous Granuloma - Structure and Histogenesis

Granuloma Structure in Tuberculosis

Histogenesis of Cells

• M. tuberculosis phagocytosed but not killed by macrophages (blocks phagolysosome fusion via ESAT-6, other virulence factors)
• Mycobacterial antigens presented on MHC II → CD4+ Th1 activation
• Th1 release IFN-γ → classical macrophage activation → reactive oxygen/nitrogen species → partial killing, but also tissue injury
• TNF-α essential for granuloma maintenance (anti-TNF therapy → granuloma breakdown → TB reactivation)
• Hypersensitivity (type IV/DTH) contributes to caseous necrosis

Outcomes of Tuberculous Granuloma

1. Healing with fibrosis: Granuloma encapsulates, fibroses, calcifies (Ghon focus in primary TB)
2. Progressive caseous necrosis: Central necrosis expands; giant cells destroyed
3. Liquefaction of caseous material: Cavity formation (post-primary pulmonary TB - the basis of infectivity)
4. Calcification: Dystrophic calcification of caseous material (Ghon complex = calcified primary focus + lymph node)
5. Reactivation: Years later if immunity declines (immunosuppression, HIV, anti-TNF therapy) → reactivation TB with cavity formation

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General Pathological Anatomy - Topics 26-55

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26. Syphilis - Gumma and Specific Inflammation. Tertiary Syphilis. Outcomes.

Causative Agent

Stages and Specific Inflammation

• Chancre: Firm, painless ulcer at inoculation site; histology shows dense plasma cell infiltrate + macrophages + lymphocytes + obliterative endarteritis (endothelial proliferation → intimal fibrosis → lumen narrowing). This endarteritis is pathognomonic and present in all stages.
• Regional lymphadenopathy (nonspecific or plasma cell-rich).

• Widespread mucocutaneous lesions (macules, papules on palms/soles, oral mucosa)
• Histology: same plasma cell infiltrate and obliterative endarteritis as primary, but less intense
• Condyloma lata (genital flat warts)

Tertiary Syphilis - Solitary Gumma

• White-gray, rubbery masses; solitary or multiple
• Size: microscopic (resembling tubercles) to several centimeters
• Common sites: skin, subcutaneous tissue, bone, liver, testis

• Center: Coagulated necrotic material (similar to caseous necrosis but less "cheesy"; treponemes extremely sparse and difficult to demonstrate)
• Margin: Plump palisading macrophages + fibroblasts + dense plasma cell infiltrate (key differentiating feature from TB granuloma)
• Surrounding obliterative endarteritis of small vessels
• No true epithelioid cells or Langhans giant cells (differs from TB)

Tertiary Syphilis - Interstitial (Diffuse) Inflammation

• Endarteritis of the vasa vasorum of the proximal aorta
• Occlusion of vasa vasorum → ischemic scarring of the tunica media → elastic fiber destruction → loss of aortic elasticity → aneurysm of the ascending aorta and aortic arch
• Subintimal scarring → narrowing of coronary artery ostia → myocardial ischemia
• Gross: "tree-bark" intimal wrinkling (obliterative endarteritis scarring)
• Leads to: aortic root dilation → aortic regurgitation; aortic arch aneurysm

• Meningovascular syphilis: Endarteritis of meningeal and cortical vessels → ischemic strokes; meningitis
• Tabes dorsalis: Demyelination of posterior columns and dorsal nerve roots → ataxia, lightning pains, Argyll Robertson pupils
• General paresis: Cortical atrophy, plasma cell infiltrates, neuronal loss → dementia

• Hepar lobatum: extensive gummatous scarring of liver → deep lobulation of liver surface (distinctive gross pattern)

• Periostitis, osteitis; gummas in bone → cortical destruction

Outcomes

• Gummas: fibrosis and scarring (most common); calcification (rare); complete healing if treated early with penicillin
• Cardiovascular: aortic aneurysm rupture, heart failure (aortic regurgitation), sudden death
• Neurosyphilis: progressive dementia, disability
• Differences from TB granuloma:

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27. Leprosy (Hansen Disease)

Clinical-Anatomical Forms Based on Immune Status

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• Immune status: Strong Th1 response (IFN-γ, IL-2, Th17); effective macrophage activation; low bacterial burden
• Skin lesions: Few, well-defined hypopigmented patches with raised erythematous borders; dry, anhidrotic (sweat glands destroyed); reduced/absent sensation (anesthesia)
• Nerve involvement: Prominent asymmetric involvement of large peripheral nerves; palpably enlarged, tender nerves (ulnar, common peroneal, great auricular, facial); nerve thickening → claw hand, foot drop, lagophthalmos
• Histology: Well-formed epithelioid granulomas with Langhans giant cells in dermis; sparse or no AFB (Fite stain negative or weakly positive); lymphocytic cuffing; nerve destruction within granulomas
• Lepromin test: Strongly positive (Mitsuda reaction - indicates competent CMI)
• Bacterial index (BI): 0 (no organisms detectable)

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• Immune status: Weak Th1 response; regulatory T cells/Th2 predominance; absent cell-mediated immunity; highest bacterial burden
• Skin lesions: Symmetric, diffuse skin thickening; nodular lesions (lepromas); leonine facies (lion-like face due to facial infiltration); loss of eyebrows (madarosis); nasal stuffiness → saddle nose
• Nerve involvement: Symmetric distal sensory neuropathy; widespread invasion of Schwann cells + endoneurial and perineural macrophages; glove-and-stocking anesthesia
• Histology: Dermis packed with foamy macrophages ("lepra cells" or Virchow cells) loaded with M. leprae; no granuloma formation; massive AFB on Fite stain (globi - clusters of bacilli); "grenz zone" (clear zone of uninvolved collagen under epidermis); lymphocytes absent or sparse
• Lepromin test: Negative
• Bacterial index: 4-6 (thousands to millions of organisms per field)
• Systemic involvement: Liver, spleen, lymph nodes, bone marrow, testes (orchitis → infertility)

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• Intermediate forms with mixed features; immunologically unstable
• Borderline Tuberculoid (BT): Closer to TT; some granulomas but less well formed
• Mid-Borderline (BB): Dimorphous; unstable
• Borderline Lepromatous (BL): Closer to LL; foamy macrophages predominate; AFB present

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• Paucibacillary (PB): ≤5 lesions (corresponds to TT/BT) - treated with rifampicin + dapsone
• Multibacillary (MB): >5 lesions (corresponds to BB/BL/LL) - treated with rifampicin + dapsone + clofazimine

Outcomes

• Reactional states: Type 1 (reversal reaction) - sudden upgrading toward TT, nerve damage; Type 2 (erythema nodosum leprosum/ENL) - immune complex-mediated; vasculitis, glomerulonephritis
• Peripheral neuropathy with permanent disabilities: claw hand, foot drop, lagophthalmos → exposure keratitis → blindness
• Nasal deformity (saddle nose), testicular atrophy, blindness
• With MDT (multi-drug therapy): cure achievable; relapses rare if treatment completed
• Stigma and social disability remain major issues

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28. Rhinoscleroma

Features of Granuloma Morphology (Mikulicz Cells)

• Large, vacuolated macrophages (100-200 μm) with clear cytoplasm; vacuoles contain K. rhinoscleromatis organisms (demonstrable by Giemsa, Gram stain, or Warthin-Starry silver stain)
• PAS-positive cytoplasm
• The organisms can be confirmed by culture (mucoid "bull's eye" colonies) and PCR

• Eosinophilic homogeneous intracellular inclusions in plasma cells (distended ER with immunoglobulin); present in abundance - very characteristic
• Not unique to rhinoscleroma but abundant here

1. Catarrhal/atrophic stage: Chronic non-specific rhinitis; crusting; fetid odor; mimics ozena
2. Granulomatous (proliferative) stage: Firm nodules and masses in nasal cavity; diagnostic stage - Mikulicz cells and Russell bodies present; potential airway obstruction
3. Sclerotic (fibrotic/cicatricial) stage: Dense fibrosis; scarring → stenosis of nasal vestibule, subglottic larynx, nasopharynx

• Biopsy: H&E shows Mikulicz cells and Russell bodies
• Warthin-Starry / Giemsa: demonstrates organisms within Mikulicz cells
• Culture (chocolate agar)
• PCR

Outcomes

• Nasal deformity (broadened nose - "wooden nose")
• Subglottic stenosis → airway obstruction (most dangerous complication)
• Nasopharyngeal scarring → Eustachian tube obstruction → hearing loss
• Responds to prolonged antibiotic therapy (fluoroquinolones, tetracycline); surgical excision of fibrotic stenoses may be needed
• Prognosis: good with early treatment; fibrotic stage irreversible

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29. Cellular Bases of the Immune Response

Cells Participating in the Immune Response

• Neutrophils: First responders; phagocytosis, oxidative burst, NET formation
• Macrophages (monocytes): Phagocytosis; antigen presentation (via MHC II); cytokine production (TNF, IL-1, IL-12, IL-6, IL-8); M1 (classical activation - antimicrobial) vs. M2 (alternative - repair)
• Natural Killer (NK) cells: Kill virus-infected and tumor cells without prior sensitization; cytotoxicity via perforin/granzyme; IFN-γ production
• Dendritic cells: Most potent antigen-presenting cells; capture antigens in periphery → migrate to lymph nodes → present to T cells via MHC I/II; link innate and adaptive immunity
• Mast cells/Basophils: IgE-mediated immediate hypersensitivity; vasoactive mediators
• Eosinophils: Helminth defense; allergic reactions; granule proteins (MBP, ECP)
• Complement: Opsonization (C3b), lysis (MAC), chemotaxis (C5a), inflammation (C3a, C4a)

