Index

Pathology for MRCOG Part 1 — Comprehensive Study Document

Estimated reading time: 18,000+ words of core content Last updated: May 2026 Purpose: Full-spectrum MRCOG Part 1 pathology revision covering cellular pathology, inflammation & healing, tumour pathology/oncology, gynaecological pathology (vulva, vagina, cervix, endometrium, myometrium, fallopian tube, ovary), placental pathology, gestational trophoblastic disease, endometriosis & adenomyosis, and PID.

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1. Cellular Pathology

1.1 Cell Injury — Reversible vs Irreversible

Causes of Cell Injury

• Hypoxia/ischaemia — most common cause. Hypoxia = reduced O₂ delivery; ischaemia = reduced blood flow (worse, as nutrients also depleted and waste accumulates)
• Physical agents — trauma, heat, cold, radiation
• Chemical agents & drugs — poisons, alcohol, chemotherapeutic agents
• Infectious agents — viruses, bacteria, fungi, parasites
• Immunological reactions — autoimmune, hypersensitivity
• Genetic derangements — mutations, chromosomal abnormalities
• Nutritional imbalances — deficiency or excess
• Ageing — cumulative cellular damage

Mechanisms of Cell Injury

1. ATP depletion — failure of Na⁺/K⁺-ATPase → cellular swelling
2. Mitochondrial damage — loss of oxidative phosphorylation → ↓ATP → necrosis or apoptosis via leakage of cytochrome c
3. Calcium influx — activates phospholipases, proteases, endonucleases, ATPases; damages cytoskeleton and membranes
4. Reactive oxygen species (ROS) — free radical injury
5. Membrane permeability defects — loss of selective barrier function
6. Protein misfolding and aggregation — ER stress, unfolded protein response

Reversible Cell Injury

• Cellular swelling (hydropic change) — earliest manifestation. Due to failure of Na⁺/K⁺ pump → Na⁺ and water accumulate in cytoplasm and organelles
• Fatty change (steatosis) — abnormal lipid accumulation, especially in liver (alcohol, diabetes, toxins). Seen as clear vacuoles in cytoplasm
• Ultrastructural changes: blebbing of plasma membrane, swelling of mitochondria and ER, clumping of nuclear chromatin, detachment of ribosomes
• Key point: If the injurious stimulus is removed, the cell returns to normal

Irreversible Cell Injury → Necrosis

• Two hallmark events:
• Mitochondrial dysfunction — inability to restore oxidative phosphorylation even after reperfusion → massive Ca²⁺ influx → opening of mitochondrial permeability transition pore
• Profound membrane damage — loss of phospholipids, cytoskeletal damage, free radical injury → membrane rupture
• Nuclear changes (hallmarks of necrosis):
• Pyknosis — nuclear shrinkage and increased basophilia (condensed DNA)
• Karyorrhexis — fragmentation of pyknotic nucleus
• Karyolysis — dissolution of nucleus by DNase activity

Morphological Features of Reversible vs Irreversible Injury

Feature	Reversible	Irreversible (Necrosis)
Cell size	Swollen	Swollen → ruptured
Plasma membrane	Intact, blebbing	Disrupted, ruptured
Nucleus	Normal	Pyknosis → karyorrhexis → karyolysis
Cytoplasm	Vacuolated, eosinophilic	Deeply eosinophilic, glassy
Enzyme leakage	Minimal	Abundant (LDH, AST, CK)
Inflammation	Absent	Present (due to released contents)

1.2 Necrosis — Types and Patterns

Coagulative Necrosis

• Most common type following ischaemia (except brain)
• Architecture preserved for days → ghost outline of cells remains
• Cells become eosinophilic, nuclei disappear → anucleate, coagulated mass
• Surrounded by zone of inflammation, eventually removed by phagocytes
• Microscopy: eosinophilic anucleate cells with preserved shape, loss of nuclei
• Examples: myocardial infarction (heart attack), renal infarct, splenic infarct
• Pathophysiology: denaturation of structural proteins and lysosomal enzymes → blocks proteolysis → tissue keeps its shape

Liquefactive Necrosis

• Digestion of dead tissue → conversion into liquid viscous mass
• Occurs when: lysosomal enzymes dominate → complete dissolution of tissue
• Microscopy: cystic spaces filled with necrotic debris, macrophages
• Examples:
• Brain infarction — CNS is rich in lipids and has little connective tissue → liquefies
• Abscess formation — neutrophils release proteolytic enzymes → pus (liquefied tissue + neutrophils)
• Macroscopic: soft, often cystic, sometimes creamy (pus)

Caseous Necrosis

• Distinctive combination of coagulative + liquefactive necrosis
• Macroscopic: soft, friable, white-grey, cheeselike (caseum = cheese)
• Microscopy: amorphous, eosinophilic, granular debris surrounded by granulomatous inflammation (epithelioid macrophages, Langhans giant cells, lymphocytes)
• Classic association: Tuberculosis (also fungal infections, sarcoidosis — but TB is the prototype)
• Does NOT undergo liquefaction — remains semi-solid for long periods

Fat Necrosis

• Digestion of adipose tissue by lipases
• Two contexts:
• Traumatic fat necrosis — release of free fatty acids from damaged adipocytes → saponification with Ca²⁺ → chalky white deposits
• Enzymatic fat necrosis — in acute pancreatitis: pancreatic lipases leak into peripancreatic fat → digest triglycerides → fatty acids + Ca²⁺ → calcium soaps
• Microscopy: shadowy outlines of necrotic fat cells, basophilic calcium deposits (saponification)
• Macroscopic: chalky white, opaque foci (like candle wax drippings)

Fibrinoid Necrosis

• Deposition of fibrin-like material in vessel walls
• Microscopy: bright eosinophilic, amorphous material in arterial walls (looks like fibrin)
• Pathophysiology: immune complex deposition + plasma protein leakage into damaged vessel wall
• Examples: polyarteritis nodosa, malignant hypertension, vasculitides, peptic ulcer base
• Key: always occurs in blood vessel walls

Gangrenous Necrosis

• Not a distinct histological pattern but a clinical term for tissue necrosis
• Dry gangrene: coagulative necrosis (ischaemic, usually limbs). Tissue becomes dry, shrunken, black. Line of demarcation forms. Little bacterial involvement
• Wet gangrene: liquefactive necrosis + superadded bacterial infection. Tissue is moist, swollen, putrid, black-green. Rapid spread. Worse prognosis
• Gas gangrene: Clostridium perfringens infection → gas production in tissues → crepitus on palpation. High mortality

1.3 Apoptosis — Programmed Cell Death

Definition

• Energy-dependent, genetically programmed cell death
• Removes unwanted, damaged, or aged cells without inflammation (no release of cellular contents → no inflammatory response)
• Physiological (embryogenesis, hormone-dependent involution, cell turnover) and pathological (DNA damage, viral infection, atrophy)

Morphology of Apoptosis vs Necrosis

Feature	Apoptosis	Necrosis
Cell size	Shrunken	Swollen
Nucleus	Fragmented (apoptotic bodies)	Pyknosis → karyorrhexis → karyolysis
Plasma membrane	Intact, blebbed	Disrupted, ruptured
Cytoplasm	Condensed, organelles intact	Disrupted, organelles digested
Inflammation	None (rapid phagocytosis)	Prominent
ATP requirement	Required (active process)	Not required (passive)
DNA breakdown	Internucleosomal (ladder on gel)	Random smearing

The Caspase Cascade

Caspases (cysteine-aspartic proteases) are the central executioners of apoptosis:

• Initiator caspases: Caspase-8 (extrinsic pathway), Caspase-9 (intrinsic pathway), Caspase-2, -10
• Executioner caspases: Caspase-3, -6, -7
• Activation: initiator caspases cleave and activate executioner caspases → these cleave >400 substrates (nuclear lamins, cytoskeletal proteins, DNA repair enzymes, ICAD → CAD released → internucleosomal DNA fragmentation)
• Flow: inactive pro-caspase → (cleavage) → active caspase → proteolytic cascade → cell dismantled into apoptotic bodies

Extrinsic (Death Receptor) Pathway

• Triggered by: engagement of cell surface death receptors (Fas/FasL, TNF/TNFR1)
• Mechanism:
• Ligand (FasL, TNF) binds death receptor → receptor trimerisation
• Recruitment of adaptor proteins (FADD for Fas, TRADD for TNFR1)
• Formation of DISC (Death-Inducing Signalling Complex)
• DISC recruits and cleaves pro-caspase-8 → active caspase-8
• Active caspase-8 directly activates executioner caspases
• Type I cells: sufficient caspase-8 activation → direct execution
• Type II cells: need amplification via mitochondrial pathway (caspase-8 cleaves Bid → tBid → activates Bax/Bak → mitochondrial outer membrane permeabilisation)

