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🔬 PATHOLOGY IMPORTANT TOPICS - MBBS 2nd Year

Expert Pathologist Notes | 10-Mark Format

Each topic: Definition → Etiology → Pathogenesis → Gross → Microscopy

PART 1: GENERAL PATHOLOGY

1. ACUTE INFLAMMATION

Definition

A rapid, short-lived (hours to days) vascular and cellular response of living tissues to injury, characterized by exudation of fluid and migration of leukocytes (mainly neutrophils) to the site of injury.

Etiology

Microbial infections (bacteria, viruses, fungi)
Physical agents: burns, radiation, trauma
Chemical agents: acids, alkalis, toxins
Tissue necrosis (ischemia)
Foreign bodies
Immune reactions

Pathogenesis

Cardinal signs: Rubor (redness), Calor (heat), Tumor (swelling), Dolor (pain), Functio laesa (loss of function)

Step 1 - Vascular changes:

Brief vasoconstriction (seconds) → vasodilation (arterioles, capillaries) → increased permeability
Slowing of blood flow → stasis

Step 2 - Cellular events (PAVEMENTING → EMIGRATION):

Margination - WBCs move to vessel periphery
Rolling - WBCs roll along endothelium (via Selectins: P & E selectin)
Adhesion - firm attachment (via Integrins + ICAM-1)
Transmigration/Diapedesis - WBCs cross endothelium (CD31/PECAM)
Chemotaxis - directed movement toward injury (C5a, LTB4, IL-8, bacterial products)
Phagocytosis - engulfment and killing

Chemical mediators:

Mediator	Source	Action
Histamine	Mast cells	Vasodilation, ↑ permeability
PGE2, PGI2	Arachidonic acid	Vasodilation, pain, fever
LTB4	AA pathway	Chemotaxis
C3a, C5a	Complement	Vasodilation, chemotaxis
IL-1, TNF	Macrophages	Fever, systemic effects
PAF	Mast cells	Platelet activation, ↑ permeability

Gross Appearance

Affected tissue: red, hot, swollen, painful
Serous exudate (thin, watery) - skin blister
Fibrinous exudate - thick, yellow (lobar pneumonia)
Purulent/pus (suppurative) - abscess formation

Microscopy

Dilated congested blood vessels
Neutrophil infiltration (hallmark of acute inflammation) in early phase
Edema fluid in interstitium
Fibrin strands in exudate
Necrotic debris if severe
Later: monocytes replace neutrophils

2. CHRONIC INFLAMMATION

Definition

Inflammation of prolonged duration (weeks to months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously. Hallmark cell: Lymphocytes and Macrophages.

Etiology

Persistent infections (TB, syphilis, fungi, parasites)
Prolonged exposure to toxic agents (silica - silicosis, asbestos)
Autoimmune diseases (RA, SLE)
Follows unresolved acute inflammation

Pathogenesis

Macrophage activation is central (M1 = classically activated - destroy; M2 = alternatively activated - repair)
Macrophages release: IL-1, TNF-α, IL-6, ROS, proteases → tissue destruction
T-helper cells (Th1) release IFN-γ → activate macrophages
Fibroblast proliferation → fibrosis and scarring
Neovascularization (angiogenesis)
Tissue remodeling with MMPs (matrix metalloproteinases)

Gross Appearance

Thickened, indurated tissue
Scarring and fibrosis
Loss of normal architecture
Organ may be shrunken (e.g., cirrhotic liver, contracted kidney)

Microscopy

Mononuclear cell infiltrate: Lymphocytes + Macrophages + Plasma cells (key feature)
Tissue destruction
Fibrosis (collagen deposition)
Angiogenesis (new vessel formation)
No prominent neutrophils (unlike acute)
Epithelioid cells if granulomatous

3. GRANULOMATOUS INFLAMMATION

Definition

A specialized form of chronic inflammation characterized by aggregates of activated macrophages (epithelioid cells), often with multinucleated giant cells, lymphocytes, and plasma cells.

Etiology

Infective:

Tuberculosis (M. tuberculosis) - MOST IMPORTANT
Leprosy (M. leprae)
Syphilis (T. pallidum)
Histoplasmosis, Cryptococcosis

Non-infective:

Sarcoidosis (non-caseating granulomas)
Crohn's disease
Foreign body (suture, silica, talc)
Berylliosis

Pathogenesis

Antigen not easily degradable → persistent macrophage activation
Th1 cells release IFN-γ → macrophages transform into epithelioid cells (large, pale, polygonal)
Epithelioid cells fuse → Multinucleated Giant cells
Types of giant cells:
- Langhans type - nuclei arranged at periphery in horseshoe pattern (TB)
- Foreign body type - nuclei randomly scattered
- Touton giant cells - ring of nuclei, foamy cytoplasm (xanthomas)
Central caseous necrosis (in TB) surrounded by epithelioid cells + Langhans giant cells + lymphocytes + fibrosis

Gross Appearance

TB granuloma (tubercle): Soft, cheese-like center (caseous necrosis), grey-white nodule 1-2mm
Sarcoidosis: Hard, non-caseating nodules
Calcified old granulomas appear as calcium deposits

Microscopy

TB Granuloma - MUST KNOW:

Central caseous necrosis (pink, granular, acellular)
Surrounding epithelioid cells (large pale cells with "footprint-shaped" nuclei)
Langhans giant cells (nuclei at periphery in horseshoe)
Peripheral rim of lymphocytes
Outer zone of fibroblasts and collagen

Sarcoidosis: Same but NO caseous necrosis - "naked granuloma"

4. NECROSIS

Definition

Necrosis is the sum of morphological changes that follow cell death in a living tissue, resulting from the progressive degradative action of enzymes on the lethally injured cell.

Etiology

Ischemia/infarction (most common)
Toxins (chemicals, drugs)
Physical agents (heat, cold, radiation)
Infections (bacterial toxins, viruses)
Immune-mediated injury
Nutritional deficiency

Pathogenesis

Irreversible cell injury → cell death:

ATP depletion → Na/K pump failure → cell swelling
Intracellular Ca²⁺ rises → activates: phospholipases, proteases, endonucleases, ATPases
Mitochondrial dysfunction → free radical production
Cell membrane damage → lysosomal enzyme release
DNA fragmentation

Two enzyme systems degrade dead cells:

Autolysis - own lysosomal enzymes
Heterolysis - leukocyte enzymes

Types of Necrosis (Gross + Microscopy)

Type	Location	Gross	Microscopy
Coagulative	Heart, kidney, spleen	Firm, pale, preserved outline	Ghost cells - outlines preserved, no nuclei
Liquefactive	Brain, abscess	Soft, liquid, cystic	Complete dissolution, debris + neutrophils
Caseous	TB, fungal	Soft, cheese-like, white	Granular pink debris, NO cell outlines
Fat necrosis	Pancreas, breast	Chalky white deposits (saponification)	Fat cells with calcium soap deposits
Fibrinoid	Blood vessel walls	Not grossly visible	Bright pink, fibrin-like material in walls
Gangrenous	Limbs	Dry/wet/gas gangrene	Coagulative + putrefaction

Key Microscopic Features (Necrosis vs Apoptosis)

Feature	Necrosis	Apoptosis
Cell size	Swollen	Shrunken
Nucleus	Pyknosis → karyorrhexis → karyolysis	Fragmented, condensed
Inflammation	YES	NO
Membrane	Disrupted	Intact (blebs)
Trigger	Pathological	Physiological or pathological

5. APOPTOSIS

Definition

Apoptosis is programmed cell death - an active, energy-dependent, genetically regulated process of cell deletion that maintains tissue homeostasis. No inflammation occurs.

Etiology

Physiological:

Embryogenesis (finger formation, organ development)
Hormone withdrawal (endometrial shedding, involution of lactating breast)
Immune regulation (deletion of autoreactive T cells)
Cell turnover in epithelium

Pathological:

Viral infections (HIV, hepatitis - Councilman bodies in liver)
DNA damage beyond repair
Cytotoxic T-cell killing
Radiation, cytotoxic drugs

Pathogenesis

Two pathways:

1. Intrinsic (Mitochondrial) Pathway:

DNA damage / Growth factor withdrawal → Pro-apoptotic proteins (Bax, Bak) activated
Mitochondria releases Cytochrome C
Cytochrome C + APAF-1 → Apoptosome → activates Caspase 9 → Caspase 3
Anti-apoptotic: BCL-2 (blocks this pathway)

2. Extrinsic (Death Receptor) Pathway:

Fas ligand binds Fas (CD95) receptor
TNF binds TNF-R1
Activates Caspase 8 → Caspase 3
Caspase 3 = executioner caspase

Execution phase:

Nuclear chromatin condensation
DNA fragmentation (ladder pattern on gel - 180bp)
Cell blebbing → apoptotic bodies

Gross Appearance

Not visible grossly (individual cell death, no inflammation)

Microscopy

Cell shrinkage
Dense nuclear chromatin condensation (pyknosis)
Cytoplasmic eosinophilia
Formation of apoptotic bodies (membrane-bound fragments)
Engulfed by neighboring cells or macrophages (efferocytosis)
NO inflammatory reaction
Special stain: TUNEL assay detects fragmented DNA

6. CELLULAR ADAPTATIONS

Definition

Cellular adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment (stress or abnormal stimulation).

Etiology/Types

1. ATROPHY - decrease in cell/organ size

Causes: Disuse, denervation, inadequate nutrition, loss of blood supply, loss of endocrine stimulation, aging
Gross: Organ smaller than normal
Micro: Smaller cells, lipofuscin pigment accumulates ("wear and tear" pigment)

2. HYPERTROPHY - increase in cell SIZE (not number)

Causes: Increased workload (cardiac hypertrophy), hormonal (uterus in pregnancy), compensatory
Gross: Organ enlarged, walls thickened (e.g., heart in hypertension)
Micro: Cells larger, nuclei larger, more organelles

3. HYPERPLASIA - increase in cell NUMBER

Causes: Hormonal (endometrial hyperplasia in estrogen excess), compensatory (liver regeneration), chronic irritation
Gross: Organ enlarged, uniform
Micro: Increased cells per unit area, architecturally normal

4. METAPLASIA - replacement of one differentiated cell type by another

Causes: Chronic irritation/injury
Examples:
- Squamous metaplasia: Respiratory tract (smoking), endocervix (chronic cervicitis), bladder (stones)
- Columnar metaplasia: Barrett esophagus (GERD - squamous → columnar)
- Osseous metaplasia: Myositis ossificans
Micro: Normal cells replaced by different cell type; architecture preserved

5. DYSPLASIA - disordered cell growth, premalignant

Causes: Chronic irritation, carcinogens, HPV
Micro: Loss of polarity, nuclear pleomorphism, increased mitoses, abnormal maturation
NOT a true adaptation - potential precursor to carcinoma

Pathogenesis

Each adaptation is driven by altered gene expression in response to stress
Reversible if stimulus removed (except dysplasia which may progress)

7. EDEMA

Definition

Edema is the accumulation of excess fluid in the interstitial tissue spaces or body cavities.