• T lymphocytes (thymus-derived):
  • CD4+ helper T cells: Th1 (IFN-γ → cell-mediated immunity), Th2 (IL-4, IL-5, IL-13 → humoral/allergic), Th17 (IL-17 → neutrophil recruitment), Treg (IL-10, TGF-β → suppress)
  • CD8+ cytotoxic T cells (CTLs): Kill cells displaying antigen on MHC I; perforin/granzyme; Fas-FasL
• B lymphocytes (bone marrow-derived): Differentiate into plasma cells → antibody production; memory B cells; antigen presentation
• Plasma cells: Terminal B cell differentiation; secrete antibodies
• Memory T and B cells: Long-lived; rapid secondary response

Tissue Antigens

• Self antigens (autoantigens): Normal cell surface molecules, intracellular proteins; tolerance mechanisms prevent responses
• Non-self antigens: Foreign proteins, polysaccharides, lipopolysaccharides from pathogens
• Tumor antigens: Mutated self-proteins (neoantigens), overexpressed normal proteins, viral antigens in virus-associated cancers
• Transplant antigens (alloantigens): MHC molecules differing between individuals
• Haptens: Small molecules that become immunogenic when coupled to proteins

Major Histocompatibility Complex (MHC)

• MHC Class I (HLA-A, HLA-B, HLA-C):
  • Expressed on all nucleated cells
  • Structure: α-chain (3 domains: α1, α2, α3) + β2-microglobulin
  • Peptide groove formed by α1 + α2 domains
  • Presents endogenous (intracellular) peptides (8-10 aa), e.g., viral proteins, tumor antigens
  • Recognized by CD8+ T cells (TCR + CD8)
• MHC Class II (HLA-DR, HLA-DQ, HLA-DP):
  • Expressed on professional antigen-presenting cells (dendritic cells, macrophages, B cells) and thymic epithelium; inducible on others by IFN-γ
  • Structure: α-chain + β-chain (both polymorphic)
  • Presents exogenous (phagocytosed/endocytosed) peptides (13-25 aa) from extracellular pathogens
  • Recognized by CD4+ T cells (TCR + CD4)
• MHC Class III: Encodes complement components (C2, C4, factor B), cytokines (TNF), heat shock proteins; not antigen-presenting

1. Antigen presentation: T cells only recognize antigen as peptide fragments bound to MHC molecules (MHC restriction)
2. T cell selection in thymus: Positive selection (T cells that recognize self-MHC survive); negative selection (T cells with high affinity for self-MHC + self-peptide are deleted → self-tolerance)
3. Transplant rejection: Foreign MHC molecules recognized as non-self → allograft rejection
4. Disease susceptibility: Specific HLA alleles associated with autoimmune diseases (HLA-B27 → ankylosing spondylitis; HLA-DR4 → rheumatoid arthritis; HLA-DQ2/DQ8 → celiac disease)

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30. Humoral Immunity - B Lymphocytes, Antibodies, Regulation

B Lymphocytes - Types and Significance

• B2 cells (conventional B cells): Main population; follicular (FO) B cells in lymph nodes/spleen; require T cell help for activation (T-dependent antigens); generate germinal centers, class switching, somatic hypermutation, memory
• B1 cells: Peritoneal/pleural cavity; produce natural antibodies (mostly IgM) against T-independent antigens (polysaccharides, lipids); rapid first-line defense without T cell help
• Marginal zone (MZ) B cells: Spleen marginal zone; respond rapidly to blood-borne T-independent antigens
• Memory B cells: Long-lived; responsible for rapid secondary response; lower activation threshold
• Plasma cells (effector B cells): Terminally differentiated; high-rate immunoglobulin secretion; concentrated in bone marrow

Antibodies (Immunoglobulins) - Classes and Properties

Regulation of Antibody Production

1. T cell help (T-dependent response): CD4+ Th2 cells provide help via CD40L-CD40 interaction and cytokines (IL-4, IL-5, IL-13) → B cell activation → class switching → affinity maturation
2. Germinal center reaction: In lymph node/spleen follicles → somatic hypermutation (AID enzyme) → selection of high-affinity B cells → differentiation into plasma cells and memory cells
3. Negative regulation: FcγRIIB on B cells (ITIM motif); antigen-antibody complexes cross-link BCR + inhibitory FcγRIIB → inhibitory signal; IL-10 from Treg; loss of T cell help
4. T-independent antigens: Directly cross-link BCR (polysaccharides); no germinal center; IgM mostly; no memory

Primary vs. Secondary Immune Response

Structural Bases of Humoral Immunity

• Primary lymphoid organs: Bone marrow (B cell maturation), thymus (T cell maturation)
• Secondary lymphoid organs: Lymph nodes, spleen, MALT (Peyer's patches, tonsils) - sites of adaptive immune responses
• Germinal centers in lymphoid follicles: site of somatic hypermutation, class switching, affinity maturation
• Mantle zone: Naive B cells surrounding germinal center
• Plasma cell niches: Bone marrow; sites of long-lived plasma cells (survive decades)

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31. Tissue Manifestations of Immunopathological Processes

Type I - Immediate (Anaphylactic) Hypersensitivity

• Mechanism: Antigen (allergen) → IgE production by plasma cells → IgE binds mast cells/basophils via FcεRI → re-exposure → cross-linking → degranulation → histamine, prostaglandins, leukotrienes, PAF
• Morphology: Vascular dilation, edema, eosinophilic infiltrate; mucus hypersecretion; smooth muscle spasm
• Clinical: Urticaria, allergic rhinitis, asthma, food allergy, anaphylaxis

Type II - Antibody-Mediated (Cytotoxic) Hypersensitivity

• Mechanism: IgG or IgM antibodies against cell surface or extracellular matrix antigens → cell destruction via:
  • Complement activation → MAC lysis
  • Opsonization → phagocytosis by macrophages
  • ADCC (antibody-dependent cellular cytotoxicity) by NK cells
  • Antibody-mediated functional effects (stimulation or blockade)
• Morphology: Cell depletion (hemolysis, thrombocytopenia); tissue necrosis; inflammation at sites of immune deposits; functional abnormality without destruction
• Examples: Autoimmune hemolytic anemia, myasthenia gravis (AChR blockade), Graves disease (TSH-R stimulation), Goodpasture syndrome (anti-GBM → crescentic GN + pulmonary hemorrhage), pemphigus (anti-desmoglein)

Type III - Immune Complex-Mediated Hypersensitivity

• Mechanism: Antigen-antibody complexes form in circulation or in situ → deposit in vessel walls → complement activation (C3a, C5a) → neutrophil recruitment → neutrophil degranulation → fibrinoid necrosis (necrotizing vasculitis)
• Morphology: Fibrinoid necrosis of vessels (hallmark); neutrophilic infiltrate; "leukocytoclastic vasculitis"; complement and Ig deposits detectable by immunofluorescence
• Acute serum sickness morphology: Vasculitis, glomerulonephritis, arthritis
• Examples: SLE (immune complex GN), post-streptococcal GN, vasculitis, Arthus reaction, serum sickness

Type IV - Delayed-Type (Cell-Mediated) Hypersensitivity

• Mechanism:
  • Classical DTH (Th1-mediated): CD4+ Th1 cells → IFN-γ → macrophage activation → tissue injury; 48-72h delay
  • Direct cytotoxicity (CD8+ CTL-mediated): CD8+ T cells kill target cells via perforin/granzyme
  • Th17-mediated: IL-17 → neutrophil recruitment
• Morphology: Mononuclear (macrophage + lymphocyte) infiltrate; granuloma formation in chronic cases; tissue destruction; no vascular deposits on IF
• Examples: Tuberculin reaction, contact dermatitis, granulomatous diseases, allograft rejection, MS, type 1 DM

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32. Autoimmunization and Autoimmune Diseases

Mechanisms of Self-Tolerance (Loss leads to autoimmunity)

• T cells: Negative selection in thymus (clonal deletion of autoreactive T cells); mediated by AIRE (autoimmune regulator) gene → expression of peripheral antigens in thymic epithelium → deletion of reactive T cells
• B cells: Clonal deletion or receptor editing in bone marrow

• Anergy: T cells encountering antigen without co-stimulation (e.g., CD28-B7 signal absent) become anergic
• Regulatory T cells (Treg): FOXP3+ CD4+CD25+ cells suppress other T cells via IL-10, TGF-β, CTLA-4
• Inhibitory receptors: CTLA-4, PD-1 dampen T cell activation
• Clonal ignorance: Some antigens sequestered (eye, testis - immune privilege)

Development Mechanisms of Autoimmunity

1. Genetic predisposition: HLA associations (HLA-DR4 → RA, HLA-DQ2/8 → T1DM/celiac); PTPN22, CTLA4, FOXP3 mutations
2. Molecular mimicry: Pathogen antigens share epitopes with self-antigens → immune response cross-reacts with self (e.g., strep M protein → cardiac myosin → rheumatic fever)
3. Bystander activation: Tissue damage releases cryptic self-antigens (previously unseen by immune system); APCs become activated → break tolerance
4. Failure of regulatory T cells: FOXP3 mutations → IPEX syndrome (severe multi-system autoimmunity)
5. Polyclonal B cell activation: Some pathogens (EBV, LPS) activate B cells non-specifically → may activate autoreactive clones
6. Spread of autoantigens (epitope spreading): Initial response to one epitope → tissue damage → exposure of more epitopes → widening of autoimmune response