Intrinsic (Mitochondrial) Pathway

• Triggered by: cellular stress — DNA damage (via p53), hypoxia, growth factor withdrawal, ER stress, radiation, chemotherapy
• Key event: Mitochondrial Outer Membrane Permeabilisation (MOMP)
• Mechanism:
• Pro-apoptotic Bcl-2 family members (Bax, Bak) form pores in outer mitochondrial membrane
• Cytochrome c released from mitochondria into cytosol
• Cytochrome c + Apaf-1 + ATP + pro-caspase-9 → apoptosome complex
• Apoptosome activates caspase-9 → activates executioner caspases
• Also releases Smac/DIABLO and HtrA2/Omi — neutralise IAPs (Inhibitor of Apoptosis Proteins)

Bcl-2 Family of Proteins

• Anti-apoptotic (block MOMP): Bcl-2, Bcl-xL, Mcl-1, Bcl-w, A1
• Pro-apoptotic effectors (form pores): Bax, Bak, Bok
• Pro-apoptotic BH3-only sensors (activate effectors or neutralise anti-apoptotic): Bid, Bim, Bad, Noxa, Puma, Hrk, Bmf
• Balance determines cell fate: BH3-only proteins sense stress → neutralise anti-apoptotic proteins and/or activate Bax/Bak → MOMP → apoptosis
• Bcl-2 itself was first discovered in B-cell follicular lymphoma (t(14;18) translocation → Bcl-2 overexpression → cells resist apoptosis)

Role of p53 in Apoptosis

• p53 — "guardian of the genome"
• Activated by DNA damage, oncogene activation, hypoxia, telomere erosion
• Functions:
• Transcriptional target: p21 (cell cycle arrest), Bax, Puma, Noxa (apoptosis), GADD45 (DNA repair)
• Induces apoptosis when DNA damage is irreparable
• Loss of p53 → cells survive despite genomic damage → tumour progression
• p53 mutation found in >50% of human cancers (including high-grade serous ovarian cancer)

Other Apoptosis Pathways

• Perforin/granzyme pathway — cytotoxic T cells and NK cells release perforin (creates pores in target cell membrane) and granzyme B (enters cell, cleaves and activates caspase-10 and also directly activates executioner caspases)
• ER stress pathway — unfolded protein response → prolonged ER stress → activation of caspase-12 (rodents) → apoptosis

1.4 Autophagy

• "Self-eating" — lysosomal degradation of own cellular components
• Mechanism: formation of double-membrane autophagosome → engulfs cytoplasm/organelles → fuses with lysosome → contents degraded and recycled
• Physiological roles: nutrient deprivation survival, organelle turnover, removal of aggregated proteins
• Pathological: dysregulated in cancer, neurodegeneration, infection
• Key regulatory pathway: mTOR (mammalian target of rapamycin) — inhibits autophagy when nutrients are abundant. AMPK — activates autophagy during energy stress
• Beclin-1 — key autophagy protein (also interacts with Bcl-2 — links autophagy and apoptosis)
• Autophagy-related (ATG) genes — essential for autophagosome formation (Atg5, Atg7, Atg8/LC3, Atg12)
• MRCOG relevance: implicated in endometriosis, recurrent miscarriage, trophoblast invasion regulation

1.5 Cellular Adaptation

Atrophy

• Shrinkage in size of cells → reduced organ size
• Causes: disuse (muscle immobilisation), denervation (nerve injury), diminished blood supply, inadequate nutrition, loss of endocrine stimulation (menopause → uterine/endometrial atrophy), ageing (senile atrophy), pressure
• Mechanisms: decreased protein synthesis + increased protein degradation (ubiquitin-proteasome pathway, autophagy)
• Histology: cells smaller, fewer organelles, lipofuscin pigment accumulation (brown atrophy)
• Gynae relevance: postmenopausal endometrial/vulvar atrophy, ovarian atrophy after menopause

Hypertrophy

• Increase in cell size due to increased functional demand or hormonal stimulation
• Mechanisms: increased protein synthesis, increased gene transcription, activation of signalling pathways (PI3K/Akt, MAPK)
• Physiological: pregnancy — uterine myometrial hypertrophy (oestrogen-driven, also hyperplasia). Skeletal muscle in athletes
• Pathological: cardiac hypertrophy (hypertension)
• Nuclei: enlarged, prominent nucleoli (increased transcriptional activity)
• Note: Hypertrophy can occur without hyperplasia in permanent cells (cardiac muscle, skeletal muscle). In labile cells (uterus), both hypertrophy AND hyperplasia occur

Hyperplasia

• Increase in cell number — increased mitotic activity
• Causes: hormonal stimulation, growth factors, compensatory (after partial hepatectomy)
• Physiological: endometrial proliferative phase (oestrogen-driven), breast hyperplasia (pregnancy/lactation), hyperplasia of pregnancy (uterine, pituitary lactotrophs)
• Pathological: endometrial hyperplasia (unopposed oestrogen → risk of carcinoma), benign prostatic hyperplasia, compensatory hyperplasia of liver
• Key: hyperplasia is a controlled process that regresses when stimulus removed. If unregulated → neoplasia
• Important distinction: hyperplasia → reversible; neoplasia → irreversible

Metaplasia

• Reversible change where one differentiated cell type is replaced by another
• Typically an adaptive response to chronic irritation where the new cell type is better suited to the environment
• Most common: squamous metaplasia — columnar → squamous epithelium
• Example: cervical transformation zone — endocervical columnar cells replaced by squamous epithelium (normal phenomenon at squamocolumnar junction)
• Respiratory tract: smokers — pseudostratified columnar → stratified squamous (loss of mucociliary clearance → increased risk of infection and carcinoma)
• Other types:
• Tubal metaplasia of endometrium — endometrium takes on fallopian tube-like features (common, benign)
• Squamous metaplasia of endometrium — can be associated with endometrial carcinoma
• Aponucinous metaplasia — endocervical-like epithelium in vagina (associated with DES exposure → adenosis)
• Intestinal metaplasia — in Barrett's oesophagus (GORD) — columnar → intestinal-type epithelium — premalignant
• Osseous/cartilaginous metaplasia — in uterine leiomyomas or post-trauma
• Mechanism: reprogramming of stem cells by transcription factors (e.g., p63 for squamous differentiation)
• IMPORTANT: metaplasia itself is reversible. However, the metaplastic epithelium may have higher risk of malignant transformation (e.g., cervical SCC develops at transformation zone; Barrett's → oesophageal adenocarcinoma)

Dysplasia

• Disordered growth — loss of uniformity and architectural orientation, considered preneoplastic
• Features:
• Cellular atypia (pleomorphism, hyperchromatic nuclei)
• Increased mitotic activity (including abnormal mitoses)
• Loss of polarity
• Abnormal maturation from basal to surface layers
• Grading: mild, moderate, severe (based on extent of epithelial involvement)
• Cervical intraepithelial neoplasia (CIN) — the classic gynaecological example
• Key: dysplasia is NOT cancer — but severe dysplasia/CIN3 is carcinoma in situ — full-thickness involvement without basement membrane invasion
• Risk: more severe dysplasia → higher risk of progression to invasive carcinoma
• Distinction from reactive atypia: reactive changes lack the abnormal mitoses and full-thickness disorganisation
• p16INK4a immunostaining — surrogate marker for high-risk HPV integration → helps distinguish true dysplasia from benign mimics

1.6 Intracellular Accumulations

Steatosis (Fatty Change)

• Pathological accumulation of triglycerides within cells (mainly hepatocytes)
• Causes: alcohol, diabetes, obesity, malnutrition, toxins (CCl₄), pregnancy (acute fatty liver of pregnancy), Reye's syndrome
• Microscopy: clear cytoplasmic vacuoles (lipid dissolves during processing). May be microvesicular (many small droplets) or macrovesicular (single large droplet pushing nucleus to periphery — signet ring appearance)
• Non-alcoholic fatty liver disease (NAFLD) — common, associated with metabolic syndrome
• Gynae relevance: acute fatty liver of pregnancy — obstetric emergency, microvesicular steatosis, associated with LCHAD deficiency