Exudate: inflammatory, protein-rich, SG >1.020
Transudate: non-inflammatory, protein-poor, SG <1.012

Etiology & Pathogenesis

Starling forces govern fluid movement:

Mechanism	Examples
↑ Hydrostatic pressure	CCF (cardiac failure), portal hypertension, venous obstruction
↓ Plasma oncotic pressure	Nephrotic syndrome, liver failure (↓albumin), malnutrition (Kwashiorkor)
↑ Vascular permeability	Inflammation, burns, anaphylaxis
Lymphatic obstruction	Filariasis (elephantiasis), post-mastectomy, tumor invasion
Na⁺ & water retention	Renal failure, hyperaldosteronism

Cardiac edema: ↑ hydrostatic pressure + RAAS activation → pitting edema (legs, sacrum) Renal edema: Nephrotic - periorbital, generalized (anasarca) Cerebral edema: vasogenic (BBB breakdown) or cytotoxic (cell swelling)

Gross Appearance

Tissue appears pale, swollen, boggy
Pitting edema: pressure leaves indentation
Ascites: fluid in peritoneal cavity
Hydrothorax: pleural fluid
Pulmonary edema: lungs heavy, frothy fluid oozes on cut section

Microscopy

Pale, eosinophilic material in interstitial spaces
Widely spaced cells
Pulmonary edema: pink fluid in alveoli, dilated capillaries
Cerebral edema: pallor of white matter, vacuolation around vessels

8. SHOCK

Definition

Shock is a state of systemic hypoperfusion of tissues due to reduced cardiac output or reduced effective circulating blood volume, leading to cellular hypoxia and organ failure.

Etiology / Types

Type	Cause	Mechanism
Hypovolemic	Hemorrhage, burns, dehydration	↓ Blood volume
Cardiogenic	MI, cardiac tamponade, arrhythmia	↓ Cardiac output
Distributive (Septic)	Gram-negative sepsis (endotoxin)	Vasodilation + ↑ permeability
Neurogenic	Spinal cord injury, anesthesia	Loss of vasomotor tone
Anaphylactic	Allergy (IgE mediated)	Massive vasodilation + ↑ permeability

Pathogenesis

Three stages:

Stage 1: Compensated (Non-progressive):

Baroreceptor activation → SNS stimulation
Tachycardia, peripheral vasoconstriction, ↑ ADH, ↑ RAAS
Vital organs (heart, brain) perfused
Reversible

Stage 2: Progressive (Decompensated):

Compensatory mechanisms fail
Widespread ischemia → lactic acidosis
Acidosis → vasodilation → more hypotension
Endothelial injury → DIC

Stage 3: Irreversible:

Multiorgan failure (MOF)
Gut ischemia → bacterial translocation → sepsis
Death inevitable

Septic shock special features:

Endotoxin (LPS) → macrophage activation → TNF, IL-1, IL-6
Nitric oxide → massive vasodilation
Warm shock initially (bounding pulse), then cold shock

Gross Appearance

Organs: pale or congested
Liver: centrilobular necrosis ("nutmeg liver" in congestion)
Kidney: cortical pallor, tubular necrosis
Lungs: congestion, atelectasis, ARDS pattern
Adrenal: hemorrhagic (Waterhouse-Friderichsen in meningococcal sepsis)

Microscopy

Kidneys: Acute tubular necrosis (ATN) - tubular epithelial cell death, preserved basement membrane
Liver: Centrilobular necrosis, fatty change
Lungs: Hyaline membrane formation (ARDS)
Brain: Ischemic neuronal changes (red neurons)
Heart: Focal myocardial necrosis

9. WOUND HEALING

Definition

Wound healing is the process by which the body repairs injured tissue through a coordinated sequence of cellular and biochemical events.

Etiology (Factors affecting healing)

Local factors: Infection, poor blood supply, foreign body, radiation, wound dehiscence Systemic factors: Diabetes mellitus, malnutrition (Vit C deficiency → scurvy - defective collagen), steroids, immunosuppression, aging

Pathogenesis

Two types:

Primary intention (1° healing): Clean wound, edges apposed (surgical incision)
Secondary intention (2° healing): Open wound, large tissue loss, heals by granulation tissue

Phases of Wound Healing:

1. Hemostasis (0-few hours):

Platelet aggregation → plug
Clot formation (fibrin)
Platelets release: PDGF, TGF-β (initiate healing)

2. Inflammatory Phase (1-3 days):

Neutrophils clean bacteria and debris (first 24-48 hrs)
Macrophages arrive by day 3 (MOST IMPORTANT cell in healing)
Macrophages release: growth factors (PDGF, FGF, VEGF, TGF-β)

3. Proliferative Phase (3-21 days):

Granulation tissue forms (fibroblasts + new capillaries + macrophages)
Fibroblasts synthesize collagen (Type III first, then Type I)
Angiogenesis (VEGF driven)
Epithelialization (migration of keratinocytes across wound)
Myofibroblasts → wound contraction

4. Remodeling Phase (21 days - 1 year):

Type III collagen → Type I collagen
Tensile strength increases
Maximum tensile strength: 80% of normal (never 100%)

Gross Appearance

Primary intention: Narrow scar, hairline
Secondary intention: Wider scar, granulation tissue visible initially
Keloid: Scar extends beyond wound margins (excess collagen - common in dark skin)
Hypertrophic scar: Raised but within wound margins

Microscopy

Granulation tissue (key features):

Proliferating fibroblasts
New capillaries (thin-walled, plump endothelium)
Inflammatory cells (macrophages, neutrophils)
Loose extracellular matrix
Later: myofibroblasts, collagen deposition

10. AMYLOIDOSIS (Primary & Secondary)

Definition

Amyloidosis is a pathological condition characterized by extracellular deposition of insoluble abnormal fibrillar proteins (amyloid) in various tissues and organs, causing progressive tissue damage.

Etiology / Classification

Type	Fibril Protein	Associated Condition
AL (Primary)	Immunoglobulin light chains	Multiple myeloma, plasma cell dyscrasia
AA (Secondary)	Serum Amyloid A protein	Chronic infections (TB, osteomyelitis), RA, IBD
Aβ	Amyloid precursor protein	Alzheimer's disease
ATTR	Transthyretin	Familial amyloidosis, Senile amyloidosis
Aβ₂M	β₂-microglobulin	Long-term hemodialysis

Pathogenesis

Misfolded proteins resist proteolysis and form β-pleated sheet configuration
Aggregation into fibrils → deposit in extracellular space
Serum Amyloid P (SAP) binds fibrils → protects from degradation
Progressive organ dysfunction:
- Kidneys: ↓ filtration → nephrotic syndrome
- Heart: restrictive cardiomyopathy
- Liver: hepatomegaly
- Nerves: peripheral neuropathy

Gross Appearance

Organ enlarged, pale
"Lardaceous" appearance (bacon-like, waxy, firm)
Sago spleen: amyloid in lymphoid follicles (small granules like sago seeds)
Lardaceous spleen: amyloid in sinusoids (diffuse waxy appearance)
Kidney: enlarged, pale, waxy

Microscopy

Amorphous eosinophilic extracellular material in H&E
Congo Red stain: Pink-orange color → Apple-green birefringence under polarized light (PATHOGNOMONIC)
Metachromasia with Crystal violet
Thioflavin T: Fluorescence
Distribution: Around blood vessels, glomerular mesangium, interstitium
Pressure atrophy of adjacent parenchymal cells

11. NEOPLASIA

Definition

Neoplasia (literally "new growth") is an abnormal mass of tissue whose growth exceeds and is uncoordinated with that of normal tissues and persists in the same excessive manner after cessation of the stimuli that evoked the change. (Willis, 1952)

Tumor = Neoplasm (benign or malignant)

Etiology (Carcinogenesis)

Chemical carcinogens:

Direct acting: Alkylating agents (nitrogen mustard)
Indirect (procarcinogens → activated by P450): Polycyclic hydrocarbons (benzpyrene in smoking), azo dyes, aflatoxins

Physical:

UV radiation → pyrimidine dimers → SCC, BCC, melanoma
Ionizing radiation → AML, thyroid carcinoma

Viral:

DNA viruses: HPV (CA cervix), HBV (HCC), EBV (Burkitt lymphoma, Hodgkin), KSHV (Kaposi sarcoma)
RNA viruses: HTLV-1 (Adult T-cell leukemia)

Genetic:

Inherited mutations: BRCA1/2 (breast/ovary), APC (colon), RB (retinoblastoma), p53 (Li-Fraumeni)

Pathogenesis (Molecular Basis of Carcinogenesis)

Four fundamental alterations:

1. Self-sufficiency in growth signals (Proto-oncogenes mutated → Oncogenes):

RAS mutations (30% of all cancers) - growth signal constantly ON
MYC amplification - transcription factor, promotes cell cycle
HER2/neu amplification (breast cancer)

2. Insensitivity to growth-inhibitory signals (Tumor Suppressor Genes lost):

RB gene (retinoblastoma) - gatekeeper of cell cycle (G1 checkpoint)
p53 (guardian of the genome) - mutated in 50% of all cancers; induces apoptosis on DNA damage
APC gene (colon cancer)

3. Evasion of apoptosis:

BCL-2 overexpression (Follicular lymphoma - t(14;18))
Loss of p53

4. Limitless replication potential:

Telomerase activation - allows indefinite division

5. Angiogenesis:

VEGF upregulation → tumor neovasculature

6. Invasion and metastasis:

Loss of E-cadherin → reduced cell adhesion
MMPs dissolve basement membrane
EMT (epithelial-mesenchymal transition)

Gross Appearance

Benign tumor:

Well-encapsulated, smooth borders
Soft or firm, homogeneous cut surface
No necrosis/hemorrhage usually

Malignant tumor:

Infiltrative, no capsule, irregular borders
Heterogeneous, areas of necrosis (central) and hemorrhage
Hard (scirrhous) in some (breast carcinoma)
Papillary/fungating/ulcerating surface

Microscopy

Benign:

Closely resembles parent tissue (well-differentiated)
Uniform cells, no pleomorphism
Rare/no mitoses
No invasion of capsule or vessels
Pushing (not infiltrating) borders

Malignant:

Nuclear pleomorphism (variation in size and shape)
Hyperchromatism (dark nuclei)
Increased nuclear:cytoplasmic ratio
Abnormal mitotic figures (tripolar, etc.)
Loss of polarity
Invasion of vessels and lymphatics
Necrosis
Tumor giant cells

12. THROMBOSIS & EMBOLISM

Thrombosis - Definition

A thrombus is an abnormal, solid mass formed from blood constituents in the cardiovascular system during life.