Morphological Manifestations

• Organ-specific autoimmune diseases:
  • Hashimoto thyroiditis: lymphocytic infiltration with germinal centers; follicular destruction; Hürthle cell metaplasia
  • Type 1 DM: insulitis (lymphocytic infiltration of islets) → islet destruction
  • Multiple sclerosis: perivenular demyelination; lymphocytic infiltrates; gliosis (plaques)
  • Myasthenia gravis: thymoma in 15%; motor end-plate complement deposition; minimal structural change
• Systemic (multi-organ) autoimmune diseases:
  • SLE: Immune complex deposits in glomeruli (wire-loop lesions), skin (butterfly rash), joint synovium, blood vessels; "full house" IF (IgG, IgA, IgM, C3, C1q); anti-dsDNA, anti-Smith antibodies
  • Rheumatoid arthritis: Synovial hyperplasia (pannus formation); fibrinoid necrosis; plasma cells + macrophages; cartilage/bone erosion; rheumatoid nodules (central fibrinoid necrosis + palisading macrophages)
  • Sjögren syndrome: Lymphocytic infiltration of salivary and lacrimal glands → destruction
  • Systemic sclerosis (Scleroderma): Fibrosis of skin, lungs, GI, kidneys; obliterative endarteritis; T cell infiltrates; anti-Scl-70 (topoisomerase)

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33. Amyloidosis

• Congo red stain: Pink/red under ordinary light; apple-green birefringence under polarized light (PATHOGNOMONIC)
• Thioflavin T/S: fluorescent staining
• Electron microscopy: rigid, non-branching fibrils 7.5-10 nm diameter
• PAS: weakly positive
• All amyloid contains serum amyloid P (SAP) component and proteoglycans (heparan sulfate)

Etiology and Pathogenesis

• Compression and replacement of normal tissue
• Interference with cell function via toxicity of oligomers (soluble pre-fibrillar aggregates are most cytotoxic)
• Binding of growth factors, plasma proteins

Classification

Generalized Amyloidosis

• Most common form (~2000-3000 new cases/year in US)
• Due to clonal plasma cell proliferation (multiple myeloma, MGUS)
• λ light chains 6x more likely to form amyloid than κ
• Distribution: Heart (cardiomegaly, restrictive cardiomyopathy), kidney (nephrotic syndrome), liver (hepatomegaly), tongue (macroglossia), peripheral nerves (neuropathy), skin (purpura due to vascular amyloid)
• Morphology: Waxy, firm deposits; Congo red apple-green birefringence; perivascular, glomerular (diffuse nodular), interstitial deposits

• Complication of chronic inflammatory conditions: RA, IBD, chronic infections (TB, osteomyelitis), familial Mediterranean fever
• SAA is an acute-phase reactant → elevated chronically → conversion to AA amyloid
• Distribution: Kidney (predominant - nephrotic syndrome → renal failure), liver, spleen, adrenals
• Kidney: amyloid in mesangium and GBM → proteinuria → nephrotic syndrome → renal failure
• Spleen: Sago spleen (periarteriolar deposits - white nodules) or Lardaceous spleen (diffuse deposits - large, waxy, lard-like)

• Gross: enlarged, firm, waxy, pale organs; cut surface has "lard-like" appearance; reaction with Lugol's iodine + H2SO4 → blue-black (historical)
• Kidney: enlarged, pale, waxy cortex; amyloid in mesangium, GBM, vessels
• Liver: hepatomegaly; amyloid in space of Disse (between hepatocytes and sinusoidal endothelium)
• Heart: firm, rubbery; amyloid between myocytes; restrictive cardiomyopathy
• Diagnostic methods: Congo red (gold standard); Thioflavin T (fluorescence); immunohistochemistry (subtyping AL vs AA); mass spectrometry (definitive subtyping); serum/urine protein electrophoresis; SAP scintigraphy

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34. Regeneration - Definition, Types, Granulation Tissue, Scar Morphogenesis

Types of Regeneration

• Complete (restitutio ad integrum): Lost tissue replaced by identical functional tissue; requires intact basement membrane and extracellular matrix scaffold; occurs in tissues with good regenerative capacity (liver, epithelium)
• Incomplete: Partial replacement; rest replaced by connective tissue (scar)

• Labile cells (continuously dividing): Hematopoietic cells, surface epithelia (skin, GI, bronchus), germinal cells; stem cells in niches; best regenerative capacity
• Stable (quiescent) cells: Normally in G0; stimulated to proliferate after injury; liver hepatocytes, renal tubular cells, pancreatic acini, fibroblasts, smooth muscle; good regenerative capacity if ECM intact
• Permanent (non-dividing) cells: Neurons, cardiac myocytes, skeletal muscle (limited); repair by scar

Relationship with Inflammation

• Inflammation initiates and drives regeneration/repair through growth factor release (PDGF, TGF-β, EGF, FGF, VEGF) from macrophages, platelets, damaged cells
• Macrophages are central coordinators: M1 phase (first days - pro-inflammatory, bactericidal) → M2 phase (later - anti-inflammatory, pro-repair, produce TGF-β, PDGF, VEGF)

Granulation Tissue

1. Days 1-2: Fibrin clot fills wound; neutrophils predominate
2. Days 3-5: Macrophages dominate; angiogenesis begins; fibroblasts migrate
3. Days 5-7: Granulation tissue established - pink, granular, soft, bleeds easily

• Capillary sprouting (angiogenesis): New thin-walled capillary loops oriented perpendicular to surface; driven by VEGF from macrophages and hypoxia
• Fibroblast proliferation: Migrate from surrounding tissue; spindle-shaped; produce collagen (initially type III, later type I)
• Edematous stroma: Loose ECM (fibronectin, hyaluronan, proteoglycans)
• Inflammatory infiltrate: Macrophages, lymphocytes, plasma cells; PMNs decrease
• Gross: Pink, granular (due to capillary loops), moist; easily bleeds

• VEGF: angiogenesis
• PDGF: fibroblast and smooth muscle cell migration/proliferation
• TGF-β: fibrosis, collagen synthesis, angiogenesis modulation
• FGF (bFGF): angiogenesis, fibroblast proliferation
• EGF/KGF: epithelial proliferation

Scar Morphogenesis and ECM Remodeling

1. Granulation tissue → scar tissue:
   • Fibroblasts produce type III collagen initially → cross-linked by lysyl oxidase
   • Myofibroblasts (fibroblasts with actin filaments - wound contraction)
   • Vasculature regresses (capillaries obliterate → avascular scar)
   • Water content decreases; cell density decreases
2. Scar maturation and remodeling:
   • Type III collagen progressively replaced by type I collagen (stronger, thicker fibers)
   • ECM continuously remodeled by matrix metalloproteinases (MMPs) - collagenases, stromelysins, gelatinases (secreted by macrophages, fibroblasts, epithelial cells)
   • MMPs controlled by TIMPs (tissue inhibitors of metalloproteinases)
   • Tensile strength increases over months: at 1 week 10% of normal; at 3 months 70-80% of normal (never reaches 100%)
   • Net collagen content determined by balance of synthesis vs. degradation
3. Outcomes:
   • Normal scar: organized collagen bundles; avascular; few cells
   • Hypertrophic scar: Excess collagen confined to wound boundary; remains in wound; red, raised; may regress
   • Keloid: Excess collagen extending beyond wound boundary; does not regress; more common in darkly pigmented individuals; rich in α-SMA+ myofibroblasts; genetic predisposition
   • Contracture: Wound contraction excessive → deformity (common in burn wounds)

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35. Hypertrophy and Hyperplasia

Hypertrophy

• Increased functional demand (workload): mechanical stress → stretch-activated channels → growth signaling (IGF-1, TGF-β, MAPK, Akt/PI3K, calcineurin-NFAT pathways)
• Hormonal stimulation: estrogen → uterine smooth muscle hypertrophy; growth hormone → acromegaly
• Compensatory: after loss of paired organ (kidney) or functional tissue

• Physiological: Left ventricular hypertrophy in athletes; skeletal muscle with exercise; uterine hypertrophy in pregnancy
• Pathological: Cardiac hypertrophy in hypertension/aortic stenosis; bladder smooth muscle in outflow obstruction; acromegaly (GH excess)

Hyperplasia

• Growth factors (EGF, FGF, PDGF) acting on mitogen-activated signaling pathways (Ras-MAPK, PI3K-Akt)
• Hormonal stimulation: estrogen → endometrial hyperplasia; parathyroid hyperplasia in renal failure
• Compensatory: liver after partial hepatectomy; bone marrow in chronic hemolysis

• Physiological: Endometrium in menstrual cycle; bone marrow in high altitude; breast during lactation
• Pathological: Endometrial hyperplasia (excess estrogen), prostatic hyperplasia (DHT), adrenal cortex hyperplasia (pituitary ACTH excess), parathyroid hyperplasia

Morphofunctional Features of Myocardial Hypertrophy

• Sarcomere addition in parallel → increased wall thickness; normal/reduced cavity
• Gross: heart weight increased (normal 300-350g; can reach 700-1000g "cor bovinum"); wall thickening; relatively small ventricular cavity
• Micro: myocyte cross-sectional area enlarged; rectangular nuclei; interstitial fibrosis; capillary density relatively reduced

• Sarcomere addition in series → lengthening of myocytes; dilated cavity with proportionally thickened wall
• Gross: enlarged, dilated heart; all chambers may dilate

1. Compensated stage: Hypertrophy provides adequate function; normal cardiac output; adaptive fetal gene program re-expression (β-myosin heavy chain, atrial natriuretic peptide)
2. Decompensated stage: Hypertrophy exceeds capacity → pump failure; diastolic dysfunction first (stiffened wall); then systolic dysfunction; increased wall stress, impaired coronary reserve, fibrosis, apoptosis
3. Heart failure: Dilated cardiomyopathy phenotype; increased risk of arrhythmia (fibrosis)

• Mechanical stretch → angiotensin II, endothelin-1, catecholamines
• Activation of calcineurin-NFAT pathway, Akt/PI3K, MAPK
• Upregulation of fetal gene program; increased protein synthesis
• TGF-β → fibroblast activation → interstitial fibrosis
• Mitochondrial dysfunction; oxidative stress; autophagy impairment