Glycogen Accumulation

• Excess glycogen storage in cells
• Physiological: pregnancy — endometrium, myometrium (glycogen-rich decidual reaction). Liver and muscle after meals
• Pathological:
• Glycogen storage diseases — von Gierke (type I — glucose-6-phosphatase deficiency → hepatomegaly, hypoglycaemia)
• Diabetes mellitus — glycogen nephropathy (Armanui-Ebstein lesion — clear vacuoles in renal tubular epithelial cells)
• Endometrium: glycogenated endometrium → Arias-Stella reaction (pregnancy/hormonal effect) — large cells with clear glycogen-rich cytoplasm and hyperchromatic, irregular nuclei — can mimic carcinoma

Protein Accumulations

• Rough ER with excess protein → eosinophilic droplets
• Examples:
• Russell bodies — plasma cells filled with immunoglobulin (hyaline eosinophilic cytoplasmic inclusions)
• Mallory bodies/Mallory-Denk bodies — eosinophilic cytoplasmic inclusions in hepatocytes (alcoholic liver disease) — composed of cytokeratin and ubiquitin
• Reabsorption droplets in proximal renal tubules (proteinuria → protein reuptake droplets)
• Neurofibrillary tangles — tau protein aggregates in Alzheimer's
• Hyaline change — non-specific term for glassy eosinophilic appearance (e.g., in leiomyomas, vessels in hypertension)

Lysosomal Storage Diseases

• Inherited defects of lysosomal enzymes → accumulation of metabolites in lysosomes
• Most are autosomal recessive
• Examples:
• Gaucher's disease — glucocerebrosidase deficiency → glucocerebroside accumulation → Gaucher cells (macrophages with fibrillary "crumpled tissue paper" cytoplasm). Hepatosplenomegaly, bone pain
• Niemann-Pick disease — sphingomyelinase deficiency → sphingomyelin accumulation → foam cells
• Tay-Sachs disease — hexosaminidase A deficiency → GM₂ ganglioside in neurons → cherry-red spot on macula, neurodegeneration
• Hunter and Hurler syndromes — mucopolysaccharidoses → glycosaminoglycan accumulation → coarse facies, skeletal abnormalities
• Gynae relevance: rare, but may present during pregnancy

1.7 Pathological Calcification

Dystrophic Calcification

• Calcium deposition in dead/damaged tissue with normal serum calcium and phosphate
• Mechanism: damaged cell membranes expose phospholipid binding sites + phosphatases release phosphate → calcium phosphate precipitates
• Examples:
• Psammoma bodies — concentrically laminated basophilic calcified bodies in papillary serous carcinoma of ovary (also thyroid papillary ca, meningioma). Seen in peritoneal washings — helpful diagnostic clue
• Dystrophic calcification in atheromatous plaques, old TB granulomas (Ghon focus), necrotic tumours, heart valves (degenerative), leiomyomas (especially after menopause)
• Calcification in placenta — common after 36 weeks (may be excessive in preeclampsia, diabetes)
• Morphology: basophilic, granular, amorphous deposits. May be psammoma bodies (laminated spheres)

Metastatic Calcification

• Calcium deposition in NORMAL tissues due to hypercalcaemia
• Causes of hypercalcaemia:
• Hyperparathyroidism (primary — parathyroid adenoma; secondary — renal failure)
• Bone metastases (breast, lung, renal, thyroid) — osteoclastic bone destruction
• Multiple myeloma — osteoclast-activating factors (IL-1, TNF, RANKL)
• Sarcoidosis — macrophages produce 1,25-dihydroxyvitamin D (calcitriol)
• Paraneoplastic — PTHrP (SCC of lung, renal cell, breast, ovarian SCC)
• Milk-alkali syndrome (excess Ca²⁺ + absorbable antacids)
• Addison's disease, thyrotoxicosis, immobilisation
• Sites: kidneys (nephrocalcinosis → renal stones), lungs (interstitial calcification), stomach, blood vessels, cornea (band keratopathy)
• Histology: basophilic, granular deposits in basement membranes and interstitial tissues

1.8 Ageing and Cellular Senescence

Cellular Senescence

• Irreversible cell cycle arrest — cells remain metabolically active but cannot divide
• Triggers: telomere shortening (replicative senescence), DNA damage, oxidative stress, oncogene activation (oncogene-induced senescence — OIS)
• Hallmarks: enlarged flattened morphology, senescence-associated β-galactosidase (SA-β-gal) activity, senescence-associated secretory phenotype (SASP — secretion of pro-inflammatory cytokines IL-6, IL-8, TNF, MMPs, growth factors)
• p53/p21 and p16INK4a/Rb pathways — key effectors of senescence
• Paradoxical role: (1) Tumour suppressive — prevents proliferation of damaged cells. (2) Pro-ageing — accumulation of senescent cells → tissue dysfunction. (3) SASP can promote inflammation and even tumour progression in neighbouring cells

Telomere Loss

• Telomeres — repetitive DNA (TTAGGG)n at chromosome ends, protect chromosomal integrity
• Each cell division → telomeres shorten (end-replication problem — DNA polymerase cannot replicate extreme 3' ends)
• Telomerase — enzyme that adds telomeric repeats. Composed of TERT (catalytic subunit) + TERC (RNA template)
• Somatic cells: telomerase is low/absent → progressive telomere shortening → senescence/crisis
• Germ cells, stem cells, cancer cells: express telomerase → maintain telomere length → cellular immortality
• MRCOG relevance: placental telomere length — short telomeres associated with preeclampsia, IUGR. Oocyte ageing — telomere shortening correlates with reduced fertility and increased aneuploidy

Free Radical Injury / Oxidative Stress

• Free radicals — molecules with unpaired electron (highly reactive)
• Types:
• Reactive oxygen species (ROS): superoxide (O₂⁻), hydrogen peroxide (H₂O₂), hydroxyl radical (OH⁻)
• Reactive nitrogen species (RNS): nitric oxide (NO⁻), peroxynitrite (ONOO⁻)
• Generation:
• Normal metabolism — mitochondrial electron transport chain (leakage of electrons → O₂⁻)
• Inflammation — NADPH oxidase in neutrophils (respiratory burst)
• Radiation — radiolysis of water → OH⁻
• Enzymes — xanthine oxidase (ischaemia-reperfusion), cyclooxygenase, lipoxygenase
• Transition metals — Fe²⁺, Cu⁺ (Fenton reaction: Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + OH⁻)
• Drug metabolism — paracetamol, chemotherapeutics, alcohol
• Damage inflicted:
• Lipid peroxidation → membrane damage (especially polyunsaturated fatty acids in membranes)
• DNA damage → strand breaks, base modifications (8-hydroxydeoxyguanosine — biomarker)
• Protein damage → cross-linking, fragmentation, oxidation of amino acids
• Defence mechanisms:
• Enzymatic: superoxide dismutase (SOD — converts O₂⁻ to H₂O₂), catalase (converts H₂O₂ to H₂O + O₂), glutathione peroxidase (reduces H₂O₂ and lipid peroxides using GSH)
• Non-enzymatic: vitamin E (α-tocopherol — in membranes, breaks lipid peroxidation chain), vitamin C (ascorbate — aqueous phase), glutathione (GSH), β-carotene, selenium, uric acid, bilirubin
• Ischaemia-reperfusion injury: paradoxical worsening of tissue damage when blood flow is restored after ischaemia. Mechanisms: (1) Reintroduction of O₂ → massive ROS production (xanthine oxidase pathway, mitochondrial dysfunction). (2) Inflammatory response (complement activation, neutrophil infiltration). Clinical relevance: organ reperfusion after ischaemia (stroke, MI, transplant, ovarian torsion, preeclampsia — placental ischaemia-reperfusion)

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2. Inflammation & Healing

2.1 Acute Inflammation

Definition

• Immediate, non-specific response of vascularised tissue to injury
• Purpose: deliver leukocytes and plasma proteins (antibodies, complement) to site of injury → eliminate pathogen → initiate healing
• Cardinal signs (Celsus + Virchow): Rubor (redness — vasodilation), Calor (heat — vasodilation), Tumor (swelling — increased permeability + cellular infiltration), Dolor (pain — chemical mediators, pressure), Functio laesa (loss of function)

Vascular Events

Vasodilation

• Arteriolar dilation → increased blood flow → redness and heat
• First transient: arteriolar constriction (seconds, insignificant)
• Sustained vasodilation: mediated by histamine (immediate), nitric oxide (NO) , prostaglandins (PGE₂, PGI₂)
• Result: increased hydrostatic pressure → fluid exudation (early transient phase)