Virchow's Triad (Etiology)

Endothelial injury - atherosclerosis, hypertension, trauma (most important)
Abnormal blood flow - stasis (immobility, cardiac failure), turbulence (bifurcations)
Hypercoagulability - factor V Leiden, antiphospholipid syndrome, OCP use, malignancy

Pathogenesis of Thrombus

Endothelial injury → von Willebrand factor exposed
Platelet adhesion → activation → aggregation (platelet plug)
Coagulation cascade activated → fibrin mesh
Arterial thrombus (white thrombus): Platelets + fibrin, at site of atherosclerosis
Venous thrombus (red thrombus/phlebothrombosis): RBCs trapped in fibrin mesh (stasis-related, e.g., DVT)

Fate of thrombus:

Resolution - fibrinolysis, most common small thrombi
Organization - fibroblasts invade, scar tissue
Recanalization - new channels form through organized thrombus
Propagation - grows bigger
Embolization - breaks off → embolus

Gross Appearance

Arterial thrombus: Grey-white, laminated (Lines of Zahn - alternating platelet + RBC layers), adherent to wall
Venous thrombus (ante-mortem): Red-brown, coarsely layered, may have head (grey-white) and tail (red)
Post-mortem clot (chicken fat clot): Yellow top (plasma proteins) + red bottom (RBCs), NOT adherent, gelatinous

Microscopy

Lines of Zahn: Pale (platelet-fibrin) layers alternating with pink-red (RBC) layers
This distinguishes ante-mortem thrombus from post-mortem clot

Embolism - Definition

An embolus is any intravascular mass (solid, liquid, or gas) carried in blood and capable of lodging in a vessel too small to allow its passage, causing obstruction.

Types of Emboli

Type	Origin	Destination
Pulmonary thromboembolism	DVT (leg veins)	Pulmonary artery
Systemic thromboembolism	Left heart, aorta	Brain, limbs, kidney
Fat embolism	Bone fracture, liposuction	Lung, brain
Air embolism	IV lines, neck veins	Lung
Amniotic fluid embolism	Childbirth	Lung
Tumor embolism	Malignant tumor	Various

Pulmonary embolism (PE):

Source: DVT (95%)
Saddle embolus: straddles bifurcation → sudden death
Smaller PE → pulmonary infarction (wedge-shaped, hemorrhagic)

Fat embolism syndrome:

After long bone fractures (femur)
Triad: respiratory failure + neurological symptoms + petechial rash
Micro: Fat globules in vessels

Gross (PE)

Saddle embolus: large, fills pulmonary artery bifurcation
Smaller emboli: wedge-shaped hemorrhagic infarcts at lung periphery

Microscopy

Fibrin-platelet material in vessels
Fat embolism: empty spaces (fat dissolved) or frozen section shows fat globules (Sudan stain)
Amniotic fluid embolism: squamous cells, mucin, lanugo hair in pulmonary vessels

13. CALCIFICATION (Dystrophic vs Metastatic)

Definition

Pathological calcification is the abnormal deposition of calcium salts in tissues.

Feature	Dystrophic	Metastatic
Definition	Calcification in dead/dying tissue	Calcification in normal tissue
Serum Calcium	NORMAL	HIGH (hypercalcemia)
Causes	Old TB granulomas, atherosclerotic plaques, dead parasites, necrotic tumors, psammoma bodies	Hyperparathyroidism, Vit D excess, multiple myeloma, metastatic bone disease
Location	Anywhere dead tissue exists	Interstitial tissues of kidney, lung, gastric mucosa, blood vessels
Mechanism	Membrane damage → Ca²⁺ influx; phosphatases released	↑ Ca × P product → precipitation

Psammoma bodies (special): concentric laminar calcification in:

Papillary thyroid carcinoma
Papillary serous carcinoma of ovary
Meningioma
Mesothelioma (Mnemonic: PSaMMoMa = Papillary thyroid, Serous ovary, Meningioma, Mesothelioma)

Gross

Dystrophic: gritty, chalky white foci in necrotic tissue (e.g., calcified TB lymph node, "egg-shell calcification")
Metastatic: stone-hard, pale deposits throughout organ

Microscopy

Basophilic (blue) deposits in H&E
Fine granular or coarse clumps
Von Kossa stain: black
Alizarin red: red color

14. DYSPLASIA & CARCINOMA IN SITU

Dysplasia - Definition

Dysplasia is a loss of uniformity of individual cells and loss of architectural orientation of cells. It is a premalignant change but does not invade basement membrane.

Carcinoma In Situ (CIS)

CIS is when the full thickness of an epithelium shows dysplastic changes (all layers replaced by atypical cells) but the basement membrane is INTACT - no stromal invasion.

Etiology

Chronic irritation, chemical carcinogens
HPV (cervical dysplasia/CIN) - most important
Smoking (bronchial dysplasia)
Chronic gastritis (gastric dysplasia)

Pathogenesis

Normal → Mild dysplasia (CIN 1) → Moderate dysplasia (CIN 2) → Severe dysplasia/CIS (CIN 3) → Invasive carcinoma

Accumulation of genetic mutations with each step
Loss of p53, Rb function
HPV E6 (degrades p53), E7 (inactivates Rb)

Gross

Dysplasia: not visible grossly or appears as leukoplakia/erythroplakia
CIS: may show abnormal areas on colposcopy (acetowhite)

Microscopy

Dysplasia features:

Nuclear pleomorphism and hyperchromatism
Increased N:C ratio
Abnormal mitoses
Loss of cell polarity
Maturation disorder
Basement membrane INTACT

CIS: All above changes extend full thickness but basement membrane intact

PART 2: HEMATOLOGY / HEMATOPOIETIC PATHOLOGY

15. ANEMIAS - CLASSIFICATION & LAB DIAGNOSIS

Definition

Anemia is a condition in which the hemoglobin concentration is below the lower limit of normal for age and sex (Adult male <13 g/dL, Adult female <12 g/dL, Children <11 g/dL).

Classification

A. Morphological (MCV-based) - Most useful clinically:

Type	MCV	MCH	Example
Microcytic hypochromic	<80 fL	<27 pg	Iron deficiency, Thalassemia, Sideroblastic anemia
Normocytic normochromic	80-100 fL	27-32 pg	Aplastic anemia, Hemolytic anemia (acute), blood loss
Macrocytic (megaloblastic)	>100 fL	>32 pg	B12/Folate deficiency

B. Etiological Classification:

Blood loss: Acute or chronic hemorrhage
Decreased production (hypoproliferative):
- Nutritional deficiency: Iron, B12, Folate
- Aplastic anemia (marrow failure)
- Chronic disease (ACD)
- Renal failure (↓ EPO)
Increased destruction (hemolytic):
- Intrinsic: G6PD deficiency, Sickle cell, Thalassemia, Hereditary spherocytosis
- Extrinsic: Autoimmune hemolytic anemia, malaria, mechanical heart valves

Pathogenesis (Iron Deficiency Anemia - Most Common)

↓ Iron → ↓ Heme synthesis → ↓ Hemoglobin → microcytic hypochromic RBCs
Stages: Iron store depletion → Iron deficient erythropoiesis → Iron deficiency anemia
Lab: ↓ Serum iron, ↑ TIBC, ↓ Ferritin, ↓ Serum ferritin

Gross

Pallor of skin, conjunctiva, palms
Koilonychia (spoon-shaped nails) in IDA
Glossitis, angular stomatitis

Microscopy (Peripheral smear)

IDA: Microcytic hypochromic RBCs, pencil cells, target cells, increased central pallor (>1/3 cell diameter) Megaloblastic: Macro-ovalocytes, hypersegmented neutrophils (>5 lobes) - PATHOGNOMONIC Hemolytic: Schistocytes, spherocytes, polychromasia, reticulocytosis Sickle cell: Sickle-shaped (crescent) cells, target cells

16. HYPERSENSITIVITY REACTIONS

Definition

Hypersensitivity reactions are exaggerated or inappropriate immune responses that cause tissue injury. They are classified by Gell and Coombs into 4 types.

Etiology & Types

Type I - Immediate/Anaphylactic:

Mechanism: IgE-mediated, mast cell degranulation
Examples: Anaphylaxis (penicillin), asthma (atopic), urticaria, hay fever, food allergy
Mediators: Histamine, leukotrienes (LTC4, LTD4), PGD2
Time: Seconds to minutes

Type II - Cytotoxic:

Mechanism: IgG/IgM against cell surface antigens → complement activation or ADCC
Examples: Hemolytic transfusion reaction, autoimmune hemolytic anemia, Goodpasture syndrome, myasthenia gravis (Ab against AchR), Rh incompatibility (hemolytic disease of newborn)
Time: Hours

Type III - Immune Complex (Serum Sickness type):

Mechanism: Antigen-antibody complexes deposited in tissues → complement activation → neutrophil recruitment → damage
Examples: SLE (anti-dsDNA), post-streptococcal glomerulonephritis, serum sickness, hypersensitivity pneumonitis (farmer's lung)
Time: Hours to days

Type IV - Delayed/Cell-mediated (DTH):

Mechanism: Sensitized T lymphocytes (Th1) → cytokines → tissue damage
Examples: Contact dermatitis (poison ivy, nickel), tuberculin test (Mantoux), organ transplant rejection, granulomatous inflammation (TB)
Time: 24-72 hours (hence "delayed")
No antibodies involved - purely cell mediated

Pathogenesis (Type I in detail)

Sensitization phase: Allergen → IgE production by B cells → IgE binds FcεRI on mast cells (sensitization)

Elicitation phase (second exposure): Allergen crosslinks IgE on mast cells → degranulation → histamine release + new synthesis of leukotrienes/prostaglandins

Early phase (0-30 min): Vasodilation, edema, smooth muscle spasm Late phase (2-8 hr): Eosinophil and basophil recruitment, tissue damage

Gross

Type I: Urticaria (wheals), laryngeal edema, bronchospasm
Type III: Vasculitis lesions (purpura), arthritis
Type IV: Papular rash with vesicles (contact dermatitis), skin induration (Mantoux)

Microscopy

Type I: Edema, vasodilation, eosinophil infiltrate in tissues
Type II: Cell lysis, complement deposits (C3b) on RBCs
Type III: Immune complex deposits in vessel walls, neutrophil infiltrate, fibrinoid necrosis
Type IV: Mononuclear cell (lymphocyte and macrophage) infiltrate, no antibodies, granulomas in some

17. MULTIPLE MYELOMA

Definition

Multiple myeloma is a malignant neoplasm of plasma cells (terminally differentiated B cells) that produce a monoclonal immunoglobulin (M protein), primarily affecting the bone marrow and causing lytic bone lesions.