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36. Atrophy

• Decreased workload (disuse atrophy): Skeletal muscle in limb immobilization/cast; ubiquitin-proteasome pathway activation; autophagy
• Loss of innervation (denervation atrophy): Muscle after peripheral nerve injury → rapid wasting; ACh-mediated trophic signals lost
• Diminished blood supply (ischemic atrophy): Brain atrophy in atherosclerosis; chronic ischemia → slow cell death + reduced synthesis
• Inadequate nutrition (nutritional atrophy): Marasmus; protein-calorie malnutrition; mobilization of fat → then muscle protein
• Loss of endocrine stimulation: Adrenal cortex atrophy after corticosteroid therapy; endometrial atrophy post-menopause; thyroid atrophy in hypothyroidism
• Pressure (pressure atrophy): Growing tumor compresses adjacent structures → atrophy
• Aging (senile atrophy): Reduced growth factor signaling, impaired autophagy, accumulation of damaged organelles

Types

• Physiological: Thymus involution in puberty; physiological age-related involution
• Pathological: As above (disuse, denervation, ischemic, nutritional, pressure)
• Local vs. General (systemic)

• Gross: reduced organ size; wrinkled surface (skin); increased relative density of connective tissue
• Micro: smaller cells; increased nuclear:cytoplasmic ratio; lipofuscin accumulation (perinuclear brown pigment); reduced organelle content; autophagy vacuoles (autophagolysosomes)

Cachexia - Brown Atrophy

• Cytokines (TNF-α "cachectin", IL-6, IL-1): suppress appetite, increase catabolism
• Tumor-derived factors (proteolysis-inducing factor, lipid-mobilizing factor)
• Hypermetabolism, malabsorption

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37. Metaplasia

Types and Morphological Characteristics

1. Squamous metaplasia (most common):
   • Ciliated columnar → squamous: Bronchial epithelium (smokers), endocervix (chronic cervicitis), gallbladder, renal pelvis (kidney stones), bladder (schistosomiasis, stones)
   • Pancreatic ducts in chronic pancreatitis
   • Micro: stratified squamous epithelium replaces normal columnar/cuboidal; may be keratinizing or non-keratinizing
   • Significance: Loss of protective function (mucus, cilia); precancerous in some settings (cervix - cervical SCC; bronchus - squamous cell carcinoma)
2. Intestinal metaplasia (Barrett esophagus):
   • Squamous (esophageal) → intestinal-type columnar (goblet cells): Response to chronic GERD
   • Micro: columnar cells with goblet cells (intestinal-type mucin); may show incomplete intestinal metaplasia (most common) or complete
   • Significance: Precancerous - risk of esophageal adenocarcinoma (30-40x increased risk); requires endoscopic surveillance
   • Types: Complete (small intestinal type, PAS-negative) vs. Incomplete (colonic type, sulfomucin-positive, sialomucin); incomplete higher risk
3. Gastric → intestinal metaplasia: Chronic gastritis (H. pylori) → intestinal metaplasia → dysplasia → gastric adenocarcinoma; Correa cascade
4. Transitional → squamous: Bladder in chronic irritation (stones, schistosomiasis); risk of squamous cell carcinoma

1. Osseous metaplasia: Connective tissue → bone; old fibrotic scars, atherosclerotic plaques, soft tissue after trauma (myositis ossificans progressiva)
2. Cartilaginous metaplasia: In scar tissue, old infarcts

Clinical Significance and Role in Carcinogenesis

• Metaplasia itself is not malignant, but the same stimuli that cause metaplasia can also cause dysplasia and ultimately carcinoma
• Sequence: Chronic irritation → metaplasia → dysplasia → carcinoma in situ → invasive carcinoma
• If the irritant is removed, metaplasia may revert (e.g., smoking cessation → reversal of bronchial squamous metaplasia)
• If irritation persists: progression to dysplasia (nuclear atypia, loss of polarity, mitoses) → carcinoma

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38. Biology of Tumor Growth - Molecular Bases of Carcinogenesis

Molecular Basis (Initiation → Promotion → Progression)

Hallmarks of Cancer (Hanahan & Weinberg)

1. Sustaining proliferative signaling (RAS mutations, EGFR amplification)
2. Evading growth suppressors (RB, p53 loss)
3. Resisting cell death (BCL-2 overexpression)
4. Enabling replicative immortality (telomerase activation)
5. Inducing angiogenesis (VEGF)
6. Activating invasion and metastasis (E-cadherin loss, MMP upregulation)
7. Reprogramming energy metabolism (Warburg effect)
8. Evading immune destruction (PD-L1 expression)
9. Genome instability (TP53 loss, mismatch repair deficiency)
10. Tumor-promoting inflammation

Key Molecular Events

• Point mutations: RAS (KRAS G12D in pancreatic cancer, colorectal cancer), BRAF (V600E in melanoma)
• Amplification: ERBB2/HER2 (breast cancer), MYCN (neuroblastoma), EGFR (lung cancer)
• Translocation: BCR-ABL (CML, Philadelphia chromosome t(9;22)); MYC-IgH (Burkitt lymphoma t(8;14)); PML-RARA (APL t(15;17))

• RB: Cell cycle checkpoint (G1/S); mutated in retinoblastoma, osteosarcoma, small cell lung cancer
• TP53: "Guardian of the genome"; DNA damage checkpoint, apoptosis induction; mutated in >50% of human cancers; Li-Fraumeni syndrome (germline)
• APC: β-catenin/Wnt pathway; FAP; colorectal cancer
• BRCA1/BRCA2: DNA repair; breast/ovarian cancer
• CDKN2A (p16): Cyclin-CDK inhibitor; melanoma, pancreatic cancer

• MLH1, MSH2, MSH6, PMS2: mismatch repair; Lynch syndrome (HNPCC) - colorectal, endometrial cancer; microsatellite instability (MSI-H)
• BRCA1/2: homologous recombination repair
• XP genes: nucleotide excision repair; xeroderma pigmentosum

Morphogenesis of Tumors

• Dysplasia: nuclear atypia + architectural disorganization; no invasion through BM
• CIS: full-thickness dysplasia; still no invasion
• Invasive: breach of basement membrane by malignant cells

Metastatic Cascade

1. Local invasion: Loss of E-cadherin (CDHL loss → β-catenin free → Wnt activation), upregulation of N-cadherin, vimentin (EMT - epithelial-mesenchymal transition); MMP production → ECM degradation → cell migration
2. Intravasation: Tumor cells enter blood vessels or lymphatics; VEGF-C → lymphangiogenesis; circulating tumor cells (CTCs)
3. Survival in circulation: Resistance to anoikis; clumping with platelets (immune evasion)
4. Extravasation: Tumor cells adhere to endothelium → cross vessel wall → enter stroma of target organ
5. Colonization: Growth in new site; requires compatible "soil" (Paget's seed-and-soil hypothesis); establish pre-metastatic niche via exosomes/tumor-secreted factors; angiogenesis

• Lymphatic: most carcinomas; regional nodes first
• Hematogenous: most sarcomas and carcinomas; liver (portal vein drainage), lungs, bone, brain
• Transcoelomic: through body cavities (peritoneal, pleural); ovarian cancer → peritoneal seeding (Krukenberg tumor to ovary)

TNM Staging

• T (Tumor): T1-T4 based on size/local invasion
• N (Nodes): N0 (no nodes) → N1-N3 (regional lymph node involvement)
• M (Metastasis): M0 (no distant mets) → M1 (distant metastasis)
• Stage groupings (I-IV) determine prognosis and treatment

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39. Tumors - Nomenclature, Classification, Histogenesis, Differentiation, Atypism

Nomenclature and Classification Principles

• Suffix: -oma added to cell/tissue of origin
• Examples: adenoma (glandular epithelium), lipoma (fat), fibroma (fibrous tissue), chondroma (cartilage), hemangioma (blood vessels), leiomyoma (smooth muscle)

• Carcinoma: From epithelial origin; suffix -carcinoma
  • Adenocarcinoma: Glandular epithelium (colon, breast, prostate, endometrium)
  • Squamous cell carcinoma (SCC): Stratified squamous epithelium or squamous metaplasia (skin, cervix, lung, esophagus)
  • Transitional cell carcinoma (TCC/urothelial carcinoma): Bladder, renal pelvis
  • Undifferentiated carcinoma
• Sarcoma: From mesenchymal (connective tissue) origin; suffix -sarcoma
  • Fibrosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma
• Exceptions: Lymphoma, leukemia, melanoma, seminoma (malignant despite -oma suffix); glioma (can be malignant)

Histogenesis and Cytogenesis

• Morphology (light microscopy)
• Immunohistochemistry (keratin for carcinoma, vimentin for sarcoma, CD markers for lymphoma, S100/HMB45 for melanoma)
• Ultrastructure (EM)
• Molecular markers (genomics, FISH, PCR)

• Well-differentiated (Grade 1): Resembles parent tissue; low nuclear/cytoplasmic ratio; rare mitoses
• Moderately differentiated (Grade 2): Intermediate features
• Poorly differentiated (Grade 3): Barely resembles parent; high N:C ratio; many mitoses
• Undifferentiated/anaplastic (Grade 4): No recognizable differentiation; bizarre cells, giant cells, atypical mitoses

Types of Tumor Growth

• Expansive (pushing) growth: Tumor expands outward compressing surrounding tissue; pseudocapsule forms; typical of benign tumors
• Infiltrative (invasive) growth: Tumor cells penetrate surrounding structures; no capsule; typical of malignant tumors
• Exophytic growth: Into a lumen (e.g., polyp)
• Endophytic: Inward invasion
• Apposition (surface) growth

Morphological Atypism

• Marked pleomorphism (variation in cell size and shape)
• High nuclear:cytoplasmic ratio
• Nuclear pleomorphism: irregular contour, coarse chromatin, prominent nucleoli
• Atypical mitoses: Tripolar, quadripolar, ring mitoses
• Giant tumor cells, multinucleated cells
• Loss of polarity