Increased Vascular Permeability

• Mechanisms:
• Immediate transient response (5-10 min post-injury) — histamine, bradykinin, leukotrienes → contraction of endothelial cells in venules (creates gaps between endothelial cells)
• Immediate sustained response (severe injury — burns, toxins) — direct endothelial damage → necrosis → leakage from all microvessels (venules, capillaries, arterioles)
• Delayed prolonged leakage (UV radiation, mild thermal injury) — endothelial cell contraction + mild damage → starts at 2-12 hours, lasts days
• Leukocyte-mediated — leukocyte adhesion and transmigration → local endothelial damage (from neutrophil proteases and ROS)
• Increased transcytosis — VEGF, histamine → increased transport via vesiculo-vacuolar organelles
• Result: protein-rich fluid (exudate) leaves vessels → oedema

Cellular Events (Leukocyte Recruitment)

Steps:

1. Margination & Rolling
2. Normal flow: RBCs central, WBCs peripheral (margination)
3. Selectins mediate rolling:
   • P-selectin (Weibel-Palade bodies in endothelial cells) — rapid (histamine, thrombin → mobilisation to surface)
   • E-selectin (endothelial cells) — slower (IL-1, TNF → transcription)
   • L-selectin (leukocytes)

4. Selectins bind sialyl-Lewis X-modified glycoproteins on leukocytes

5. Adhesion (Firm adhesion)

6. Integrins on leukocytes (LFA-1, Mac-1) bind ICAM-1, VCAM-1 on endothelium
7. Integrins must be activated from low-affinity to high-affinity state (by chemokines — IL-8, MCP-1 — immobilised on endothelial surface)

8. Activated endothelium (IL-1, TNF) upregulates ICAM-1, VCAM-1

9. Transmigration (Diapedesis)

10. Leukocytes squeeze between endothelial cells (mainly at intercellular junctions of venules)
11. PECAM-1 (CD31) — expressed on both leukocytes and endothelial junctions — mediates transmigration
12. CD99 also involved

13. Transcellular migration — through endothelial cell body (minor route)

14. Chemotaxis

15. Movement of leukocytes towards chemical gradient at injury site
16. Exogenous: bacterial products (N-formyl peptides)
17. Endogenous:
    • Cytokines: IL-8 (CXCL8) → neutrophils; MCP-1 (CCL2) → monocytes
    • Complement: C5a, C3a
    • Arachidonic acid metabolites: LTB₄ (leukotriene B₄)
    • Chemokines — large family of chemoattractant cytokines (CC, CXC, C, CX₃C families)
18. Receptors: G-protein coupled receptors → cytoskeletal rearrangement → pseudopod extension → directional movement

Phagocytosis & Degradation

Steps:

1. Recognition and attachment
2. Opsonins coat microbe → enhance phagocytosis:
   • IgG (Fc receptor on phagocyte)
   • C3b (CR1/CR3 receptor)
   • Collectins (mannose-binding lectin)
3. Mannose receptors — bind bacterial mannose
4. Scavenger receptors — bind various microbial components

5. CD14 — binds LPS (via LBP — LPS-binding protein)

6. Engulfment

7. Pseudopods extend around microbe → form phagosome (membrane-bound vacuole)

8. Phagosome fuses with lysosome → phagolysosome

9. Killing and degradation

10. Oxygen-dependent (respiratory burst):
    • NADPH oxidase in phagosome membrane → generates superoxide O₂⁻
    • Superoxide → H₂O₂ (SOD)
    • Myeloperoxidase (MPO) — neutrophil azurophilic granules → converts H₂O₂ + Cl⁻ → HOCl (hypochlorous acid — bleach) — potent microbicide
    • Also produces hydroxyl radical (OH⁻) and singlet oxygen
11. Oxygen-independent:
    • Defensins (cationic peptides — form pores in microbe membrane)
    • Lysozyme — degrades bacterial cell wall peptidoglycan
    • Bactericidal/permeability-increasing protein (BPI) — binds to Gram-negative bacterial LPS
    • Lactoferrin — binds iron (essential for bacterial growth)
    • Proteases — elastase, cathepsin G, collagenase
12. Note: Chediak-Higashi syndrome — defective lysosomal fusion → recurrent infections

Outcomes of Acute Inflammation

1. Resolution — complete return to normal (mild injury, short duration, minimal tissue destruction, adequate regeneration)
2. Suppuration (pus formation) — neutrophil-rich exudate → abscess formation
3. Organisation — ingrowth of granulation tissue → fibrosis (scarring)
4. Progression to chronic inflammation — persistent injury, unresolved acute inflammation, autoimmune response

2.2 Mediators of Inflammation

Cell-Derived Mediators

Histamine

• Source: mast cells, basophils, platelets
• Stored in: mast cell granules
• Release triggered by: physical injury, immune complexes, complement (C3a, C5a — anaphylatoxins), IgE cross-linking, substance P, IL-1, IL-8, neuropeptides, mechanical trauma
• Actions:
• Vasodilation (arterioles) → rubor, calor
• Increased vascular permeability (venules) → oedema/tumor
• Bronchoconstriction
• Itching (pruritus)
• Receptors: H₁ (vascular permeability, bronchoconstriction, itching), H₂ (gastric acid secretion), H₃ (CNS), H₄ (eosinophil chemotaxis)
• Drugs: antihistamines (H₁ blockers — chlorpheniramine, cetirizine, loratadine)

Prostaglandins & Thromboxane (Arachidonic Acid Metabolites)

• Arachidonic acid released from membrane phospholipids by phospholipase A₂
• Cyclooxygenase pathway (COX-1 and COX-2) → prostaglandins, thromboxane
• COX-1: constitutive — stomach, kidney, platelets (housekeeping)
• COX-2: induced by IL-1, TNF, growth factors, LPS — inflammation
• Key prostanoids:
• PGD₂: mast cells — vasodilation, enhances oedema
• PGE₂: vasodilation, potentiates oedema, pain (hyperalgesia), fever
• PGF₂α: vasoconstriction, broncoconstriction, uterine contraction
• PGI₂ (prostacyclin): vasodilation, inhibits platelet aggregation
• TxA₂ (thromboxane A₂): platelet aggregation, vasoconstriction
• NSAIDs: inhibit COX (aspirin — irreversible acetylation; ibuprofen, diclofenac — reversible competitive inhibition)
• COX-2 selective inhibitors: celecoxib, rofecoxib — lower GI side effects but increased cardiovascular risk

Leukotrienes (5-Lipoxygenase Pathway)

• 5-Lipoxygenase → arachidonic acid → leukotriene A₄ (LTA₄)
• LTA₄ → LTB₄: neutrophil chemotaxis, adhesion, activation
• LTA₄ → LTC₄ → LTD₄ → LTE₄ (cysteinyl leukotrienes): vasoconstriction, bronchoconstriction, increased vascular permeability
• Role in asthma — leukotriene receptor antagonists (montelukast)
• Zileuton: 5-lipoxygenase inhibitor

Lipoxins

• Anti-inflammatory lipids — synthesised from arachidonic acid via interactions between neutrophils and platelets/endothelial cells
• Actions: inhibit neutrophil recruitment, promote macrophage clearance of apoptotic neutrophils (resolution of inflammation)
• Part of "specialised pro-resolving mediators" (SPMs) — along with resolvins, protectins, maresins

Platelet-Activating Factor (PAF)

• Source: neutrophils, monocytes/macrophages, mast cells, platelets, endothelial cells
• Actions:
• Potent platelet aggregation and degranulation
• Vasodilation (low dose) or vasoconstriction (high dose)
• Increased vascular permeability
• Neutrophil activation, chemotaxis, adhesion
• Bronchoconstriction
• Priming effect — enhances response to other mediators

Nitric Oxide (NO)

• Source: endothelial cells (eNOS), macrophages (iNOS), neurons (nNOS)
• Synthesis: L-arginine → NO + L-citrulline by nitric oxide synthase (NOS)
• Actions:
• Vasodilation — relaxes vascular smooth muscle via cGMP
• Inhibits platelet aggregation and adhesion
• Microbicidal — macrophages produce high NO via iNOS → kills microbes
• Regulates leukocyte adhesion — NO reduces adhesion molecule expression
• Clinical: nitroglycerin (NO donor) → angina. Excess NO (sepsis) → hypotension (refractory shock)

Cytokines & Chemokines

• TNF (Tumour Necrosis Factor) & IL-1:
• Major pro-inflammatory cytokines — activate endothelial cells (↑ adhesion molecules), fever (hypothalamic PGE₂), acute phase response (liver → CRP, SAA, fibrinogen), cachexia (TNF = cachectin), shock (high levels — sepsis syndrome)
• TNF — source: macrophages, T cells. IL-1 — source: macrophages, epithelial cells

• IL-1 receptor antagonist (IL-1ra) — natural inhibitor. Anakinra (recombinant IL-1ra) used in rheumatoid arthritis

• IL-6:

• Source: macrophages, T cells, fibroblasts, endothelial cells
• Major inducer of acute phase proteins (CRP, SAA, hepcidin, fibrinogen)
• Growth factor for B cells (antibody production), T cell proliferation

• Tocilizumab — anti-IL-6 receptor antibody (rheumatoid arthritis, COVID-19 cytokine storm)

• IL-8 (CXCL8):

• Chemokine — potent neutrophil chemoattractant and activator
• Source: macrophages, endothelial cells, epithelial cells

• Binds CXCR1 and CXCR2 on neutrophils

• Chemokine families:

• CC chemokines: MCP-1 (CCL2 — monocyte chemoattractant), RANTES (CCL5 — T cells, eosinophils, basophils), Eotaxin (CCL11 — eosinophils)
• CXC chemokines: IL-8 (CXCL8 — neutrophils), SDF-1 (CXCL12 — lymphocyte homing), IP-10 (CXCL10 — T cells)
• C chemokine: Lymphotactin (XCL1 — T cells)

• CX₃C: Fractalkine (CX₃CL1 — monocytes, T cells)

• Acute Phase Proteins (liver-derived):

• CRP (C-reactive protein) — opsonin, binds phosphocholine on bacteria. Rapid rise (6 hours, peaks 48h). Sensitive but non-specific marker of inflammation
• SAA (Serum Amyloid A) — rises dramatically, can deposit as AA amyloid in chronic inflammation
• Fibrinogen → increased ESR
• Haptoglobin, α₁-antitrypsin, α₂-macroglobulin — protease inhibitors
• Ferritin, hepcidin — iron metabolism (hypoferraemia of inflammation)
• Complement proteins — increased
• Albumin — decreased (negative acute phase reactant)

Complement System

• Three activation pathways:
• Classical — immune complexes (IgG, IgM) → C1q, C1r, C1s → C4 + C2 → C3 convertase (C4b2a)
• Alternative — microbial surfaces (LPS, teichoic acid, IgA) → factor B + factor D → properdin stabilised C3 convertase (C3bBb)

• Lectin — mannose-binding lectin (MBL) binds microbial mannose → MASP-1/2 → cleaves C4 + C2 → same C3 convertase as classical

• C3 convertase → splits C3 → C3a + C3b

• C3a: anaphylatoxin (mast cell degranulation, smooth muscle contraction)

• C3b: opsonin (binds complement receptors on phagocytes)

• C5 convertase (C4b2a3b or C3bBb3b) → splits C5 → C5a + C5b

• C5a: potent anaphylatoxin and neutrophil chemoattractant

• C5b → C6-C9 → Membrane Attack Complex (MAC) — lytic pore in cell membrane

• Regulatory proteins: C1 inhibitor (deficiency → hereditary angioedema), DAF (CD55 — decays C3 convertase), MCP (CD46), CD59 (protectin — blocks MAC), factor H, factor I

• Clinical relevance: complement is activated in many gynaecological conditions — endometriosis (peritoneal fluid complement activation), preeclampsia (placental complement deposition), recurrent pregnancy loss (complement dysregulation)

2.3 Chronic Inflammation

Characteristics

• Prolonged duration (weeks to months to years)
• Simultaneous tissue destruction and repair (fibrosis)
• Cellular infiltrate: macrophages, lymphocytes, plasma cells
• Can follow acute inflammation or begin insidiously (low-grade, smouldering)

Causes

1. Persistent infections — TB, syphilis, fungi, parasites
2. Hypersensitivity/autoimmune diseases — RA, SLE, IBD
3. Prolonged exposure to non-degradable toxins — silica (silicosis), asbestos (asbestosis)
4. Foreign bodies — suture material, talc, implant debris
5. Obesity — low-grade chronic inflammation (adipose tissue macrophage infiltration → metabolic syndrome)

Cellular Components

Macrophages

• Central orchestrator of chronic inflammation
• Origin: blood monocytes (recruited by chemokines CCL2/MCP-1, GM-CSF) + tissue-resident macrophages (Kupffer cells in liver, alveolar macrophages in lung, microglia in brain, peritoneal macrophages)
• Activation:
• Classical (M1): IFN-γ, LPS → pro-inflammatory (IL-1, TNF, IL-6, ROS, NO, MMPs) — microbicidal, tumouricidal
• Alternative (M2): IL-4, IL-13 → anti-inflammatory, tissue repair, fibrosis (IL-10, TGF-β, arginase, VEGF) — wound healing, tumour-associated macrophages (TAMs)
• Functions: phagocytosis, antigen presentation (MHC II to T cells), cytokine secretion, growth factor secretion (PDGF, FGF, VEGF, TGF-β → fibrosis), tissue remodelling
• Special morphologic forms:
• Epithelioid macrophages — activated macrophages that resemble epithelial cells (large, pale pink cytoplasm, oval/elongated nucleus). Hallmark of granuloma
• Multinucleated giant cells — fusion of epithelioid macrophages
  • Langhans giant cells — horseshoe/ring of nuclei at periphery (TB)
  • Foreign body giant cells — irregular nuclear arrangement (suture, talc)
  • Touton giant cells — foamy cytoplasm, ring of nuclei (xanthogranulomatous inflammation, fat necrosis)

Lymphocytes

• T cells:
• CD4+ helper T cells (Th1 — IFN-γ → macrophage activation; Th2 — IL-4, IL-13 → allergy, IgE; Th17 — IL-17 → neutrophil recruitment; Treg — IL-10, TGF-β → suppression)
• CD8+ cytotoxic T cells — kill infected/neoplastic cells
• B cells → plasma cells → antibody production
• Lymphocyte-macrophage cross-talk is central to chronic inflammation (TNF, IFN-γ, IL-2, IL-4, IL-10)

Plasma Cells

• Terminally differentiated B cells — produce antibodies
• Morphology: large, round/oval, eccentric nucleus with clock-face chromatin, perinuclear hof (Golgi zone), basophilic cytoplasm
• Russell bodies: eosinophilic cytoplasmic inclusions (accumulated immunoglobulins)
• Prominent in: chronic cervicitis, endometritis (plasma cell endometritis = chronic endometritis), SLE, rheumatoid synovitis, multiple myeloma

Eosinophils

• Allergic reactions, parasitic infections, some autoimmune conditions
• Morphology: bilobed nucleus, large eosinophilic granules (major basic protein, eosinophil cationic protein, eosinophil peroxidase)
• Gynae relevance: eosinophils in endometrium — can be seen in normal endometrium and IUD use; prominent in eosinophilic cystitis

Granuloma Formation

Definition

• Focal, organised collection of epithelioid macrophages, often with multinucleated giant cells, surrounded by lymphocytes

Types

Caseating Granuloma: - Central caseous necrosis — amorphous, eosinophilic, granular debris - Classic for: Tuberculosis (Mycobacterium tuberculosis) - Also: fungal infections (histoplasmosis) - Langhans giant cells present - AFB stain (Ziehl-Neelsen) → red, beaded rods

Non-Caseating Granuloma: - No central necrosis - Classic for: - Sarcoidosis — non-caseating "naked" granulomas (thin lymphocyte rim, may have stellate inclusions — Schaumann bodies, asteroid bodies) - Crohn's disease — non-caseating granulomas in gut wall - Foreign body reaction — suture material, talc, silicone - Berylliosis, leprosy, CATS scratch disease

Other types: - Foreign body granuloma — epithelioid macrophages + foreign body giant cells surrounding exogenous material (suture, talc, silicone, keratin) - Rheumatoid nodule — central fibrinoid necrosis surrounded by palisading epithelioid macrophages and giant cells, outer lymphocyte cuff - Xanthogranulomatous inflammation — foamy macrophages (lipid-rich) + chronic inflammation. e.g., xanthogranulomatous pyelonephritis, xanthogranulomatous endometritis

Granulomatous Diseases in Gynaecology

• Genital TB: fallopian tube involvement (common cause of infertility in endemic areas), endometrial TB (caseating granulomas, AFB positive), chronic salpingitis
• Sarcoidosis: can involve any gynaecological site (rare)
• Talc granulomas: from glove powder → peritoneal granulomas (surgical, old)
• Keratin granulomas: from spilled contents of dermoid cyst (ovarian teratoma) → granulomatous peritonitis
• Malakoplakia: rare chronic granulomatous disease (Michaelis-Gutmann bodies — basophilic targetoid inclusions) — can involve vulva, vagina, cervix, endometrium