Etiology

Age: >60 years, M>F
Risk factors: Radiation exposure, genetic factors, MGUS (precursor)
Most common: IgG (55%) > IgA > IgD

Pathogenesis

Malignant plasma cells proliferate in bone marrow
Produce M protein (monoclonal) detectable as M spike on serum protein electrophoresis (SPEP)
RANKL upregulation → osteoclast activation → lytic bone lesions (punched-out on X-ray)
↓ Normal Ig → recurrent infections
Light chain (Bence-Jones protein) deposits in kidney → Myeloma kidney (cast nephropathy)
Bone marrow crowding → pancytopenia

CRAB criteria (diagnostic):

C - Calcium elevated (hypercalcemia)
R - Renal failure
A - Anemia
B - Bone lytic lesions

Gross

Bone: multiple punched-out (lytic) lesions on skull, vertebrae, ribs - "salt and pepper" skull on X-ray
Vertebral collapse → kyphosis
Kidney: enlarged, pale (amyloid or cast nephropathy)

Microscopy

Bone marrow biopsy: sheets of plasma cells >10% (often >30%)
Plasma cells: eccentrically placed nucleus, "clock-face" chromatin, abundant basophilic cytoplasm, perinuclear hof (clear zone = Golgi apparatus)
Flame cells: bright red cytoplasm (IgA myeloma)
Mott cells: cytoplasm filled with Russell bodies (Ig globules)
Rouleaux formation in peripheral smear (RBCs stack like coins due to ↑ proteins)

18. LEUKEMIAS

Definition

Leukemias are malignant neoplasms of hematopoietic stem cells or early progenitor cells characterized by accumulation of leukemic cells in bone marrow and blood, leading to bone marrow failure.

Classification

Type	Age	Key Features
ALL (Acute Lymphoblastic)	Children (2-10 yrs)	Lymphoblasts; t(12;21) most common; best prognosis
AML (Acute Myeloblastic)	Adults	Myeloblasts; Auer rods; t(15;17) in M3 (APL)
CLL (Chronic Lymphocytic)	>60 yrs, most common adult leukemia	Small mature lymphocytes; smudge cells
CML (Chronic Myeloid)	Middle-aged	Philadelphia chromosome t(9;22); BCR-ABL

Etiology

Radiation, benzene, alkylating agents
Down syndrome (21x risk of ALL)
Viruses: HTLV-1 (Adult T-cell leukemia)
Genetic: CML (Ph chromosome)

Pathogenesis

CML:

t(9;22) → BCR-ABL fusion protein → constitutively active tyrosine kinase → uncontrolled proliferation
Treatment: Imatinib (Gleevec) - targeted therapy, blocks BCR-ABL

AML:

Maturation arrest at myeloblast stage
Auer rods (red needle-like cytoplasmic inclusions) - PATHOGNOMONIC of AML

Gross

Pale, infiltrated bone marrow
Lymphadenopathy, splenomegaly, hepatomegaly
Meningeal involvement (ALL - CNS spread)

Microscopy

ALL: Lymphoblasts - large nucleus, scant cytoplasm, indistinct nucleoli, PAS positive AML: Myeloblasts with Auer rods (eosinophilic needle inclusions), myeloperoxidase positive CLL: Small mature lymphocytes, smudge/basket cells (fragile cells ruptured on smear) - HALLMARK CML: All stages of myeloid maturation, myelocytes predominate, ↓ LAP score (leukocyte alkaline phosphatase)

19. HODGKIN vs NON-HODGKIN LYMPHOMA

Hodgkin Lymphoma (HL)

Definition: A lymphoid neoplasm characterized by the presence of Reed-Sternberg (RS) cells in an appropriate cellular background.

Etiology:

EBV association (50% of cases)
Bimodal age: young adults (15-35) and elderly (>50)

RS Cell (Pathognomonic):

Large binucleated or multilobated cell
"Owl eye" nucleoli - large, eosinophilic, surrounded by clear halo
CD15+, CD30+ (tumor markers)

WHO Classification (Subtypes):

Subtype	RS Cells	Background	Prognosis
Nodular sclerosis (most common)	Lacunar RS cells	Collagen bands, lymphocytes	Good
Mixed cellularity	Classic RS cells	Eosinophils, plasma cells, lymphocytes	Intermediate
Lymphocyte rich	Few RS cells	Many lymphocytes	Best
Lymphocyte depleted	Many RS cells	Few lymphocytes	Worst

Gross: Rubber, discrete enlarged lymph nodes; "fish flesh" cut surface

Microscopy: RS cells in background of lymphocytes, eosinophils, plasma cells, fibrosis

Non-Hodgkin Lymphoma (NHL)

Definition: A heterogeneous group of lymphoid malignancies (B-cell or T-cell) that do not contain RS cells.

Key differences from HL:

Feature	Hodgkin	Non-Hodgkin
Spread	Contiguous (orderly)	Non-contiguous (skips nodes)
RS cells	Present	Absent
Mediastinal	Common	Less common
Extranodal involvement	Rare	Common
EBV association	Yes	Some
Prognosis	Generally better	Variable

Common NHL types:

Follicular lymphoma: t(14;18), BCL-2 overexpression, indolent
Diffuse large B-cell (DLBCL): Most common aggressive NHL
Burkitt lymphoma: t(8;14), c-MYC translocation, "starry sky" pattern (EBV+, jaw mass in African children)
Mantle cell lymphoma: t(11;14), Cyclin D1, aggressive

Microscopy (NHL): Monotonous proliferation of lymphoid cells, loss of normal architecture, neoplastic cells in follicular or diffuse pattern

20. PLATELET DISORDERS

Definition

Platelet disorders are conditions characterized by abnormalities in platelet number or function, leading to bleeding tendencies (especially mucosal bleeding, petechiae, purpura).

Classification

A. Thrombocytopenia (↓ platelets <150,000/µL):

Mechanism	Examples
↓ Production	Aplastic anemia, marrow infiltration (leukemia), B12/folate deficiency
↑ Destruction (immune)	ITP (Immune Thrombocytopenic Purpura) - autoantibodies (IgG) against GPIIb/IIIa
↑ Destruction (non-immune)	TTP (Thrombotic Thrombocytopenic Purpura), DIC, HUS
Sequestration	Hypersplenism

ITP - Key Points:

Acute ITP: children, post-viral, self-limiting
Chronic ITP: adults, especially women; antiplatelet antibodies
Mega-karyocytes normal or increased in marrow (increased production to compensate)
Treatment: Steroids, IVIG, splenectomy

B. Thrombocytosis (↑ platelets):

Reactive (infection, post-splenectomy, iron deficiency)
Neoplastic (essential thrombocythemia)

C. Platelet Dysfunction:

Glanzmann thrombasthenia (deficient GPIIb/IIIa)
Bernard-Soulier syndrome (deficient GPIb - can't bind vWF)
Storage pool disease

Gross

Petechiae (pin-point hemorrhages <3mm) - skin, mucosae
Purpura (3-10mm)
Ecchymoses (>10mm bruises)

Microscopy

Peripheral smear: decreased or absent platelets
Bone marrow biopsy (ITP): normal/increased megakaryocytes
DIC/TTP: schistocytes (fragmented RBCs) due to microangiopathic hemolytic anemia

21. HAEMOPHILIA

Definition

Haemophilias are X-linked recessive coagulation disorders caused by deficiency of specific clotting factors, characterized by prolonged bleeding after trauma.

Types

Feature	Haemophilia A	Haemophilia B
Factor deficient	Factor VIII	Factor IX
Gene	X chromosome (Xq28)	X chromosome (Xq27)
Other name	Classic haemophilia	Christmas disease
Frequency	80% of haemophilias	15-20%

Etiology

X-linked recessive: males affected, females carriers
30% cases: new mutations (no family history)
vWD (von Willebrand disease): most common inherited bleeding disorder (deficiency of vWF - needed for platelet adhesion AND Factor VIII carrier)

Pathogenesis

Factor VIII/IX are part of intrinsic pathway → activates Factor X → common pathway → thrombin → fibrin
Deficiency → clot cannot form properly → bleeding into joints (hemarthrosis), muscles, prolonged after minor cuts

Lab findings:

Prolonged aPTT (intrinsic pathway test)
Normal PT (extrinsic pathway intact)
Normal bleeding time (platelets normal)
↓ Factor VIII or IX assay (confirmatory)

Gross

Hemarthrosis: swollen, tender joint (knee most common)
Hematoma in muscles
Hematuria
Intracranial hemorrhage (serious)

Microscopy

Joints: hemosiderin deposition, synovial hyperplasia, cartilage erosion
"Rusty" brown deposits from repeated bleeds

PART 3: SYSTEMIC PATHOLOGY - CARDIOVASCULAR & RESPIRATORY

22. ATHEROSCLEROSIS

Definition

Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries characterized by intimal thickening due to accumulation of lipids, cells, and matrix (atherosclerotic plaque/atheromas).

Etiology (Risk Factors)

Non-modifiable: Age, male sex, family history Modifiable: Hyperlipidemia (LDL↑ most important), hypertension, smoking, diabetes mellitus, obesity

Pathogenesis (Response to Injury Hypothesis)

Endothelial injury → increased permeability, leukocyte adhesion
Monocyte adhesion and migration into intima → transform to macrophages
Macrophages take up oxidized LDL via scavenger receptors → become foam cells
Fatty streak (earliest lesion) forms
Smooth muscle migration from media → intima
Smooth muscle proliferation + collagen synthesis → fibrous plaque
Plaque grows → narrowing of lumen → ischemia
Plaque rupture → thrombosis → MI, stroke

Gross Appearance

Stages:

Fatty streak: Flat, yellow, intimal streaks in aorta (earliest; seen in children)
Fibrous plaque (raised atheromatous plaque): Pearly white, raised, hard, protruding into lumen
Complicated plaque: Ulceration, calcification, hemorrhage into plaque, thrombosis

Most common site: Aorta > Coronary arteries > Carotid arteries

Microscopy

Foam cells (macrophages + lipid) - key feature of early lesion
Fibrous cap: smooth muscle cells + collagen
Necrotic core: lipid, cholesterol clefts, dead foam cells, calcium
Cholesterol clefts (clear spaces where cholesterol crystals dissolved in processing)
Inflammatory cells at periphery: lymphocytes, macrophages

23. MYOCARDIAL INFARCTION (MI)

Definition

MI is coagulative necrosis of myocardium due to prolonged ischemia (usually >20-40 minutes), most commonly from acute coronary artery occlusion by thrombus at site of ruptured atherosclerotic plaque.

Etiology

Coronary artery thrombosis (90%) - from ruptured atherosclerotic plaque
STEMI: Complete occlusion of coronary artery
NSTEMI: Partial occlusion
LAD (left anterior descending) = most commonly occluded ("widow maker")

Pathogenesis

Plaque rupture/fissure → platelet aggregation → thrombus → occlusion
Ischemia: reversible for first 20-40 min; irreversible beyond
Energy failure (ATP depletion) → cell swelling → membrane damage → necrosis
Wavefront phenomenon: Subendocardium (most vulnerable, poorest perfusion) → transmural

Enzyme markers (Serology):

Marker	Rises	Peaks	Returns to normal
Troponin I/T (most sensitive)	3-4 hrs	24-48 hrs	7-10 days
CK-MB	4-8 hrs	18-24 hrs	2-3 days
LDH	24-48 hrs	3-6 days	8-14 days

Gross Appearance (Time-based changes)

Time	Gross Finding
0-6 hrs	No visible change
6-12 hrs	Pale area (pallor)
18-24 hrs	Pale, yellow-grey area
3-7 days	Yellow-grey, soft, mushy center (liquefaction) - MAX RISK OF RUPTURE
1-3 weeks	Red-brown (granulation tissue) around yellow center
2+ months	White, firm scar (fibrosis)

Complications:

Arrhythmias (1st day - most common cause of death)
Cardiogenic shock
Pericarditis (fibrinous) - day 3-5
Rupture (days 5-7) → tamponade/hemopericardium
Ventricular aneurysm
Mural thrombus → embolism
Dressler syndrome (autoimmune pericarditis) - weeks later

Microscopy

Time	Microscopy
0-6 hrs	No change (or waviness of fibers)
6-24 hrs	Coagulative necrosis: ghost cells (cytoplasm pink, no nuclei), hypereosinophilia
24-72 hrs	Neutrophil infiltration
3-7 days	Macrophage infiltration, start of granulation tissue
1-3 weeks	Granulation tissue (fibroblasts + capillaries)
>2 months	Dense fibrous scar (collagen), acellular

24. RHEUMATIC FEVER & RHEUMATIC HEART DISEASE

Definition

Rheumatic fever is an acute, immunologically mediated inflammatory condition that follows Group A beta-hemolytic Streptococcal (GABHS) pharyngitis, affecting the heart, joints, skin, and CNS.