• Disorganized architecture; loss of normal tissue pattern
• Lack of maturation (no surface differentiation)
• Abnormal glandular structures; irregular cords
• Loss of basement membrane (invasive tumors)

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40. Epithelial Tumors Without Specific Localization

Benign Epithelial Tumors

• Finger-like or warty projections of epithelium (squamous, transitional, or cylindrical) supported by fibrovascular stalks
• Squamous papilloma: skin (HPV), larynx (HPV 6/11), esophagus
• Transitional cell papilloma: bladder (low-grade urothelial neoplasm)

• Glandular epithelium; forms glands, acini, or tubules
• Liver cell adenoma (hepatic adenoma), thyroid adenoma, adrenal cortical adenoma, colonic tubular/villous adenoma, parathyroid adenoma
• Tubular adenoma: branching tubules; villous adenoma: finger-like processes
• Cystadenoma: adenoma with cyst formation (ovary, pancreas)

• Any mass projecting from a mucosal surface; may be hyperplastic, inflammatory, or neoplastic
• Neoplastic polyps (adenomas): pre-malignant; tubular, tubulovillous, villous adenoma

Malignant Epithelial Tumors

• Anywhere stratified squamous epithelium or squamous metaplasia exists: skin, lip, oral cavity, pharynx, esophagus, larynx, cervix, vulva, lung, anus
• Histology: Islands and nests of squamous cells with intercellular bridges; keratin pearls (whorls of keratinized cells); individual cell keratinization (dyskeratosis); poorly diff: no keratin, more anaplastic
• Grading: Based on degree of keratinization and nuclear atypia

• Forms glandular/tubular structures; produces mucin
• Histology: Glands (well-diff), irregular cribriform glands (moderate), solid sheets (poorly diff); mucin production (PAS/Alcian blue positive); signet ring cells (mucin displaces nucleus) in diffuse type
• Site-specific patterns: Acinar, papillary, micropapillary, solid, mucinous subtypes

• No recognizable differentiation; diagnosed by IHC (keratins positive, vimentin negative usually)
• Giant cell carcinoma, spindle cell carcinoma, small cell carcinoma

• Full-thickness epithelial dysplasia; no invasion through BM; pre-invasive stage
• High cure rate if detected and treated

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41. Renal Tumors

Benign Renal Tumors

• Renal oncocytoma: Tubular cell origin; mahogany-brown, well-demarcated; oncocytes (large cells with abundant eosinophilic granular cytoplasm packed with mitochondria); "spoke-wheel" scar; benign
• Angiomyolipoma: Mixture of fat, smooth muscle, abnormal thick-walled vessels; associated with tuberous sclerosis (80% of TS patients have AML); benign but can bleed
• Papillary adenoma: <15mm cortical papillary tumor; incidental finding; low malignant potential

Malignant Epithelial Tumors

• Origin: Proximal tubular epithelium
• Genetics: VHL gene mutation/deletion (chromosome 3p25); VHL → HIF-α accumulates → VEGF, PDGF → angiogenesis (rationale for anti-VEGF therapy)
• Morphology: Rounded mass; yellow-orange (due to lipid and glycogen); golden-yellow cut surface; hemorrhage and necrosis; surrounded by fibrous pseudocapsule
• Histology: Sheets/nests of clear cells (glycogen + lipid dissolved in processing) with small round nuclei and prominent nucleoli (Fuhrman grade); delicate sinusoidal vasculature; nuclear grade (ISUP/Fuhrman 1-4)
• Prognosis: Depends on stage and Fuhrman grade; mets to lung, bone, brain, liver; responds to sunitinib, nivolumab; radical nephrectomy curative if localized
• Paraneoplastic syndromes: Polycythemia (EPO), hypercalcemia (PTHrP), hypertension (renin), Stauffer syndrome (non-metastatic liver dysfunction)

• Type 1 (sporadic, low grade) or Type 2 (high grade); hereditary papillary RCC (MET mutation)
• Papillary architecture; foamy macrophages and psammoma bodies in papillae
• Bilateral and multifocal in hereditary form

• Larger pale cells with plant cell-like appearance; perinuclear halos; Hale colloidal iron (+); best prognosis

Wilms Tumor (Nephroblastoma)

• Most common primary renal tumor of childhood (peak 3-4 years)
• Associated syndromes: WAGR (Wilms, Aniridia, GU abnormalities, intellectual disability - WT1 deletion), Beckwith-Wiedemann syndrome (WT2/IGF2 locus), Denys-Drash syndrome (WT1 missense)
• Genetics: WT1 tumor suppressor (chromosome 11p13)
• Morphological characteristics:
  • Gross: large, encapsulated, bulging; variegated cut surface (gray-white + yellow + hemorrhage/cysts); arises in cortex
  • Histology (classic triphasic pattern):
    1. Blastemal component: Sheets of small, round blue cells with high N:C ratio; undifferentiated nephrogenic rests
    2. Stromal component: Spindle cells (mesenchymal); may show heterologous differentiation (cartilage, smooth muscle, adipose)
    3. Epithelial component: Tubular or glomeruloid structures
  • Favorable histology: No anaplasia; 90%+ 5-year survival
  • Unfavorable histology (anaplasia): Tripolar mitoses, enlarged hyperchromatic nuclei, anaplastic cells; present in 5-10%; worse prognosis
• Clinical: Abdominal mass, hematuria, hypertension; found incidentally
• Prognosis: Excellent with multimodal therapy (surgery + chemo ± radiation); 85-90% cure rate for stage I-III favorable histology

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42. Trophoblastic Disease

Classification (WHO)

1. Molar pregnancy: Complete hydatidiform mole; partial hydatidiform mole
2. Gestational trophoblastic neoplasms (GTN): Invasive hydatidiform mole; Choriocarcinoma; Placental site trophoblastic tumor (PSTT); Epithelioid trophoblastic tumor (ETT)

Complete Hydatidiform Mole

• Genetics: Diploid (46,XX or 46,XY); entirely paternal origin (dispermy or diandry - egg loses maternal DNA); no fetal tissue
• Gross: Grape-like cluster of hydropic chorionic villi filling uterine cavity; no fetus/embryo
• Histology: Diffuse hydropsia (swollen, edematous villi with central cisternae); diffuse trophoblastic hyperplasia (both cytotrophoblast and syncytiotrophoblast); empty villi (no fetal vessels)
• β-hCG: Markedly elevated
• Risk of GTN: 15-20% progress to invasive mole or choriocarcinoma
• Clinical: Uterus large for dates; passage of grape-like tissue; hyperemesis; preeclampsia before 20 weeks; "snowstorm" appearance on US

Partial Hydatidiform Mole

• Genetics: Triploid (69,XXX or 69,XXY); one maternal + two paternal haploid sets; partial embryo/fetus present
• Gross: Mixed - some hydropic villi and some normal villi; incomplete fetus/embryo often present
• Histology: Focal hydropsia; focal trophoblastic hyperplasia; "scalloped" contours of villi; fetal vessels with nucleated RBCs; mixed normal and enlarged villi
• Risk of GTN: <5%

Invasive Hydatidiform Mole

• Molar villi invade myometrium and may extend to parametrium or distant sites (lung)
• Destructive, locally invasive but not metastatic in true oncologic sense (villi present = mole)
• Histology: molar villi in myometrial tissue and/or vessels
• Treatment: chemotherapy (methotrexate); curative in >95%

Choriocarcinoma

• Highly malignant GTN; no chorionic villi
• Can arise after: mole (50%), normal pregnancy (25%), ectopic pregnancy (2-5%), spontaneous abortion (25%)
• Morphology:
  • No villi; sheets of malignant cytotrophoblast + syncytiotrophoblast
  • Hemorrhagic, necrotic mass in uterus
  • Histology: biphasic pattern - mononuclear cytotrophoblast cells + multinucleated syncytiotrophoblast; massive hemorrhage and necrosis; no stroma; vascular invasion
• β-hCG: Extremely high
• Metastases: Early hematogenous spread - lungs (most common), vagina, brain, liver
• Prognosis: Despite widespread mets, highly chemosensitive; 90%+ cure with EMA-CO regimen (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine)
• PSTT: Intermediate trophoblast invasion; hPL produced; less chemosensitive

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43. Thyroid Cancer

Classification (WHO)

1. Papillary thyroid carcinoma (PTC) - 80-85%
2. Follicular thyroid carcinoma (FTC) - 10-15%
3. Hürthle cell (oncocytic) carcinoma

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• Most common; any age; excellent prognosis (>95% 10-year survival)
• Genetics: BRAF V600E mutation (60%), RET/PTC translocations (radiation-related), RAS mutations
• Morphology:
  • Gross: often poorly defined; white-grey, firm (fibrotic); may be cystic
  • Histology: True papillary fronds with fibrovascular cores; nuclear features are diagnostic:
    • "Orphan Annie eye" nuclei: clear/empty nuclei (optical clearing artifact)
    • Nuclear grooves (longitudinal)
    • Nuclear pseudoinclusions (invaginations of cytoplasm)
  • Psammoma bodies: Concentric calcified spherules (found in ~50%); pathognomonic in thyroid
  • Variants: Classical; follicular variant (all-follicular but nuclear features of PTC); tall cell (aggressive); diffuse sclerosing; solid
• Lymphatic spread → regional cervical nodes (does NOT worsen prognosis significantly)
• Treatment: thyroidectomy ± RAI; excellent outcome

• Older patients; NO lymph node involvement; vascular and capsular invasion distinguish from adenoma
• Genetics: RAS mutations, PAX8-PPARG translocation
• Morphology:
  • Gross: encapsulated, with areas of capsular/vascular invasion
  • Histology: Follicular pattern (difficult to distinguish from adenoma on cytology); diagnosis requires histological evidence of:
    • Capsular invasion: Tumor cells penetrating or breaching the capsule
    • Vascular invasion: Tumor cells within vessels (often capsular veins)
  • Minimally invasive vs. widely invasive
• Hematogenous spread: Bone (most common), lung, liver (unlike PTC which is lymphatic)
• Prognosis: worse than PTC; widely invasive - poor