2.4 Wound Healing

Healing by Primary vs Secondary Intention

Primary Intention (First Intention): - Clean, uninfected surgical incision with apposed edges (sutured) - Minimal tissue loss, minimal clot/scab - Steps: 1. Incisional clot + fibrin seal (hours) 2. Neutrophils (day 1-2) — clean debris 3. Epithelial regeneration — basal cells migrate across wound (by day 2), full thickness by day 5-7 4. Granulation tissue (day 3-5) — minimal 5. Collagen deposition — cross-linked (day 3 onwards) 6. Scar maturation — collagen remodelling (weeks-months) - Result: Thin scar, minimal contraction, faster healing

Secondary Intention (Second Intention): - Open wound with tissue loss — edges cannot be apposed (e.g., pressure ulcer, surgical wound left open, excision biopsy) - Steps: 1. Larger clot, more fibrin, more debris 2. More inflammation — more neutrophils, macrophages 3. More granulation tissue — fills the wound defect 4. Epithelial regeneration — must migrate across larger surface 5. Wound contraction — myofibroblasts pull wound edges together 6. Extensive collagen deposition → abundant scar - Result: Larger scar, more contraction, slower healing (weeks-months), higher risk of infection and hypertrophic scarring

Phases of Wound Healing

1. Haemostasis Phase (Immediate)

• Vasoconstriction (minutes) → platelet plug formation
• Platelets release: PDGF, TGF-β, EGF, FGF, serotonin, histamine (→ vasodilation after initial constriction)
• Fibrin mesh forms (coagulation cascade) — provides scaffold for cell migration

2. Inflammatory Phase (Day 1-3)

• Neutrophils peak at 24-48h — phagocytose bacteria, debris, secrete proteases (MMPs) to clear damaged matrix
• Macrophages peak at 48-96h — key orchestrators:
• Phagocytose debris, apoptotic neutrophils
• Secrete growth factors (PDGF, TGF-β, FGF, VEGF, EGF)
• Secrete cytokines (IL-1, TNF, IL-6)
• Transition from M1 (early inflammation) to M2 (proliferation/repair)
• Lymphocytes appear at day 5-7 — modulate repair

3. Proliferative Phase (Day 3-14)

• Angiogenesis — new blood vessel formation from pre-existing vessels
• Key driver: VEGF (hypoxia-induced via HIF-1α), also FGF-2, PDGF
• Steps: endothelial cell activation → basement membrane degradation (MMPs) → migration → tube formation → maturation (pericyte recruitment by PDGF, Angiopoietin-1)
• Granulation Tissue Formation:
• Appearance: pink, soft, granular, friable
• Components: newly formed capillaries + fibroblasts + inflammatory cells + loose ECM
• Macrophages central — secrete angiogenic and fibrogenic factors
• Epithelialisation:
• Epithelial cells at wound edge lose contact inhibition → proliferate, migrate (lamellipodia)
• Re-epithelialisation begins within hours, using extracellular matrix as scaffold
• Cell migration: integrin-mediated adhesion to fibronectin, vitronectin, collagen
• Once contact with opposing epithelial cells → contact inhibition → differentiation (basal → squamous maturation)
• Fibroplasia — Fibroblast → Myofibroblast:
• Fibroblasts recruited from surrounding tissue (PDGF, FGF) + proliferation
• TGF-β induces differentiation of fibroblasts into myofibroblasts
• Myofibroblasts express α-smooth muscle actin (α-SMA) → contractile properties → wound contraction
• Synthesise collagen (type III initially → type I later), fibronectin, proteoglycans, elastin
• Wound contraction begins ~5-7 days (secondary intention)

4. Remodelling Phase (Day 8 → Months-Years)

• Collagen remodelling:
• Initial: type III collagen (reticulin) — weak, randomly oriented
• Maturation: type III → type I collagen (by MMP cleavage and new synthesis)
• Cross-linking (lysyl oxidase) → increased tensile strength
• Wound strength: week 1 = 10% of normal; 3 months = 80%
• Scar avascularity: regression of vessels (apoptosis of endothelial cells)
• Matrix turnover: balance of MMPs (matrix metalloproteinases) and TIMPs (tissue inhibitors of MMPs)
• MMP-1 (collagenase-1), MMP-2 (gelatinase A), MMP-9 (gelatinase B)
• TIMPs — inhibit MMP activity

Role of Key Growth Factors in Wound Healing

Growth Factor	Source	Key Actions
TGF-β	Platelets, macrophages, fibroblasts	Fibroblast chemotaxis and proliferation, myofibroblast differentiation, collagen synthesis, ECM deposition, anti-inflammatory (later stage). Most potent profibrotic cytokine
PDGF	Platelets, macrophages, fibroblasts	Fibroblast and smooth muscle cell chemotaxis, proliferation, collagen synthesis, angiogenesis (indirect via VEGF)
VEGF	Macrophages, keratinocytes, fibroblasts, endothelial cells (hypoxia-induced)	Endothelial cell migration, proliferation, tube formation → angiogenesis. Vascular permeability
FGF-2 (bFGF)	Macrophages, fibroblasts, endothelial cells	Fibroblast and endothelial cell proliferation, angiogenesis, wound contraction
EGF	Platelets, macrophages, keratinocytes	Keratinocyte migration and proliferation → re-epithelialisation
KGF (FGF-7)	Fibroblasts	Keratinocyte proliferation

Collagen Types in Wound Healing

Type	Structure	Location	Role in Wound
I	Fibrillar (thick, strong)	Skin, bone, tendon, uterus, cervix	Mature scar — gives tensile strength
III	Fibrillar (thin, reticular)	Foetal tissues, blood vessels, skin, uterus	Early wound — laid down first, then remodelled to type I
IV	Network-forming	Basement membranes	Basement membrane repair
V	Fibrillar (regulates type I fibril size)	Co-distributed with type I	Fine-tuning of collagen fibrillogenesis

• Normal skin: 80% type I, 20% type III
• Early wound: predominantly type III
• Mature scar: predominantly type I (approaches 80:20 ratio)

Factors Affecting Wound Healing

Local Factors

Factor	Effect
Infection	Most important local cause of delayed healing. Bacteria → prolonged inflammation, impaired epithelialisation, increased MMPs → wound breakdown
Ischaemia	Poor blood supply → ↓ O₂ → impaired fibroblast function, collagen synthesis, angiogenesis. Critical in pressure ulcers, peripheral vascular disease
Foreign body	Suture material, debris, glass, etc. → persistent inflammation → delayed healing
Tissue trauma	Crush injury → more necrotic tissue → prolonged inflammatory phase
Radiation	Endarteritis obliterans → ischaemia → impaired healing
Pressure	Pressure ulcers — constant pressure over bony prominences → ischaemic necrosis
Wound haematoma	Separates wound edges, provides medium for bacterial growth
Poor surgical technique	Tension, poor apposition, devascularisation, dead space
Temperature	Cold → vasoconstriction → impaired healing

Systemic Factors

Factor	Effect
Nutrition	Protein deficiency → impaired collagen synthesis. Vitamin C deficiency (scurvy) → impaired hydroxylation of proline/lysine → weak collagen. Zinc deficiency → impaired cell proliferation. Vitamin A deficiency → impaired epithelialisation
Diabetes mellitus	Major risk factor — multifactorial: microvascular disease (ischaemia), neuropathy (repeated trauma), impaired immune function (neutrophil dysfunction, ↓ chemotaxis), hyperglycaemia → advanced glycation end-products (AGEs) impair collagen function, impaired angiogenesis, increased infection risk
Steroids (glucocorticoids)	Inhibit inflammation (↓ cytokine production, ↓ leukocyte recruitment), inhibit fibroblast proliferation and collagen synthesis, inhibit TGF-β effects, impair wound contraction. Anti-inflammatory phase-dependent — most detrimental in early (proliferative) phase
Smoking	Vasoconstriction (nicotine), ↑ COHb → reduced O₂ delivery, impaired neutrophil function, ↑ thrombotic tendency, ↓ collagen synthesis, ↑ MMP activity → impaired wound healing, increased infection, increased dehiscence
Uraemia	Impairs platelet function, immune dysfunction, malnutrition → delayed healing
Jaundice (obstructive)	Malabsorption of fat-soluble vitamins (A, D, E, K) → vitamin K deficiency → clotting defect → haematoma → impaired healing
Ageing	Slower epithelialisation, reduced collagen synthesis, reduced angiogenesis, reduced growth factor responsiveness
Obesity	Poor vascularity of adipose tissue, increased wound tension, increased infection risk, impaired immune function
Immunosuppression	Chemotherapy, HIV, radiation → impaired inflammatory response → infection risk, impaired healing
Anaemia	↓ O₂ delivery → impaired collagen synthesis (less significant if no tissue hypoxia)