Etiology

Group A Streptococcus (S. pyogenes) pharyngitis → triggers immune response
Molecular mimicry: Streptococcal M protein antigens share epitopes with cardiac proteins (myosin, tropomyosin)
Antibodies attack heart tissue → Rheumatic heart disease (RHD)

Pathogenesis

Strep infection → Anti-streptococcal antibodies
Cross-react with cardiac proteins (valves, myocardium)
Type II (cytotoxic) + Type III hypersensitivity
Aschoff body forms in myocardium = PATHOGNOMONIC

Gross Appearance

Acute RHD:

Verrucous endocarditis: Small (1-2 mm), warty, vegetation along line of closure of valve (mitral >> aortic)
Vegetation: sterile, firm, rough
Pancarditis: pericarditis (fibrinous - "bread and butter" pericarditis), myocarditis, endocarditis

Chronic RHD:

Mitral stenosis (most common residual lesion)
Thickened, fused valve cusps, "fish mouth" or "button-hole" mitral valve
Chordae tendineae: thickened, fused, shortened → subvalvular stenosis

Microscopy

ASCHOFF BODY (pathognomonic of acute RHD):

Central area of fibrinoid necrosis
Surrounded by Aschoff cells (modified macrophages with "owl eye" or "caterpillar/Anichkov" nuclei)
Peripheral lymphocytes and plasma cells
Located in interstitial connective tissue of myocardium

Chronic RHD:

Valve: fibrosis, neovascularization, calcification
Fused commissures, thickened leaflets

25. INFECTIVE ENDOCARDITIS

Definition

Infective endocarditis (IE) is a microbial infection of the endocardial surface of the heart, particularly the heart valves, characterized by the formation of vegetations (infected thrombi).

Etiology

Type	Organism	Setting
Acute (ABE)	S. aureus (most common)	Normal valve, IV drug users
Subacute (SBE)	S. viridans (most common)	Damaged valve (RHD), dental procedures
IV drug user	S. aureus, Candida	Tricuspid valve affected
Nosocomial	S. epidermidis, Enterococcus	Prosthetic valves, catheters

Pathogenesis

Turbulent blood flow → endothelial injury → sterile thrombus
Bacteremia (dental/IV procedure) → bacteria adhere to thrombus → multiply
Vegetation grows: bacteria + platelets + fibrin + inflammatory cells
Emboli from vegetation → septic emboli → metastatic abscesses

Gross Appearance

Acute IE:

Large (1-5 cm), irregular, friable, destructive vegetations
On any part of valve (often destructive - perforate cusps)
Vegetations: yellow-grey, ragged, irregular

Subacute IE:

Smaller, firmer vegetations on valve line of closure
Less destructive

Vegetations comparison:

Type	Vegetation	Organism
Infective	Large, destructive, friable	Bacteria
Rheumatic	Small, warty, along line of closure	Sterile
Non-bacterial thrombotic (Marantic)	Small, sterile	No organisms
Libman-Sacks (SLE)	Both surfaces	Sterile

Microscopy

Vegetation: Inflammatory cells (neutrophils), bacteria, platelets, fibrin
Bacterial colonies within vegetation - confirmatory
Valve tissue: necrosis, neutrophilic infiltration
Underlying valve: fibrosis in chronic cases

Osler's nodes (painful, immune complex - finger tips), Janeway lesions (painless, septic emboli - palms/soles)

26. PNEUMONIA

Definition

Pneumonia is acute inflammation of the lung parenchyma (alveoli and terminal bronchioles) caused by infectious or non-infectious agents.

Classification

Type	Pathogen	Pattern
Lobar pneumonia	S. pneumoniae (most common)	Entire lobe consolidated
Bronchopneumonia	S. aureus, H. influenzae, gram-neg	Patchy, around bronchi
Interstitial pneumonia	Viruses, Mycoplasma	Interstitium involved
Primary atypical	Mycoplasma, Legionella, Chlamydia	"Walking pneumonia"

Etiology

Community-acquired: S. pneumoniae (#1)
Hospital-acquired (nosocomial): Gram-negative organisms (Klebsiella, Pseudomonas), S. aureus
Aspiration: Anaerobes
Immunocompromised: PCP (Pneumocystis jirovecii), CMV, Aspergillus

Pathogenesis

Organisms reach alveoli → innate immune response
Exudate fills alveoli → consolidation → impaired gas exchange

Gross Appearance (Lobar pneumonia - 4 stages)

Stage	Time	Appearance
Congestion	Day 1-2	Heavy, boggy, red lung; wet on cut section
Red Hepatization	Day 2-4	Firm, red, liver-like (hepatization); dry, airless on cut section
Grey Hepatization	Day 4-8	Grey-yellow, dry, granular; fibrin + WBCs replace RBCs
Resolution	Day 8+	Enzymatic digestion of exudate, lung returns to normal

Microscopy

Stage	Microscopy
Congestion	Dilated capillaries, serous exudate, few bacteria in alveoli
Red hepatization	Alveoli filled with: RBCs + neutrophils + fibrin
Grey hepatization	Neutrophils + fibrin (RBCs lysed), macrophages appear
Resolution	Macrophages phagocytose debris, alveolar architecture restored

Bronchopneumonia: Patchy, multifocal; bronchi and surrounding alveoli filled with neutrophils and pus; septal thickening

27. TUBERCULOSIS (TB)

Definition

TB is a chronic granulomatous infectious disease caused by Mycobacterium tuberculosis (acid-fast bacilli), primarily affecting the lungs but capable of affecting any organ.

Etiology

M. tuberculosis (human) - most common
M. bovis (bovine) - through milk
Transmission: Droplet nuclei (airborne)
Virulence: Cord factor (trehalose dimycolate) - inhibits phagosome-lysosome fusion
Ghon focus: Primary lesion (usually subpleural, upper zone of lower lobe or lower zone of upper lobe)

Pathogenesis

Primary TB:

Inhalation → alveolar macrophages phagocytose bacteria
Bacteria survive in phagosome (cord factor prevents fusion with lysosome)
Bacteria multiply, macrophages die → bacteremia
3-8 weeks: Th1 response activated → DTH (Type IV HSR)
Granuloma forms (see Granulomatous inflammation)
Ghon focus + Hilar lymph node granuloma = Ghon complex

Secondary (Post-primary) TB:

Reactivation in immunocompromised
Apical (upper lobe, Simon's focus) - most common
Cavitation (hallmark) - central caseous necrosis liquefies, drains via bronchus

Gross Appearance

Primary TB:

Ghon focus: 1-2 cm subpleural focus of grey-white consolidation, with caseous center
Ghon complex: Ghon focus + hilar lymphadenopathy

Secondary/Post-primary TB:

Apical cavities: irregular walled cavities, caseous walls
Cavities contain grey necrotic material
Upper lobe consolidation and fibrosis
Miliary TB: Tiny 1-2mm millet seed-like granulomas throughout lung (hematogenous spread)

Microscopy

Classic caseating granuloma:
- Central caseous (cheese-like, pink, granular, acellular) necrosis
- Epithelioid cells with Langhans giant cells
- Peripheral lymphocyte cuff
- Outer rim fibroblasts
AFB stain (Ziehl-Neelsen/ZN): Red bacilli on blue background (acid-fast positive)

28. EMPHYSEMA & COPD

Definition

COPD: A chronic, progressive respiratory disease characterized by airflow limitation that is not fully reversible. Two main subtypes: Emphysema and Chronic Bronchitis.

Emphysema: Permanent abnormal enlargement of airspaces distal to terminal bronchioles, accompanied by destruction of alveolar walls WITHOUT significant fibrosis.

Etiology

Smoking (most important for both)
Alpha-1 antitrypsin (AAT) deficiency → emphysema (especially panacinar, in non-smokers, young adults)
Air pollution, occupational dusts

Pathogenesis

Protease-antiprotease theory:

Smoking → inflammation → macrophages + neutrophils release elastase and other proteases
Proteases digest elastin in alveolar walls → alveolar destruction
Normally: AAT (alpha-1 antitrypsin) inhibits elastase
Smoking or AAT deficiency → protease activity unopposed → alveolar wall destruction → emphysema

Types of emphysema:

Type	Location	Cause
Centriacinar (centrilobular)	Central acinus (respiratory bronchioles)	Smoking - most common
Panacinar (panlobular)	Entire acinus	AAT deficiency, smoking
Paraseptal	Distal acinus, subpleural	Spontaneous pneumothorax in young
Irregular	Irregular	Scarring

Gross Appearance

Lungs hyperinflated, barrel-shaped chest
Large air spaces (bullae) - especially in subpleural areas
Emphysematous bullae: thin-walled, > 1 cm air spaces
Pale, voluminous lungs
On palpation: abnormally light, crackle on compression
Centriacinar: more severe in UPPER lobes
Panacinar: more severe in LOWER lobes

Microscopy

Enlarged air spaces with destruction of alveolar walls (septa)
Reduced number of alveolar septa
Loss of pulmonary capillaries
No fibrosis
Centriacinar: central dilation, peripheral alveoli preserved
Inflammatory cells, mucus glands (in chronic bronchitis)
"Pink puffer" (emphysema-dominant): thin, barrel chest, pursed lip breathing, no cyanosis

29. BRONCHIECTASIS

Definition

Bronchiectasis is a permanent, abnormal dilatation of the bronchi and bronchioles (>2mm diameter) due to destruction of the bronchial wall, associated with chronic infection and inflammation.