• Parafollicular C cells → calcitonin-secreting
• Sporadic (70%) or familial/hereditary (30% - MEN2A, MEN2B, familial MTC) - RET mutation (chromosome 10); screening family members with RET testing
• Morphology:
  • Nests/sheets of polygonal to spindle cells; stroma contains amyloid (calcitonin-derived - Congo red positive)
  • IHC: calcitonin positive, CEA positive, synaptophysin, chromogranin
• Markers: Serum calcitonin (diagnostic and monitoring); CEA
• Prognosis: Intermediate; 10-year survival ~80% in sporadic; MEN2B worse

• Most aggressive of all thyroid cancers; median survival 3-6 months
• Elderly patients with rapidly enlarging neck mass; may arise in pre-existing goiter/differentiated cancer
• Morphology: Pleomorphic giant cells, spindle cells, squamoid cells; necrosis; vascular invasion; highly mitotic; no thyroid differentiation markers (TTF-1 negative)
• Often TP53 mutations superimposed on RAS/BRAF of predecessor
• No effective treatment; novel: larotrectinib (NTRK fusion), targeted therapy in selected cases

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44. Breast Cancer

Classification (WHO/Morphological)

1. Invasive ductal carcinoma (IDC) - No Special Type (NST): 70-80%
2. Invasive lobular carcinoma (ILC): 10-15%
3. Special types: Mucinous (colloid), tubular, medullary-like, papillary, micropapillary, metaplastic, inflammatory carcinoma, Paget disease of nipple

• Ductal carcinoma in situ (DCIS)
• Lobular carcinoma in situ (LCIS) (marker of elevated risk)

Morphological Characteristics

• Gross: hard, white-grey, spiculated ("stellate") lesion; gritty (calcifications); adherent to surrounding tissue; skin dimpling (Cooper's ligament tethering)
• Histology: irregular nests, cords, and sheets of atypical cells in desmoplastic stroma; variable tubule formation
• Grading (Nottingham/Elston-Ellis): Tubule formation (1-3) + nuclear pleomorphism (1-3) + mitotic count (1-3) → Grade 1 (3-5), Grade 2 (6-7), Grade 3 (8-9)

• Gross: ill-defined, may be multifocal/bilateral (E-cadherin loss allows cells to disperse)
• Histology: Indian file pattern (single cells in linear rows); dyscohesive cells (loss of E-cadherin); targetoid pattern around ducts; signet ring cell variant
• Difficult to detect clinically and by mammography; higher rate of bilateral disease

• Malignant epithelial cells within ducts, intact basement membrane
• Types: comedo (central necrosis with calcification), cribriform, solid, papillary, micropapillary
• Comedo DCIS: most aggressive; central necrosis → "comedocarcinoma"

• Rapid onset of breast edema, erythema, warmth, skin thickening (peau d'orange)
• Dermal lymphatic invasion by tumor emboli → obstruction of lymphatics → edema → peau d'orange
• T4d; poor prognosis

Routes of Spread and Metastasis

• Into breast parenchyma; skin (dimpling, ulceration, peau d'orange); chest wall/pectoral muscle fixation

• Axillary lymph nodes (Level I → II → III): most common primary nodal drainage
• Internal mammary nodes (inner quadrant tumors)
• Supraclavicular nodes (N3 disease)
• Sentinel lymph node biopsy first

1. Bone (most common; osteolytic and osteoblastic) - pathological fractures, hypercalcemia
2. Lung - pleural effusion
3. Liver - hepatomegaly
4. Brain - especially TNBC, HER2+
5. Adrenal, ovary (Krukenberg)

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45. Mesenchymal Tumors - Nomenclature and Distinctive Features

• Benign: cell type + -oma (lipoma, fibroma, leiomyoma, rhabdomyoma, chondroma, osteoma, hemangioma, lymphangioma, schwannoma)
• Malignant: cell type + -sarcoma (liposarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, chondrosarcoma, osteosarcoma, angiosarcoma)

Distinctive Features Compared to Other Tumors

• Difficult; relies on: cellularity, nuclear atypia, mitotic rate, tumor size, necrosis, infiltrative margins
• French FNCLCC grading (1-3): Based on differentiation score (1-3) + mitotic count score (1-3) + necrosis score (0-2)

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46. Uterine Leiomyoma and Leiomyosarcoma

Leiomyoma (Fibroid)

• Most common uterine tumor; most common tumor in women overall (present in 25-50% of reproductive-age women); benign
• Origin: Smooth muscle of uterine wall; monoclonal; driven by estrogen and progesterone
• Genetics: MED12, HMGA2, fumarate hydratase (FH) mutations; multiple independent clones in same uterus

• Intramural: Within myometrium (most common)
• Submucosal: Beneath endometrium → abnormal uterine bleeding, infertility; pedunculated submucosal may prolapse through cervix
• Subserosal: Beneath serosa; may be pedunculated; rarely parasitic (gets blood supply from omentum)
• Cervical: Less common

• Gross: firm, pale, whorled cut surface; well-demarcated (pseudocapsule); may be multiple; round; may undergo secondary changes: hyaline degeneration, cystic, calcific, red/carneous degeneration (during pregnancy - ischemic), myxoid
• Histology: interlacing bundles of smooth muscle cells (cigar-shaped nuclei, pale eosinophilic cytoplasm, no atypia, very rare mitoses); abundant ECM; hyaline stroma
• IHC: SMA+, desmin+, ER+, PR+

Leiomyosarcoma (LMS)

• Malignant smooth muscle tumor of uterus; rare (~1% of uterine malignancies); occurs independently of leiomyoma (not transformation, usually)
• Peak incidence: postmenopausal women (50-60 years)

• Gross: large, irregular, hemorrhagic, necrotic; soft/fleshy; ill-defined margins; infiltrating myometrium
• Histology: Diagnostic criteria (Stanford/Bell criteria):
  • Coagulative tumor cell necrosis
  • Marked nuclear atypia
  • Mitotic rate ≥10 mitoses per 10 HPF
  • Two of three criteria are sufficient for diagnosis
• IHC: SMA+, desmin+, h-caldesmon+; MDM2 amplification in low-grade endometrial stromal sarcoma subset
• Ki-67: high proliferation index

• Rapidly enlarging uterine mass; postmenopausal uterine growth (suspicious)
• Abnormal uterine bleeding; pelvic pain
• Staging: FIGO staging (I-IV)
• Prognosis: Poor; 5-year survival Stage I: ~50%; Stage IV: <10%
• Recurrence common; spreads hematogenously (lung, liver, bone)
• Treatment: surgery (hysterectomy) + adjuvant chemotherapy (gemcitabine + docetaxel); radiation limited role

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47. Vascular Tumors

Classification

• Hemangioma (capillary, cavernous, juvenile), lymphangioma, glomus tumor, bacillary angiomatosis (reactive)

• Kaposiform hemangioendothelioma, retiform hemangioendothelioma

• Angiosarcoma, Kaposi sarcoma, epithelioid hemangioendothelioma

Key Tumors

• Most common vascular tumor; often in skin/subcutaneous tissue; liver
• Juvenile hemangioma (strawberry nevus): Present at birth or first weeks; rapid growth in infancy → involutes by age 5-8
• Histology: small, thin-walled capillary vessels lined by flat endothelium; lobular architecture

• Deep dermis/subcutaneous; liver (most common benign liver tumor); brain
• Histology: large, dilated, blood-filled spaces lined by flat endothelium; thin stroma; may thrombose/calcify (phleboliths)
• Liver cavernous hemangioma: characteristic MRI findings; biopsy avoided (bleeding risk)

• Benign; from glomus body (arteriovenous anastomosis); subungual (under fingernail) - extremely painful; also soft tissue
• Histology: nests of glomus cells (round, regular, smooth muscle actin+) around vascular spaces

• Malignant tumor of endothelial cells; rare; high grade
• Sites: Skin (scalp in elderly), liver (vinyl chloride, arsenic, Thorotrast exposure), breast (post-radiation), deep soft tissue
• Gross: spongy, hemorrhagic masses; ill-defined
• Histology: irregular anastomosing vascular channels lined by atypical endothelial cells with nuclear atypia, mitoses; solid areas in high-grade; IHC: CD31, CD34, ERG, FLI1 positive
• Prognosis: poor; 5-year survival 10-35%

• Caused by HHV-8 (KSHV); associated with HIV/AIDS
• Types: Classic (elderly Eastern European/Mediterranean men); African endemic; AIDS-related (CD4 <200/μL); Iatrogenic (transplant immunosuppression)
• Morphology:
  • Patch stage: Dilated jagged vascular spaces in dermis; plasma cells and promontory sign
  • Plaque stage: More extensive; fascicles of spindle cells; slit-like vascular spaces; extravasated RBCs; hemosiderin
  • Nodular stage: Densely packed spindle cells forming fascicles; slit-like spaces; mitoses; hemorrhage
• IHC: HHV-8 LANA nuclear staining (diagnostic); CD31, CD34
• Sites: skin (lower extremities most often), GI, lung
• Treatment: HAART for AIDS-KS; chemotherapy (liposomal doxorubicin, paclitaxel)

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48. Bone and Cartilaginous Tissue Tumors

Classification

Osteoma

• Benign proliferation of cortical (compact) bone; often on skull, paranasal sinuses, mandible
• Histology: mature compact or cancellous bone; no atypism; grows slowly
• Associated with Gardner syndrome (multiple osteomas + intestinal polyposis + desmoid tumors)
• Prognosis: excellent; surgical excision if symptomatic