Keloid vs Hypertrophic Scar

Feature	Hypertrophic Scar	Keloid
Scar extent	Confined to original wound boundaries	Extends beyond original wound margins (invasive growth)
Time course	Develops early, may regress over time	Develops late (months after injury), does not regress
Genetic predisposition	Less pronounced	Strong (more common in darker skin types)
Common sites	Any site, especially across flexures	Earlobes, chest, shoulders, back (high-tension areas)
Histology	Collagen bundles parallel to skin surface, more type III	Thick hyalinised collagen bundles, haphazard orientation, abundant mucoid ground substance, pseudocapsule at deep margin
Treatment response	Better response to pressure, silicone	Poor response, high recurrence after excision
Growth factors	Balanced TGF-β1:TGF-β3 ratio	Excess TGF-β1 (profibrotic), reduced TGF-β3 (anti-fibrotic), increased PDGF, VEGF
Regression	Spontaneous regression possible	Never regresses spontaneously

Pressure Ulcers (Decubitus Ulcers / Bedsores)

• Pathophysiology: prolonged pressure over bony prominence → ischaemic necrosis of skin + subcutaneous tissue
• Stages:
• Stage 1: non-blanchable erythema (intact skin)
• Stage 2: partial-thickness skin loss (abrasion/blister)
• Stage 3: full-thickness skin loss (extends to subcutaneous tissue, not through fascia)
• Stage 4: full-thickness tissue loss with exposed bone/tendon/muscle
• Unstageable: full-thickness with slough/eschar
• Common sites: sacrum, heels, greater trochanters, ischial tuberosities, occiput
• Prevention: pressure relief (repositioning every 2 hours), special mattresses, nutrition, moisture management

Organising Pneumonia

• Proliferation of fibroblasts and capillaries within alveolar exudate → Masson bodies (intra-alveolar buds of granulation tissue)
• Can organise into fibrous tissue in the alveoli, complicating pneumonia recovery
• Gynae relevance: organising pneumonia can complicate post-surgical care in elderly/debilitated patients
• Cryptogenic organising pneumonia (COP) — idiopathic form

Adhesions

• Abnormal fibrous connections between tissues or organs — common after abdominal/pelvic surgery
• Pathophysiology: peritoneal injury → inflammation → fibrin deposition → if not cleared (impaired fibrinolysis) → fibrin persists → fibroblast ingrowth → collagen deposition → permanent fibrous adhesion
• Risk factors: previous surgery (most common), PID, endometriosis, peritonitis, radiation, foreign body (glove talc, suture)
• Complications: chronic pelvic pain, infertility (tubal adhesions → impaired fimbrial function), bowel obstruction, difficult repeat surgery
• Prevention: gentle tissue handling, minimising ischaemia, meticulous haemostasis, avoiding talc, anti-adhesion barriers (icodextrin 4%, hyaluronic acid/carboxymethylcellulose films [Seprafilm], oxidised regenerated cellulose [Interceed])

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3. Tumour Pathology / Oncology

3.1 Neoplasia — Fundamental Concepts

Definitions

• Neoplasia: "new growth" — abnormal, uncoordinated, excessive proliferation that persists after cessation of the initiating stimulus
• Tumour: swelling (originally). Now means neoplasm
• Neoplasm: clonal proliferation of cells with genetic alterations → abnormal growth
• Hyperplasia vs Neoplasia: hyperplasia is polyclonal, reversible, controlled; neoplasia is monoclonal, irreversible, autonomous
• Hamartoma: benign, disorganised overgrowth of mature tissues native to the site (e.g., pulmonary chondroid hamartoma). NOT a true neoplasm — growth is self-limited
• Choristoma: ectopic rest of normal tissue at an abnormal site (e.g., pancreatic tissue in stomach wall)

Benign vs Malignant Neoplasms

Feature	Benign	Malignant
Differentiation	Well-differentiated (resembles parent tissue)	Poorly differentiated to anaplastic
Anaplasia	Absent	Present (cellular atypia, pleomorphism, hyperchromasia, high N:C ratio, abnormal mitoses)
Rate of growth	Slow, progressive; may stop or regress	Rapid, may be erratic; invasive pattern
Mitotic activity	Low; normal mitoses	High; abnormal mitoses (tripolar, quadripolar, atypical)
Local invasion	Encapsulated; cohesive, expansile, pushing border	Invasive; infiltrative, irregular border; no capsule
Metastasis	Never	Frequent
Recurrence after excision	Rare (if completely excised)	Common (especially if margins involved)
Effects on host	Local (compression, obstruction) unless endocrine; rarely fatal	Cachexia, invasion, metastasis, paraneoplastic syndromes; often fatal if untreated
Vascularity	Usually well-formed vessels	Abnormal, leaky vessels (angiogenic)
Necrosis/haemorrhage	Rare	Common (rapid growth outgrows blood supply)

Terminology — Nomenclature

Benign Epithelial Tumours: - Papilloma — finger-like projections (squamous or glandular epithelium) - Adenoma — glandular epithelium (colorectal adenoma, thyroid adenoma) - Cystadenoma — cystic glandular tumour (ovarian serous cystadenoma) - Papillary cystadenoma — papillary projections into cystic spaces - Polyp — macroscopic projection from mucosal surface (can be neoplastic or non-neoplastic) - Fibroadenoma — benign tumour of breast (both epithelial + stromal components)

Malignant Epithelial Tumours (Carcinomas): - Adenocarcinoma — malignant glandular epithelium - Squamous cell carcinoma (SCC) — malignant squamous epithelium - Transitional cell carcinoma (TCC) — from urothelium - Undifferentiated carcinoma — no glandular or squamous differentiation

Benign Mesenchymal Tumours: - Named by cell type + -oma suffix: lipoma (fat), leiomyoma (smooth muscle), fibroma (fibrous), chondroma (cartilage), osteoma (bone), haemangioma (blood vessels), lymphangioma (lymphatics), meningioma (meninges), schwannoma (nerve sheath)

Malignant Mesenchymal Tumours (Sarcomas): - Named by cell type + -sarcoma: liposarcoma, leiomyosarcoma, fibrosarcoma, chondrosarcoma, osteosarcoma, angiosarcoma, rhabdomyosarcoma, synovial sarcoma

Other Naming Conventions: - Mixed tumours: more than one neoplastic cell type derived from one germ layer. e.g., pleomorphic adenoma of salivary gland (epithelial + myoepithelial + stromal) - Hamartoma: disorganised benign proliferation of native tissues - Teratoma: more than one germ layer (ectoderm, endoderm, mesoderm). Occur in gonads (especially ovary — dermoid cyst) and occasionally extragonadal (mediastinum, sacrococcygeal) - Mature (benign) teratoma — well-differentiated tissues (skin, hair, teeth, bone, thyroid, neural tissue) - Immature (malignant) teratoma — incompletely differentiated tissues (immature neuroepithelium) - Blastoma: malignant tumour resembling embryonic tissue — typically in children. e.g., nephroblastoma (Wilms' tumour), neuroblastoma, retinoblastoma, hepatoblastoma - Note: Some blastomas are mixed — Wilms' tumour contains blastema, epithelial, and stromal elements - Carcinosarcoma (MMMT — Malignant Mixed Müllerian Tumour): malignant tumour with both carcinoma (epithelial) and sarcoma (mesenchymal) components. In uterus — aggressive, biphasic - Carcinoma in situ (CIS): full-thickness dysplasia/cellular atypia without invasion through basement membrane. Pre-invasive

Features of Malignancy — Anaplasia

• Anaplasia: lack of differentiation ("backwards formation")
• Cellular pleomorphism — variation in cell size and shape
• Nuclear abnormalities:
• Nuclear pleomorphism — variation in nuclear size and shape
• Hyperchromasia — increased DNA content → darkly stained nuclei
• Increased nuclear-to-cytoplasmic (N:C) ratio — normal 1:4-6 → can be 1:1
• Prominent nucleoli — increased ribosome production
• Irregular nuclear membrane — chromatin clumping, coarse texture
• Abnormal mitoses: tripolar, quadripolar, asymmetrical, ring forms, atypical mitotic figures
• Loss of polarity — loss of normal orientation (e.g., nuclei not at basal aspect of glandular cells; architectural disorganisation)
• Tumour giant cells — large, bizarre cells with single or multiple hyperchromatic nuclei

3.2 Carcinogenesis

Initiation → Promotion → Progression

The Multistep Model of Carcinogenesis

1. Initiation:
2. Irreversible genetic alteration (mutation) in a single cell
3. Caused by chemical carcinogens, radiation, viruses
4. Mutated cell may remain dormant for months-years
5. Requires cell proliferation to "fix" the mutation (before DNA repair can correct it)