Etiology

Post-infectious: TB, measles, whooping cough, childhood pneumonia
Obstruction: tumor, foreign body → distal dilatation
Cystic fibrosis (most common cause in West)
Primary ciliary dyskinesia (Kartagener syndrome)
Immune deficiency: hypogammaglobulinemia

Pathogenesis

Infection → chronic inflammation → proteases destroy bronchial wall (elastin, cartilage)
Loss of structural support → permanent dilation
Vicious cycle: dilation → mucus pooling → more infection → more destruction

Gross Appearance

Most common: lower lobes, bilateral
Bronchi abnormally dilated to periphery (normally taper)
Types: cylindrical, varicose, saccular (most severe)
Purulent mucus in dilated bronchi
Cut surface: "honeycomb" appearance due to cystic spaces
Peribronchial fibrosis

Microscopy

Dilated bronchi/bronchioles with thickened, inflamed walls
Destroyed cartilage and elastic tissue
Mucosal ulceration and squamous metaplasia
Marked chronic inflammation (lymphocytes, plasma cells, neutrophils in lumen)
Peribronchial fibrosis
Mucus plugging

30. ADULT RESPIRATORY DISTRESS SYNDROME (ARDS)

Definition

ARDS (also called Diffuse Alveolar Damage - DAD) is a clinical syndrome of severe, acute respiratory failure characterized by non-cardiogenic pulmonary edema due to diffuse alveolar injury.

Etiology (Triggers)

Direct lung injury: Pneumonia (most common), aspiration, toxic gas inhalation, near-drowning
Indirect (systemic): Sepsis (most common indirect cause), severe trauma, burns, blood transfusions (TRALI), pancreatitis

Pathogenesis

Trigger → diffuse alveolar injury → endothelial + epithelial cell damage
↑ Vascular permeability → protein-rich fluid floods alveoli
Surfactant loss → alveolar collapse
Hyaline membranes form (fibrin + necrotic epithelial cells)
Impaired gas exchange → hypoxemia

Gross Appearance

Lungs: heavy, dark red, meaty, congested ("hepatized")
Airless, non-crepitant
Diffuse consolidation
Subpleural petechiae

Microscopy

Exudative phase (acute, 1-7 days):

Alveolar edema
Hyaline membranes lining alveolar walls (PAS+, eosinophilic) - HALLMARK
Alveolar macrophages, neutrophils
Capillary congestion with microthrombi

Proliferative phase (1-3 weeks):

Type II pneumocyte hyperplasia (attempts to repair)
Organization of exudate
Fibroblast proliferation

Fibrotic phase (>3 weeks):

Interstitial and intra-alveolar fibrosis
Thickened alveolar walls
Destruction of architecture

PART 4: SYSTEMIC PATHOLOGY - KIDNEY & GI

31. GLOMERULONEPHRITIS

Definition

Glomerulonephritis (GN) is inflammation of the glomeruli, usually immunologically mediated, leading to impaired filtration, proteinuria, hematuria, and eventual renal failure.

Etiology & Types

Two main immunological mechanisms:

Immune complex deposition (Type III HSR): most common
Anti-GBM antibody (Type II HSR): Goodpasture syndrome

Common GN types:

Type	Clinical Presentation	Microscopy	IF	EM
Post-strep GN (most common in children)	Nephritic syndrome	Hypercellular glomeruli, "lumpy-bumpy" IF	Granular (coarse)	Subepithelial humps ("camel humps")
IgA Nephropathy (Berger's)	Recurrent hematuria	Mesangial proliferation	Mesangial IgA deposits	Mesangial deposits
Membranous GN	Nephrotic syndrome	Thickened GBM, "spike and dome"	Granular, subepithelial	Subepithelial deposits ("spikes")
Minimal Change Disease	Nephrotic syndrome (children)	Normal by LM	Negative IF	Effacement of foot processes (EM only)
FSGS	Nephrotic syndrome	Focal segmental sclerosis	Focal IgM, C3	Foot process effacement
Goodpasture	RPGN + lung hemorrhage	Crescentic GN	Linear IgG (anti-GBM)	GBM disruption
Crescentic GN (RPGN)	Rapidly progressive renal failure	Crescents (Bowman's space filled)	Variable	-

Pathogenesis (Post-Streptococcal GN)

Group A Strep infection (skin/throat) → antigen-antibody complexes in circulation → deposit in glomeruli
Complement activation → neutrophil recruitment → glomerular damage
↑ Permeability → hematuria, proteinuria
Epithelial "humps" = subepithelial immune complexes

Gross Appearance

Kidney enlarged, swollen
Flea-bitten kidney: multiple petechial hemorrhages on surface (acute GN)
In chronic GN: small, granular contracted kidney

Microscopy

Post-Strep GN:

Diffuse glomerular hypercellularity (endothelial + mesangial + neutrophil infiltration)
Glomerular capillary loops compressed
"Lumpy bumpy" pattern on IF (granular IgG, C3)
Subepithelial humps on EM

32. NEPHROTIC vs NEPHRITIC SYNDROME

Feature	Nephrotic	Nephritic
Proteinuria	Massive (>3.5 g/day)	Mild to moderate
Hematuria	Absent or mild	Present (RBC casts)
Edema	Severe, generalized	Mild
Hypertension	Mild	Prominent
Renal function	Initially preserved	Reduced GFR, oliguria
Key finding	Hypoalbuminemia	Active urinary sediment
Causes	MCD, Membranous GN, FSGS, Diabetic nephropathy	Post-Strep GN, IgA nephropathy, Goodpasture, Crescentic GN

33. PYELONEPHRITIS

Definition

Pyelonephritis is bacterial infection of the renal pelvis, calyces, and parenchyma, classified as acute (suppurative) or chronic.

Etiology

Most common organism: E. coli (80%) - has P-fimbriae for uroepithelial adhesion
Others: Klebsiella, Proteus, Enterococcus
Route: Ascending infection (most common) from bladder via ureter
Risk factors: Female sex (short urethra), pregnancy, urinary tract obstruction, vesicoureteral reflux (VUR), catheterization, diabetes

Pathogenesis

Ascending route:

Bacteria colonize perineum/urethra → bladder → ureter (retrograde) → renal pelvis → parenchyma
VUR facilitates ascent
Obstruction (stones, BPH) causes stasis → bacterial growth

Gross Appearance

Acute pyelonephritis:

Enlarged kidney, edematous
Yellow-white abscesses in cortex and medulla (wedge-shaped or random)
Yellow streaks from medulla to cortex
Pelvic mucosa hyperemic, covered with purulent exudate

Chronic pyelonephritis:

Small, contracted kidney with irregular surface
Cortical scars overlying dilated calyces (hallmark)
Blunted calyces
Thyroidization of tubules (tubules filled with eosinophilic material like thyroid colloid)

Microscopy

Acute:

Tubules filled with neutrophil casts (WBC casts in urine - diagnostic)
Interstitial edema with neutrophil infiltration
Glomeruli spared (early)
Microabscesses

Chronic:

Interstitial fibrosis and tubular atrophy
Chronic inflammation (lymphocytes, plasma cells)
Thyroidization: tubules filled with eosinophilic colloid-like material
Glomerular sclerosis
Vascular sclerosis

34. PEPTIC ULCER DISEASE (PUD)

Definition

A peptic ulcer is a break in the mucosa of the GI tract (stomach or duodenum) extending through the muscularis mucosae into the submucosa or deeper, due to imbalance between acid/pepsin (aggressive) and mucosal defense (protective) factors.

Etiology

H. pylori infection (most common cause - 95% of duodenal, 70% of gastric ulcers)
NSAIDs (↓ prostaglandins → ↓ mucus + ↓ blood flow)
Zollinger-Ellison syndrome (gastrinoma - massive acid secretion)
Stress ulcers (Curling - burns; Cushing - brain injury)
Smoking, alcohol, steroids

Pathogenesis

H. pylori: Urease → NH₃ → cytotoxins (CagA, VacA) → mucosal damage; impairs mucosal repair
NSAIDs: Inhibit COX-1 → ↓ PGE2 → ↓ mucus, ↓ bicarbonate, ↓ blood flow

Gross Appearance

Benign peptic ulcer:

Round/oval, punched-out ulcer with clean base, smooth, vertical walls
Mucosal folds radiate to ulcer edge ("sun-ray" pattern)
Typically single
Gastric ulcer: lesser curvature, antrum
Duodenal ulcer: first part of duodenum (anterior wall)

Malignant ulcer (carcinoma):

Irregular, overhanging, heaped-up edges
Nodular, necrotic base
Folds do NOT radiate to ulcer edge

Microscopy

Benign peptic ulcer (4 zones from base to surface):

Zone of necrosis - fibrinous debris
Zone of fibrinoid necrosis - bright pink, homogeneous
Zone of granulation tissue - fibroblasts, new capillaries, macrophages
Zone of fibrosis - dense collagen (deepest layer)

Active ulcer: neutrophil infiltration at edges H. pylori: curved bacilli on mucosal surface (Giemsa, Warthin-Starry stains)

35. HEPATITIS B

Definition

Hepatitis B is a viral hepatic infection caused by Hepatitis B Virus (HBV), a DNA virus (Hepadnaviridae), transmitted by blood/body fluids, with potential for chronic liver disease, cirrhosis, and hepatocellular carcinoma.

Etiology

HBV (DNA virus, double-stranded, partially)
Transmission: Blood transfusion, IV drug use, sexual contact, perinatal (vertical)
High-risk for HCC: HBV (especially Asian genotypes B, C)

Serological markers:

Marker	Meaning
HBsAg	Surface antigen - present in active infection
Anti-HBs	Recovery/vaccination
HBeAg	Replicating virus, HIGH infectivity
Anti-HBe	↓ viral replication
HBcAg	Core antigen (not in serum)
Anti-HBc IgM	Acute infection
Anti-HBc IgG	Past infection
"Window period"	HBsAg gone, anti-HBs not yet; only anti-HBc IgM positive

Pathogenesis

HBV is NOT directly cytopathic - liver injury is immune-mediated (CD8+ CTL attack hepatocytes expressing HBV antigens)
Acute HBV → resolves in 90% adults
5-10% → chronic hepatitis → cirrhosis → HCC
Integration of HBV DNA → activation of proto-oncogenes → HCC

Gross Appearance

Acute hepatitis:

Liver: enlarged, soft, congested, yellow

Chronic active hepatitis:

Enlarged, nodular (early cirrhosis)
Biliary cirrhosis appearance eventually

Cirrhosis (end stage):

Small, firm, micronodular liver (1-3mm nodules)

Microscopy

Acute hepatitis:

Hepatocyte ballooning degeneration (swollen, pale cells)
Acidophil bodies (Councilman bodies): shrunken, eosinophilic hepatocytes = apoptosis
Portal tract inflammation (lymphocytes, macrophages)
Interface hepatitis (periportal necrosis)
Kupffer cell hypertrophy

Chronic hepatitis:

Ground glass hepatocytes (HBsAg accumulation in ER) - PATHOGNOMONIC for HBV
Piecemeal necrosis / interface hepatitis
Portal-to-portal bridging necrosis
Progressive fibrosis → cirrhosis
Orcein stain, Shikata orcein: highlights ground glass cells (HBsAg)

36. FATTY LIVER (HEPATIC STEATOSIS)

Definition

Fatty liver (hepatic steatosis) is the abnormal accumulation of triglycerides within hepatocytes (>5% of liver cells contain fat).