Osteosarcoma

• Most common primary malignant bone tumor (excluding myeloma); peak 10-25 years (adolescent growth spurt, second peak >65 years post-Paget/radiation)
• Sites: Metaphysis of long bones; distal femur > proximal tibia > proximal humerus ("around the knee")
• Pathogenesis: RB and TP53 mutations; CDK4 amplification; MDM2 amplification; Li-Fraumeni, hereditary RB predisposition
• Morphology:
  • Gross: destructive lytic mass with periosteal reaction; "sunburst" pattern on X-ray (perpendicular periosteal spicules); Codman triangle (periosteal elevation)
  • Histology: anaplastic tumor cells producing osteoid (pink, homogeneous, amorphous material) - this is the defining feature; malignant spindle to polygonal cells; abundant atypical mitoses; may also form cartilage or fibrous tissue (osteosarcoma can be osteoblastic, chondroblastic, fibroblastic subtypes)
• Metastasis: Hematogenous to lungs (most common), bone ("skip mets")
• Prognosis: With neoadjuvant chemotherapy + surgery, ~60-70% 5-year survival; good response (>90% necrosis) to preoperative chemo = favorable prognostic sign
• Treatment: Chemotherapy (methotrexate, doxorubicin, cisplatin - MAP regimen) + limb-salvage surgery

Chondroma (Enchondroma)

• Benign tumor of hyaline cartilage; within medullary cavity (enchondroma) or on bone surface (ecchondroma/periosteal)
• Sites: Small bones of hands and feet most common; also femur, humerus
• Multiple enchondromas: Ollier disease (risk of chondrosarcoma); with hemangiomas: Maffucci syndrome
• Histology: lobules of mature hyaline cartilage; chondrocytes in lacunae; minimal cellularity/atypia; no myxoid change (unlike low-grade chondrosarcoma)
• Prognosis: excellent; risk of malignant transformation in large/axial enchondromas

Chondrosarcoma

• Malignant cartilaginous tumor; adults/elderly (40-70 years); rarely children
• Sites: Central skeleton (pelvis, shoulder girdle, ribs, proximal femur) - differs from osteosarcoma
• Types: Conventional (central/peripheral), dedifferentiated (high grade), mesenchymal, clear cell
• Histology:
  • Lobules of cartilaginous tissue; cellularity/atypia determines grade
  • Grade I (low): Low cellularity; small dark nuclei; occasional binucleation; minimal myxoid change
  • Grade II: Moderate cellularity; more atypia; myxoid matrix areas
  • Grade III: High cellularity; marked atypia; mitoses; necrosis
• No osteoid production (distinguishes from osteosarcoma)
• Metastasis: hematogenous to lungs; also bone
• Prognosis: Grade I: 90% 5-year; Grade III: <30%; treatment: wide surgical resection (chemotherapy and radiation usually ineffective)

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49. Connective Tissue (Fibroblastic) Tumors

Fibroma

• Benign fibroblastic tumor; rare as a primary tumor; mostly fibrous overgrowth/reactive lesions
• Nuchal fibroma, nasopharyngeal fibroma (fibromatosis)
• Desmoid tumor (deep fibromatosis): Locally aggressive, non-metastasizing; APC mutation (FAP-associated); infiltrates along fascial planes; high local recurrence; no true capsule; surgery ± imatinib/sorafenib for unresectable
• Histology: bland spindle cells (fibroblasts) in collagen matrix; no atypia; rare mitoses

Fibrosarcoma

• Malignant fibroblastic tumor; rare (most previously diagnosed fibrosarcomas are now reclassified by molecular methods)
• Adults (30-55 years); extremities (thigh most common), retroperitoneum
• Morphology:
  • Gross: fleshy, white-gray, often with hemorrhage/necrosis; locally infiltrative
  • Histology: herringbone (fishbone) pattern - interlacing fascicles of fibroblasts at acute angles; cells are spindle with tapered nuclei; degree of cellularity and mitoses determines grade
  • Low-grade: "Storiform" architecture; fewer mitoses; fibrocollagenous stroma
  • High-grade: Increased cellularity; pleomorphism; mitoses; necrosis
  • IHC: vimentin+; CD34+/- ; keratin-; S100-
• Prognosis: Highly grade-dependent; high-grade 5-year survival ~30-50%
• Treatment: Wide surgical resection + radiation (± chemo for high-grade)
• Note: Low-grade fibromyxoid sarcoma (Evans tumor) - deceptively bland histology but metastatic; FUS-CREB3L2 translocation

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50. Melanocytic Tumors

Classification

• Common melanocytic nevus (junctional, compound, intradermal), dysplastic nevus, Spitz nevus, congenital nevus, blue nevus

• Melanoma (cutaneous, mucosal, uveal, leptomeningeal)

Melanocytic Nevi (Moles)

• Junctional nevus: Nests of nevus cells at dermal-epidermal junction; flat; pigmented
• Compound nevus: Nests at junction AND in dermis; slightly raised
• Intradermal nevus: Nests entirely in dermis; dome-shaped; skin-colored or pale; mature (type A, B, C cells)
• Dysplastic (atypical) nevus: Architectural disorder + cytological atypia; enlarged; asymmetric; irregular pigmentation; marker of elevated melanoma risk (nevus syndrome)

Melanoma

• Epidemiology: Increasing incidence; most lethal skin tumor; UV radiation key risk factor; also BRAF mutations, familial (CDKN2A germline)
• Precursor: Radial growth phase (RGP) → vertical growth phase (VGP) → metastasis

1. Superficial Spreading Melanoma (SSM): Most common (70%); any site; prolonged radial growth phase; pagetoid spread (single atypical melanocytes throughout epidermis); variable pigmentation
2. Nodular Melanoma: Rapid vertical growth from onset; uniformly dark, raised; worst prognosis of clinical types; deep invasion at diagnosis
3. Lentigo Maligna Melanoma: Sun-damaged skin in elderly; on face; long radial growth phase (lentigo maligna = in situ); peripheral spread; BRAF wild-type usually; better prognosis
4. Acral Lentiginous Melanoma: Palms, soles, subungual; most common in Asians and African Americans; often diagnosed late; KIT mutations

• Pagetoid spread (single cells through epidermis) in radial phase
• Vertical phase: irregular nests in dermis; pleomorphic melanocytes; large nuclei with prominent eosinophilic "cherry-red" nucleoli; mitoses
• Pigmented (melanin) or amelanotic
• IHC: S100, HMB-45, Melan-A/MART-1, SOX10, MiTF

• Breslow depth (mm): <1mm (excellent), 1-4mm (intermediate), >4mm (poor)
• Mitotic rate; ulceration; Clark level; sentinel node status; AJCC staging

• BRAF V600E (50%): vemurafenib + cobimetinib (MEK inhibitor)
• NRAS mutations (20%): less targetable
• KIT mutations (acral/mucosal): imatinib
• Immunotherapy: anti-PD-1 (nivolumab, pembrolizumab), anti-CTLA4 (ipilimumab); transformed prognosis for metastatic disease

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51. CNS and Peripheral Nerve Tumors

Classification (WHO 2021 CNS Classification)

Glioma

• WHO grades 2 (no necrosis/microvascular proliferation) and 3 (anaplastic, with necrosis)
• IDH1 R132H mutation (most common); also IDH2; detected by immunohistochemistry (IHC R132H antibody)
• ATRX loss, TP53 mutation (typical astrocytoma molecular profile)
• Histology grade 2: mild hypercellularity; nuclear pleomorphism; no necrosis, no endothelial proliferation
• Grade 3 (Anaplastic): increased cellularity; mitoses; no necrosis/MVP yet
• Prognosis: grade 2 ~8 years median; grade 3 ~3 years median; IDH mutation = better prognosis vs. wildtype

Glioblastoma (GBM) - Grade 4, IDH-Wildtype

• Most common primary malignant brain tumor; median survival 14-16 months with treatment
• Molecular: IDH-wildtype; TERT promoter mutation (>90%); EGFR amplification/mutation (EGFRvIII); PTEN loss; CDK4 amplification; whole chromosome 7 gain + 10 loss (+7/-10)
• Primary GBM: de novo, rapid onset, elderly
• Secondary GBM: progresses from lower-grade glioma; IDH mutant (better prognosis if IDH mutant)
• Morphology:
  • Gross: large, diffuse; geographic necrosis; hemorrhage; "butterfly" pattern crossing corpus callosum
  • Histology:
    • Pseudopalisading necrosis: Tumor cells palisade around necrotic foci (pathognomonic)
    • Microvascular proliferation (glomeruloid bodies): Bizarre endothelial proliferation (VEGF-driven)
    • High cellularity; marked pleomorphism; mitoses; giant cells; multinucleated cells; GFAP expression variable
• Treatment: Stupp protocol: surgery + radiotherapy + temozolomide; MGMT promoter methylation → better response to temozolomide
• IHC: GFAP+, S100+, SOX2+; IDH R132H negative (wild-type)

Oligodendroglioma

• IDH-mutant AND 1p/19q codeletion (both required for diagnosis)
• Grades 2-3; better prognosis than astrocytoma
• Histology: "fried egg" appearance (clear cytoplasm around round regular nuclei); chicken-wire capillary pattern; calcifications (very characteristic); microcalcifications
• Prognosis: grade 2 ~12 years median; responds to PCV chemotherapy

Schwannoma

• Benign tumor of Schwann cells (myelinating cells of peripheral nerves)
• Most common benign peripheral nerve tumor; also called neurinoma or neurilemmoma
• Sites: Vestibular nerve (acoustic neuroma → hearing loss, tinnitus, vertigo - 8th cranial nerve); spinal roots; peripheral nerves; rarely malignant transformation
• Associated with NF2 (bilateral acoustic neuromas); NF2 gene (merlin protein) on chromosome 22q
• Morphology:
  • Gross: encapsulated, smooth, gray-white; eccentric on nerve (can be dissected off)
  • Histology: Antoni A (compact, bipolar spindle cells in fascicles; Verocay bodies - nuclear palisading around acellular eosinophilic material) alternating with Antoni B (loose, myxoid, hypocellular areas; lipid-laden macrophages; hyalinized vessels)
  • IHC: S100++, SOX10+, GFAP-/+
• Prognosis: Excellent; benign; surgical cure; rarely recur; very rarely undergo sarcomatous transformation