Etiology

Most common causes:

Alcohol (most common worldwide)
Obesity + Metabolic syndrome (non-alcoholic fatty liver disease - NAFLD)
Diabetes mellitus
Drugs: Steroids, methotrexate, amiodarone, tetracycline
Pregnancy (acute fatty liver of pregnancy)
Starvation/protein deficiency (Kwashiorkor)

Pathogenesis

Alcohol-induced:

Alcohol → acetaldehyde → disrupts lipid oxidation
↓ Fatty acid oxidation + ↑ fatty acid synthesis
↓ Lipoprotein export (VLDL)
Net: fat accumulates as triglycerides in hepatocytes

NAFLD:

Insulin resistance → ↑ FFA delivery to liver → triglyceride accumulation
Oxidative stress → progression to NASH (non-alcoholic steatohepatitis) → fibrosis

Gross Appearance

Enlarged liver (hepatomegaly)
Soft, yellow-colored
Greasy feel, floats on water
Smooth edges (no cirrhosis in early stage)
Massive fatty change: "foie gras" appearance

Microscopy

Large clear cytoplasmic vacuoles displacing nucleus to periphery (macrovesicular steatosis) - MOST COMMON
Microvesicular steatosis: small droplets around nucleus (acute fatty liver of pregnancy, Reye syndrome)
Alcoholic hepatitis: Macrovesicular steatosis + Mallory-Denk bodies (Mallory hyaline - pink rope-like cytoplasmic inclusions) + neutrophil infiltration
Special stain: Oil red O (stains fat red, on frozen section)

37. HEPATOCELLULAR CARCINOMA (HCC)

Definition

HCC is the most common primary malignant tumor of the liver, arising from hepatocytes, usually developing in the background of chronic liver disease/cirrhosis.

Etiology

Hepatitis B (most common worldwide) - HBV DNA integrates into host genome
Hepatitis C - more common in developed countries
Cirrhosis (from any cause)
Aflatoxin B1 (fungal toxin from Aspergillus in grain - common in Africa/Asia) - forms aflatoxin-p53 adducts
Alcohol-related cirrhosis
NASH → cirrhosis → HCC
Hereditary hemochromatosis, Wilson's disease

Tumor marker: AFP (Alpha-fetoprotein) - elevated in >70% HCC

Pathogenesis

Chronic hepatocyte injury → regeneration → mutations accumulate
Key mutations: p53, β-catenin, TERT promoter
HBV: X protein inactivates p53; viral DNA integration causes chromosomal instability

Gross Appearance

Massive type: Single large mass replacing one lobe
Nodular type: Multiple nodules throughout liver (common in cirrhosis)
Diffuse type: Barely distinguishable from cirrhotic liver
Tumor: grey-white or yellow-green (bile staining), soft, necrotic
Bile production by tumor cells (pathognomonic)
Portal vein invasion → tumor thrombus
Hepatic vein invasion → IVC spread

Microscopy

Cells resemble hepatocytes but with nuclear pleomorphism, prominent nucleoli
Trabecular pattern (most common) - tumor cells arranged in thick trabeculae (2-3+ cells wide)
Sinusoidal blood spaces between trabeculae
Bile production in cytoplasm (green pigment)
Mallory-Denk bodies may be present
Pseudo-glandular (acinar) pattern
Vascular invasion - key finding
Fibro-lamellar HCC (special variant): young patients, NO cirrhosis, large eosinophilic cells with pale fibrous bands, better prognosis

38. PORTAL HYPERTENSION

Definition

Portal hypertension is elevated pressure in the portal venous system (>5 mmHg above inferior vena cava pressure; normal 5-10 mmHg; portal HTN >12 mmHg).

Etiology / Classification

Level	Causes
Pre-hepatic	Portal vein thrombosis, splenic vein thrombosis
Intra-hepatic (sinusoidal)	Cirrhosis (most common), schistosomiasis, sarcoidosis
Post-hepatic (outflow obstruction)	Budd-Chiari syndrome (hepatic vein thrombosis), cardiac failure

Pathogenesis

Liver fibrosis (cirrhosis) → architectural distortion → increased resistance to portal flow
↑ Portal pressure → development of portosystemic collaterals
Congestion of spleen → splenomegaly + hypersplenism

Gross Appearance

Liver: cirrhotic (firm, nodular, small)
Splenomegaly (congestive splenomegaly - "Banti syndrome")
Ascites (peritoneal fluid)

Portosystemic collaterals (Gross):

Esophageal varices (left gastric → azygos system) - most important (rupture → fatal hemorrhage)
Rectal varices (superior → inferior rectal veins)
Caput medusae (paraumbilical veins dilated)
Retroperitoneal collaterals

Microscopy

Cirrhotic liver: regenerative nodules surrounded by fibrous septa (Masson trichrome stain: blue fibrosis)
Spleen: dilated sinusoids, hemosiderin deposits, fibrosis ("Gamma-Gandy" bodies)
Esophageal varices: dilated, thin-walled submucosal veins

39. INFLAMMATORY BOWEL DISEASE (IBD)

Crohn's Disease vs Ulcerative Colitis

Feature	Crohn's Disease	Ulcerative Colitis
Distribution	Any part of GI tract (mouth to anus); patchy ("skip lesions")	Colon only; continuous from rectum
Rectum	Usually spared	Always involved
Depth	Transmural (all layers)	Mucosa + submucosa only
Granulomas	YES (non-caseating)	NO
Fistulae	Common (transmural)	Rare
Strictures	Common ("cobblestone" + "skip")	Rare
Gross	"Cobblestone" mucosa, "Creeping fat," "Hosepipe" bowel	Pseudopolyps, ulcers, hyperemia
Risk of cancer	Slightly increased	Markedly increased (colitis-associated CA)
Extraintestinal	More common	Less common

Etiology (both): Genetic (NOD2 in Crohn's), dysregulated immune response to gut flora, smoking (worsens Crohn's, protective in UC)

Pathogenesis

Abnormal Th1 (Crohn's) or Th2 (UC) response to gut bacteria
Mucosal barrier dysfunction → bacterial invasion → inflammation
Crohn's: granulomatous transmural inflammation
UC: superficial mucosal inflammation with crypt abscesses

Gross

Crohn's:

Skip lesions (alternating normal and diseased segments)
"Cobblestone" mucosa (edematous islands between linear ulcers)
"Creeping fat" (mesenteric fat wraps around bowel)
Fistulae, sinuses
Strictures → obstruction ("Hosepipe/lead pipe sign" on barium)

UC:

Continuous involvement from rectum
Mucosal hemorrhage, ulcers
Pseudopolyps (islands of regenerating mucosa between ulcers)
"Lead pipe" colon on X-ray (loss of haustrations)
Toxic megacolon in severe cases

Microscopy

Crohn's: Transmural chronic inflammation, non-caseating granulomas, lymphoid aggregates in all layers UC: Mucosal and submucosal inflammation; Crypt abscesses (crypts filled with neutrophils); goblet cell depletion; crypt architectural distortion (branching)

PART 5: SYSTEMIC PATHOLOGY - GYNECOLOGY/ONCOLOGY/BONE

40. CARCINOMA CERVIX

Definition

Carcinoma cervix is a malignant tumor of the cervix uteri, most commonly squamous cell carcinoma, arising from the transformation zone (squamocolumnar junction), strongly associated with HPV infection.

Etiology

Human Papillomavirus (HPV) - present in >99% cases
- High-risk types: HPV 16 (SCC) and HPV 18 (Adenocarcinoma) - most important
Multiple sexual partners, early sexual activity
Smoking, oral contraceptives, immunosuppression
Previous STIs (Chlamydia, HSV)

Pathogenesis

HPV infects transformation zone epithelium (squamocolumnar junction)
E6 oncoprotein binds and degrades p53 → no apoptosis
E7 oncoprotein binds and inactivates Rb → uncontrolled cell cycle progression
Normal → CIN1 → CIN2 → CIN3/CIS → Invasive SCC
HPV 16/18 integration into host genome → stable malignant transformation

Gross Appearance

Preclinical/CIN: Acetowhite areas on colposcopy, erosion
Exophytic type (most common): Cauliflower-like, friable mass
Ulcerative type: Necrotic ulcer with everted, ragged edges
Infiltrative (barrel-shaped): Expanded, hard cervix
Invades vagina, bladder, rectum, parametrium

Microscopy

CIN (cervical intraepithelial neoplasia):

Koilocytes (HPV-infected cells): large squamous cells with perinuclear halo (clear space) + nuclear enlargement and hyperchromasia - PATHOGNOMONIC of HPV
CIN 1: lower 1/3 involved
CIN 2: lower 2/3 involved
CIN 3/CIS: full thickness involved, BM intact

Invasive SCC:

Keratin pearls (squamous eddies) - concentric whorls of keratinizing cells - HALLMARK of well-differentiated SCC
Intercellular bridges between cells
Invasion through BM into stroma
Desmoplastic stroma around nests

41. CARCINOMA BREAST

Definition

Carcinoma of the breast is a malignant epithelial tumor of the breast, most commonly arising from the ductal epithelium of the terminal duct lobular unit (TDLU).

Etiology

Female sex, increasing age (most important risk factors)
BRCA1 (chromosome 17q - associated with triple negative CA) and BRCA2 (13q) mutations - hereditary
Hormonal: early menarche, late menopause, nulliparity, OCP use, HRT
Radiation, obesity, alcohol
Family history
Previous benign breast diseases: atypical ductal hyperplasia

Pathogenesis

Hormonal influence: estrogen stimulates ductal proliferation
Mutations in BRCA1/2 → impaired DNA repair → genomic instability
ER+, PR+, HER2+ tumors have targeted therapy available
Triple negative (ER-, PR-, HER2-) = worst prognosis, no targeted therapy, BRCA1-related

Classification:

In situ: DCIS (Ductal Carcinoma in situ) - no invasion
Invasive/Infiltrating:
- Invasive ductal carcinoma (IDC/NST) - most common (70%)
- Invasive lobular carcinoma (ILC) - 15%
- Special types: Mucinous, Tubular, Medullary

Gross Appearance

IDC:

Stony-hard, irregular, stellate mass
Scirrhous consistency (dense fibrous stroma - "desmoplasia")
Grey-white with gritty texture on cut section
Irregular, infiltrative borders
Skin retraction, nipple retraction
"Peau d'orange" (skin dimpling, dermal lymphatic obstruction)

Microscopy

IDC (Not Otherwise Specified):

Irregular nests, cords, tubules of malignant cells in desmoplastic stroma
Nuclear pleomorphism, hyperchromatism, prominent nucleoli
Mitoses
Necrosis (comedonecrosis in DCIS)
Lymphatic/vascular invasion
Lymph node metastasis

DCIS: Malignant cells filling ducts, BM intact; comedonecrosis (central necrosis + calcification in high-grade DCIS) - calcification visible on mammogram

IHC markers: ER, PR, HER2 (scored by IHC or FISH) - determines therapy (Tamoxifen for ER+, Trastuzumab/Herceptin for HER2+)

42. OSTEOSARCOMA

Definition

Osteosarcoma is the most common primary malignant tumor of bone (excluding myeloma), characterized by the production of osteoid or bone directly by malignant cells (tumor osteoid).