• From Schwann cells + fibroblasts + perineural cells; contains residual axons (vs. schwannoma)
• Localized (solitary, sporadic) or plexiform (pathognomonic of NF1 - neurofibromatosis type 1)
• NF1: chromosome 17q11; neurofibromin (RAS-GAP tumor suppressor); café-au-lait spots, Lisch nodules, plexiform neurofibromas
• Plexiform neurofibromas: risk of malignant transformation → MPNST (malignant peripheral nerve sheath tumor)
• Histology: wavy spindle cells in collagen matrix; "shredded carrots" collagen; scattered mast cells; mucin; axons within tumor (EMA+ perineural cells)

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52. Acute Leukemia

Types

• Acute Myeloid Leukemia (AML): Myeloid/monocytic/erythroid/megakaryocytic precursors
• Acute Lymphoblastic Leukemia/Lymphoma (ALL): B-cell or T-cell precursors

Diagnostic Methods

1. Peripheral blood/bone marrow smear: Blasts ≥20% BM; Auer rods (AML - pink rod-like crystalline inclusions of azurophilic granules fused - pathognomonic of AML)
2. Cytochemistry: MPO (myeloperoxidase - AML+), Sudan Black B (AML+), PAS (ALL+, AML variable), NSE (non-specific esterase - monocytic AML+)
3. Immunophenotyping (flow cytometry): CD markers distinguish AML vs ALL and subtypes:
   • AML: CD13, CD33, CD117 (c-kit), CD34 (stem), MPO; M3 (APL): CD33++, CD34-
   • B-ALL: CD19, CD10 (CALLA), CD22, CD79a, TdT+
   • T-ALL: CD3, CD7, CD2, TdT+
4. Cytogenetics/FISH/PCR: Crucial for classification and prognosis:
   • AML: t(8;21) - RUNX1-RUNX1T1 (good prognosis); t(15;17) - PML-RARA (APL - excellent with ATRA); inv(16) - CBFβ-MYH11 (good); FLT3-ITD (poor); NPM1 mutation (intermediate-good)
   • B-ALL: t(9;22) BCR-ABL (Philadelphia+, poor - needs TKI); t(12;21) ETV6-RUNX1 (pediatric, good); t(1;19), t(4;11) MLL-AF4 (infant, poor)

Clinical and Morphological Characteristics

• Bone marrow failure: anemia (fatigue, pallor), thrombocytopenia (bleeding, petechiae, purpura), neutropenia (infections)
• Leukemic infiltration: lymphadenopathy, splenomegaly, hepatomegaly, skin (leukemia cutis), gum hyperplasia (especially monocytic AML - M5), CNS (meningeal leukemia)
• Hyperuricemia (tumor lysis), DIC (especially APL)

• Bone marrow: hypercellular, effaced architecture, sheets of blasts
• Peripheral blood: may show leukocytosis (many blasts), leukopenia, or normal WBC with blasts
• Lymph nodes: effacement by blasts

Complications

• Severe infections (gram-negative sepsis, fungal - Aspergillus, Candida)
• Hemorrhage (DIC in APL; thrombocytopenia)
• CNS leukemia
• Tumor lysis syndrome (hyperuricemia, hyperkalemia, hyperphosphatemia, ARF)
• Treatment toxicity (anthracycline cardiotoxicity, mucositis)

Causes of Death

• Infection (most common): gram-negative sepsis, invasive fungal infection
• Hemorrhage (DIC especially in APL)
• CNS hemorrhage
• Refractory disease/relapse
• Organ failure

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53. Chronic Leukemia

Chronic Myeloid Leukemia (CML)

• CBC: leukocytosis (50,000-500,000/μL); all stages of myeloid maturation on smear; basophilia (hallmark), eosinophilia; thrombocytosis
• Bone marrow: Hypercellular; full spectrum of myeloid maturation; increased megakaryocytes; minimal blasts (<10%)
• Philadelphia chromosome: Cytogenetics (G-banding); FISH; RT-PCR for BCR-ABL1 (most sensitive - detects minimal residual disease)
• LAP (leukocyte alkaline phosphatase) score: low in CML (vs. high in leukemoid reaction)

• Chronic phase (CP): Insidious onset; splenomegaly (massive); fatigue; WBC very high; <10% blasts; responds to TKI
• Accelerated phase (AP): 10-19% blasts; increasing basophilia; thrombocytopenia; cytogenetic evolution (additional chromosome abnormalities)
• Blast phase (BP/blast crisis): ≥20% blasts (myeloid 70%, lymphoid 30%); behaves like acute leukemia; refractory

Chronic Lymphocytic Leukemia (CLL)

• CBC: lymphocytosis >5000/μL; smudge (basket) cells on smear (fragile CLL cells smear out)
• Bone marrow: infiltration by small lymphocytes (interstitial, nodular, or diffuse pattern)
• Immunophenotyping: CD19+, CD23+, CD5+ (co-expression of B cell CD19 with T cell marker CD5 = pathognomonic), CD10-, surface Ig dim; FMC7-
• Cytogenetics/FISH: del(13q) - most common, good prognosis; del(17p)/TP53 - worst; del(11q) - intermediate; trisomy 12 - intermediate
• IGHV mutation status: mutated IGHV (post-GC cell, good prognosis); unmutated (pre-GC, worse)
• ZAP-70 expression (unfavorable), CD38+ (unfavorable)

• Peripheral blood: mature small lymphocytes, smudge cells
• Lymph nodes: diffuse effacement by small round lymphocytes; proliferation centers (pseudofollicles = pathognomonic of CLL)
• Splenomegaly (white pulp expansion), hepatomegaly
• Bone marrow infiltration
• Autoimmune hemolytic anemia (AIHA), ITP (warm antibody type)
• Hypogammaglobulinemia → recurrent infections
• Staging: Rai (0-IV) or Binet (A-C)

• Infections (hypogammaglobulinemia, neutropenia)
• Richter transformation (transformation to diffuse large B cell lymphoma - DLBCL): aggressive, median survival 6 months
• Disease progression
• Autoimmune cytopenias

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54. Hodgkin Lymphoma (Lymphogranulomatosis)

Clinical and Morphological Characteristics

Histopathological Types (WHO Classification)

• Different biology; "popcorn" (LP) cells: CD20+, CD45+, CD30-, CD15-; EBV-negative
• Nodular pattern; lymphocytes and histiocytes (B cells predominate)
• Excellent prognosis; potential for late DLBCL transformation

Staging (Ann Arbor/Lugano)

• Stage I: Single lymph node region or single extranodal site
• Stage II: ≥2 node regions, same side of diaphragm
• Stage III: Both sides of diaphragm
• Stage IV: Disseminated extranodal involvement
• B symptoms: fever >38°C, drenching night sweats, weight loss >10% body weight (unfavorable)

Spread Pattern

• Contiguous spread (characteristic of cHL): spreads to adjacent lymph node regions in orderly fashion (vs. NHL which is non-contiguous)

Prognosis and Causes of Death

• Overall: excellent; cure rate ~80-90% with modern therapy (ABVD - doxorubicin, bleomycin, vinblastine, dacarbazine; or BEACOPP; + radiation for limited stage)
• Poor prognostic factors: Stage IV, B symptoms, large mediastinal mass, ≥4 nodal sites, low albumin/hemoglobin, leukocytosis
• Causes of death: Disease progression/relapse; late effects of treatment (secondary malignancies - AML, DLBCL, breast/lung cancer; cardiotoxicity - doxorubicin; pulmonary toxicity - bleomycin; hypothyroidism from radiation)

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55. Non-Hodgkin Lymphomas (NHL)

Principles of Classification (WHO Classification of Hematolymphoid Tumors, 5th ed.)

1. Cell lineage: B-cell vs. T/NK-cell vs. histiocytic/dendritic cell
2. Stage of differentiation: Precursor (lymphoblastic) vs. mature (peripheral)
3. Morphology + Immunophenotype + Genetics + Clinical features - all integrated

• B-cell lymphomas (85-90% of NHL)
• T/NK-cell lymphomas (10-15%)

Key B-Cell Lymphomas

Key T/NK-Cell Lymphomas

Diagnostic Methods

• Biopsy: Lymph node excision (preferred over core needle for architecture); bone marrow trephine; extranodal site
• Morphology: H&E; effaced lymph node architecture; pattern (follicular, diffuse, mantle zone, marginal zone, sinusoidal)
• Immunohistochemistry (IHC) panel: CD20, CD3, CD5, CD10, CD23, CD30, BCL2, BCL6, cyclin D1, Ki-67, MYC, ALK, MUM1/IRF4
• Flow cytometry: Rapid immunophenotyping of blood/BM; light chain restriction (clonality)
• Cytogenetics/FISH: Specific translocations t(14;18), t(8;14), t(11;14), t(2;5); del(17p)
• Molecular: PCR for Ig/TCR gene rearrangement (clonality); NGS (somatic mutations, MYD88 in Waldenstrom)
• PET-CT: Staging and response assessment (Deauville criteria)

Prognosis and Causes of Death

• Wide spectrum: indolent (FL, CLL) to aggressive (Burkitt, PTCL)
• Prognostic scoring: IPI (International Prognostic Index) for aggressive NHL: age, LDH, performance status, stage, extranodal sites
• Causes of death: Disease progression; infections (immunosuppression from disease and treatment); treatment toxicity (cardiotoxicity, secondary AML); transformation to higher-grade lymphoma; CNS involvement; organ failure

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