Etiology

Peak age: 10-20 years (adolescents), second peak in elderly (Paget's disease, radiation)
Males > Females
Most common site: Metaphysis of long bones (distal femur > proximal tibia > proximal humerus = around the knee)
Risk: RB gene mutation (hereditary retinoblastoma patients have 500x risk), p53 mutation, Paget's disease, radiation, Li-Fraumeni syndrome

Pathogenesis

Loss of tumor suppressor genes (RB, p53) + activation of oncogenes
Malignant osteoblasts produce tumor osteoid (immature woven bone directly by tumor cells)
Tumor breaks through cortex → periosteal reaction

Serum alkaline phosphatase: Elevated (osteoblastic activity)

Gross Appearance

Metaphyseal location
Tumor: grey-white, gritty (calcified areas), with areas of hemorrhage and necrosis
Cortical destruction + extension into soft tissues
Periosteum lifted → Codman's triangle (reactive bone at periosteal margin)
"Sunburst pattern" on X-ray (radiating spicules of bone)

Microscopy

Malignant osteoblasts (pleomorphic, hyperchromatic, mitoses)
Tumor osteoid (pink, amorphous, lace-like, irregular matrix) - DIAGNOSTIC KEY
Tumor osteoid directly produced by malignant cells (without normal trabecular organization)
Areas of chondroid and fibrous tissue also present (mixed)
Calcification in osteoid

Variants: Osteoblastic (most common), chondroblastic, fibroblastic

43. GIANT CELL TUMOUR OF BONE (GCT)

Definition

GCT is a locally aggressive benign (but can rarely be malignant) bone tumor characterized by numerous multinucleated osteoclast-like giant cells on a background of mononuclear stromal cells.

Etiology

Age: 20-40 years (young adults, after epiphyseal fusion)
More common in females
Most common site: Epiphysis of long bones (distal femur, proximal tibia, distal radius)
RANK-L mutation in stromal cells → osteoclast recruitment

Pathogenesis

Mononuclear stromal cells (neoplastic cells) produce RANKL
RANKL recruits and activates osteoclast-like multinucleated giant cells
Giant cells resorb bone → osteolytic lesion
Treatment: Denosumab (anti-RANKL antibody)

Gross Appearance

Epiphyseal location extending to articular surface (unique feature)
"Soap bubble" or "egg-shell" appearance on X-ray (eccentric, lytic, no sclerotic rim, extends to articular surface)
Tumor: red-brown, soft, vascular, with areas of hemorrhage and necrosis
Thin cortex (egg-shell cortex)
No calcification usually

Microscopy

Numerous multinucleated osteoclast-like giant cells (10-100 nuclei per giant cell) uniformly distributed - KEY FEATURE
Background of mononuclear stromal cells (spindle-shaped, oval nuclei identical to giant cell nuclei)
Rich vascularity
Hemosiderin deposits (brown pigment) - "rusty" areas
No tumor osteoid (unlike osteosarcoma)
Mitoses in stromal cells but not atypical

44. WILMS TUMOUR (NEPHROBLASTOMA)

Definition

Wilms tumour (nephroblastoma) is the most common primary renal malignancy of childhood (peak age 3-4 years), a mixed tumor containing blastemal, stromal, and epithelial elements recapitulating different stages of normal kidney development.

Etiology

Age: 3-4 years (most common)
Associated syndromes:
- WAGR syndrome: Wilms + Aniridia + Genitourinary anomalies + intellectual Retardation (WT1 gene deletion on 11p13)
- Denys-Drash syndrome: WT1 mutation + diffuse mesangial sclerosis + gonadal dysgenesis
- Beckwith-Wiedemann syndrome: WT2 gene + organomegaly, macroglossia
WT1 gene (chromosome 11p13): tumor suppressor gene

Pathogenesis

WT1 gene loss → abnormal metanephric blastema development → persistent nephrogenic rests → Wilms tumor
Mutations in WT1 and WTX genes

Gross Appearance

Large, solitary (usually), well-encapsulated tumor
Soft, homogeneous, pale grey-tan ("fish flesh") with foci of necrosis, hemorrhage, cysts
Pseudocapsule present (well-defined border)
Distorts the kidney
Usually unilateral (5-10% bilateral)

Microscopy

Classic triphasic pattern (pathognomonic):

Blastemal component: Small, closely packed oval to spindle blue cells with scant cytoplasm (sheets of primitive cells)
Epithelial component: Attempts at tubule and glomerulus formation (primitive tubular structures)
Stromal component: Spindle cells, loose myxoid stroma, may contain heterologous elements (smooth/skeletal muscle, cartilage, fat)

Anaplasia (nuclear atypia) = poor prognosis

45. CARCINOMA PROSTATE

Definition

Prostate carcinoma is the most common malignancy in elderly males (>50 years), arising predominantly from the peripheral zone of the prostate, almost always adenocarcinoma.

Etiology

Age >50 years, most common in >70 years
Race: African-Americans highest risk
Androgen dependence (testosterone drives growth)
Genetic: BRCA2, AR mutations
Dietary fat, family history

Tumor marker: PSA (Prostate-Specific Antigen) - elevated in carcinoma, BPH, prostatitis

Pathogenesis

Androgen stimulation of peripheral zone cells
Key mutations: Loss of PTEN, AR amplification, TMPRSS2-ERG fusion
PIN (Prostatic Intraepithelial Neoplasia) → precursor

Gross Appearance

Usually peripheral zone (posterior lobe, palpable on DRE)
Irregular, hard, gritty areas
Grey-white, firm, poorly defined
Difficult to distinguish from normal prostate grossly in early stage
Advanced: invades seminal vesicles, rectum

Microscopy

Gleason Grading System (key exam topic):

Grade 1: Small, uniform glands, closely packed (well-differentiated)
Grade 3: Infiltrating glands, angular
Grade 4: Fused glands, cribriform pattern
Grade 5: No gland formation, sheets of cells
Gleason Score = Primary grade + Secondary grade (e.g., 3+4=7)
Higher score = worse prognosis

Diagnostic features:

Absent basal cell layer (key feature - normal prostate has two layers; carcinoma loses basal cells)
Prominent nucleoli ("owls eye")
Nuclear pleomorphism
Perineural invasion
IHC: PSA+, PSAP+, CK903 negative (basal cells absent)
AMACR (racemase) positive - useful IHC marker for carcinoma

46. DIABETIC NEPHROPATHY

Definition

Diabetic nephropathy is the kidney disease specifically caused by diabetes mellitus (both Type 1 and 2), characterized by proteinuria, hypertension, and progressive renal failure; the most common cause of end-stage renal disease (ESRD) worldwide.

Etiology

Diabetes mellitus (Type 1 > Type 2 in severity but Type 2 more common numerically)
Risk factors: poor glycemic control, hypertension, genetic predisposition, duration of diabetes

Pathogenesis

Four major mechanisms:

Advanced Glycation End products (AGEs): Cross-link proteins in GBM → thickening + ↑ permeability
Polyol pathway activation: Sorbitol accumulates → osmotic damage
PKC (Protein Kinase C) activation: VEGF ↑ → endothelial damage
Glomerular hypertension: Early hyperfiltration (↑ GFR) → progressive glomerulosclerosis

Progression (Mogensen stages):

Stage 1: Hyperfiltration (↑GFR, normal urine)
Stage 2: Microalbuminuria (30-300 mg/day)
Stage 3: Overt proteinuria (>300 mg/day)
Stage 4: Nephrotic syndrome + declining GFR
Stage 5: ESRD

Gross Appearance

Early: kidneys enlarged
Advanced: kidneys small, granular (like other causes of CKD)
Atherosclerosis of renal arteries

Microscopy

Key lesions:

Diffuse glomerulosclerosis: Diffuse mesangial matrix expansion - most common
Nodular glomerulosclerosis (Kimmelstiel-Wilson nodules): Pathognomonic - oval, acellular, PAS-positive, hyaline nodules in mesangium at periphery of glomerulus
GBM thickening - diffuse
Hyaline arteriolosclerosis: Both afferent AND efferent arterioles (efferent involvement = pathognomonic of diabetes)
"Capsular drop" lesion: hyaline deposits between parietal epithelium and Bowman's capsule

PAS stain: Highlights the Kimmelstiel-Wilson nodules beautifully (bright pink/magenta)

47. GLIOMAS (CNS Tumours)

Definition

Gliomas are the most common primary brain tumors, arising from glial cells (astrocytes, oligodendrocytes, ependymal cells). Most common type: Glioblastoma (Grade IV astrocytoma).

Classification (WHO 2021)

Tumor	Origin	Grade	Key Feature
Pilocytic astrocytoma	Astrocyte	Grade I	Children, cerebellum, cystic, BRAF fusion, best prognosis
Diffuse astrocytoma (IDH-mutant)	Astrocyte	Grade II	Young adults, IDH mutation, slow growing
Anaplastic astrocytoma	Astrocyte	Grade III	IDH mutant
Glioblastoma (GBM)	Astrocyte	Grade IV	Most common malignant brain tumor in adults; IDH wildtype = primary GBM
Oligodendroglioma	Oligodendrocyte	Grade II-III	1p/19q co-deletion, "fried egg" cells
Ependymoma	Ependymal	Grade II-III	Children, 4th ventricle
Medulloblastoma	PNET	Grade IV	Children, cerebellum, MOST COMMON in pediatric brain

Etiology

Most are sporadic
Radiation is the only well-established environmental risk
Genetic syndromes: Neurofibromatosis (NF1/NF2), Li-Fraumeni, Turcot syndrome

Pathogenesis

GBM primary pathway: EGFR amplification → PI3K/Akt activation; PTEN loss; p16 deletion GBM secondary pathway (from lower-grade): IDH1 mutation → TP53 mutation → progression

IDH mutation = better prognosis (IDH-mutant GBM better than IDH-wildtype)

Gross Appearance

GBM:

Large, poorly defined, heterogeneous mass
Areas of hemorrhage (red-black), necrosis (yellow-white), cystic degeneration
"Butterfly glioma" - crosses corpus callosum (bilateral spread)
Pseudopalisading necrosis visible grossly

Pilocytic astrocytoma: Cystic with mural nodule (in cerebellum) Oligodendroglioma: Well-defined, grey, gelatinous, frontal lobe

Microscopy

GBM (Glioblastoma):

Pseudopalisading necrosis - neoplastic cells arranged in rows around necrotic center - HALLMARK
Microvascular proliferation (endothelial proliferation, "glomeruloid" vessels)
High mitotic activity
Nuclear pleomorphism
GFAP positive (glial fibrillary acidic protein) - IHC marker for astrocytic origin

Oligodendroglioma:

"Fried egg" appearance - cells with round nuclei + clear cytoplasmic halo (artifact of formalin)
Chicken-wire vasculature (fine branching capillaries)
1p/19q co-deletion (diagnostic molecular marker)

Pilocytic astrocytoma:

Biphasic pattern: compact fibrillar areas (Rosenthal fibers) + loose microcystic areas
Rosenthal fibers - elongated, corkscrew-shaped, eosinophilic hyaline bodies (GFAP+)

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