6. Initiated cells have a selective growth advantage

7. Promotion:

8. Reversible, prolonged exposure to promoters (non-mutagenic agents that enhance proliferation of initiated cells)
9. Promoters: oestrogen (endometrial, breast), phorbol esters (TPA — experimental), bile acids (colon), alcohol, chronic inflammation
10. Promoters do NOT cause mutations — they alter gene expression and stimulate cell division

11. Clonal expansion of initiated cells → preneoplastic lesions (e.g., CIN, endometrial hyperplasia with atypia)

12. Progression:

13. Irreversible — accumulation of further mutations
14. Development of invasiveness, metastasis, genomic instability
15. Tumour heterogeneity emerges (different subclones with different mutations)
16. Angiogenic switch — tumour acquires ability to induce new blood vessels

The Multistep Nature of Cancer — Genetic Basis

• Most cancers require 4-6 driver mutations (Vogelstein — colorectal cancer model)
• Knudson's "two-hit" hypothesis: both alleles of a tumour suppressor gene must be inactivated (e.g., Rb in retinoblastoma — hereditary: one hit inherited, one somatic; sporadic: two somatic hits)
• Hallmarks of Cancer (Hanahan & Weinberg):
• Self-sufficiency in growth signals
• Insensitivity to anti-growth signals
• Evasion of apoptosis
• Limitless replicative potential (telomerase activation)
• Sustained angiogenesis
• Tissue invasion and metastasis
• Reprogramming of energy metabolism (Warburg effect — aerobic glycolysis)
• Evading immune destruction
• Tumour-promoting inflammation
• Genomic instability and mutation

Oncogenes

• Genes that promote cell proliferation when activated (gain-of-function mutations)
• Normal cellular counterparts = proto-oncogenes — regulate normal growth and differentiation
• Activation mechanisms:
• Point mutation → constitutively active protein (e.g., Ras G12V — impaired GTPase activity → stuck in active GTP-bound state)
• Gene amplification → increased copy number → protein overexpression (e.g., HER2/neu in breast cancer, MYCN in neuroblastoma)
• Chromosomal translocation → fusion gene/enhanced expression (e.g., Philadelphia chromosome — BCR-ABL in CML; Burkitt lymphoma — c-myc/IgH)
• Retroviral insertion → promoter insertion/enhancer → proto-oncogene activated

Key Oncogenes in Gynaecological Cancers

Oncogene	Type	Cancer Association	Mechanism
K-RAS	GTPase	Ovarian (low-grade serous, mucinous), endometrial, pancreatic, colorectal	Point mutation (codon 12,13,61) → impaired GTPase activity → constitutive MAPK signalling
BRAF	Ser/Thr kinase	Ovarian low-grade serous (often mutually exclusive with KRAS), melanoma, thyroid	V600E mutation → constitutive kinase activity
PIK3CA	PI3K catalytic subunit	Endometrial endometrioid (high frequency), ovarian clear cell, cervical, breast	Activating mutation → PI3K/AKT/mTOR pathway hyperactivation
HER2/neu (ERBB2)	RTK (EGFR family)	Breast (20-30%), endometrial serous (25-30%), ovarian (10-15%)	Gene amplification → receptor overexpression → constitutive signalling
c-MYC	Transcription factor	Many cancers (Burkitt lymphoma, breast, ovarian, cervical)	Translocation (Burkitt), gene amplification
CCND1 (Cyclin D1)	Cell cycle regulator	Mantle cell lymphoma, breast, endometrial	Translocation t(11;14), amplification → cell cycle progression
EGFR (HER1/ERBB1)	RTK	Lung (NSCLC), cervical, ovarian SCC	Overexpression, activating mutation (lung)
AKT1	Ser/Thr kinase	Breast, ovarian, endometrial	Activating mutation (E17K) → constitutive PI3K/AKT signalling
ARID1A	Chromatin remodelling	Ovarian clear cell, endometrioid; endometrial	Tumour SUPPRESSOR (but listed here as frequently mutated) — loss of BAF250a expression

Tumour Suppressor Genes

• Genes that inhibit cell proliferation; loss-of-function (inactivating) mutations → cancer
• Knudson two-hit hypothesis applies: both alleles must be inactivated (or loss of heterozygosity — LOH)
• Mechanisms of inactivation: mutation (point/truncation), deletion (LOH), promoter hypermethylation (epigenetic silencing), chromosomal loss

Key Tumour Suppressor Genes

p53 (TP53) — "Guardian of the Genome" - Most commonly mutated gene in human cancers (>50% of all cancers) - Function: - Cell cycle arrest at G1/S checkpoint (via p21/CIP1 — inhibits CDK4/6-cyclin D) - DNA repair (GADD45) - Apoptosis (Bax, Puma, Noxa, Fas) - Senescence - Metabolism regulation - Mutation in gynaecology: - High-grade serous ovarian carcinoma (HGSOC) — >95% have p53 mutation (hallmark) - Serous endometrial carcinoma (Type II) — 80-90% p53 mutation - Endometrioid endometrial carcinoma: p53 mutation uncommon in low-grade; more in high-grade - Li-Fraumeni syndrome — germline p53 mutation → early-onset multiple cancers (breast, sarcoma, brain, adrenal) - p53 immunohistochemistry: mutant p53 often accumulates in nucleus → strong diffuse nuclear positivity (or complete null pattern) → surrogate marker for TP53 mutation

RB (Retinoblastoma) - First tumour suppressor gene discovered - Function: controls G1/S checkpoint. Hypophosphorylated Rb binds E2F → blocks transcription of S-phase genes. Cyclin-CDK phosphorylation inactivates Rb → releases E2F → cell cycle progression - Mechanism of inactivation: mutation + LOH; or oncogenic viral proteins — HPV E7 binds and degrades Rb (mechanism in cervical cancer) - Associated cancers: retinoblastoma (childhood), osteosarcoma, small cell lung cancer, bladder, breast

APC (Adenomatous Polyposis Coli) - Function: regulates β-catenin/Wnt signalling. APC binds β-catenin → targets it for degradation. Loss of APC → β-catenin accumulates → translocates to nucleus → activates TCF/LEF transcription → c-MYC, cyclin D1 upregulation - Hereditary: Familial Adenomatous Polyposis (FAP) — germline APC mutation → hundreds of colorectal adenomas by teens → inevitable colon cancer by age 40 - Sporadic: mutations in ~80% of sporadic colorectal cancers - Gynae relevance: increased risk of desmoid tumours (FAP); also hepatoblastoma and thyroid cancer

BRCA1 & BRCA2 - Function: double-strand DNA break repair via homologous recombination (HR). BRCA1/2 are part of the same DNA repair complex — essential for error-free repair of DNA double-strand breaks - Hereditary breast and ovarian cancer syndrome: - 5-10% of breast cancers and 15-20% of ovarian cancers are hereditary - BRCA1 (chr17q21) — 40-60% lifetime breast cancer risk, 20-45% ovarian cancer risk - BRCA2 (chr13q12) — 40-55% lifetime breast cancer risk, 10-20% ovarian cancer risk (also male breast cancer, pancreatic, prostate) - High-grade serous ovarian carcinoma is the dominant ovarian cancer type in BRCA carriers - Also increased risk of fallopian tube and primary peritoneal carcinoma - BRCA1/2 mutation testing is indicated for: ovarian cancer at any age, breast cancer <50, triple-negative breast cancer <60, family history of breast/ovarian, male breast cancer, Ashkenazi Jewish ancestry - PARP inhibitors (olaparib, niraparib) — exploit synthetic lethality in HR-deficient (BRCA-mutated) tumours - BRCA1-related ovarian cancers have better overall survival than sporadic (better response to platinum chemotherapy)

PTEN (Phosphatase and Tensin Homolog) - Function: lipid phosphatase — dephosphorylates PIP₃ → antagonises PI3K/AKT signalling (tumour suppressor) - Most commonly mutated gene in endometrioid endometrial carcinoma (40-80%) - Germline mutation: Cowden syndrome — multiple hamartomas (breast, thyroid, GI), increased risk of breast, thyroid (follicular), and endometrial cancer - Loss of PTEN → constitutive AKT activation → increased cell growth, survival, proliferation - PTEN loss is an early event in endometrioid endometrial carcinogenesis (seen in endometrial hyperplasia with atypia) - Immunohistochemistry: loss of PTEN expression = mutation/loss of protein

Others: - VHL (von Hippel-Lindau): E3 ubiquitin ligase targets HIF-1α → loss → HIF accumulation → angiogenic tumours (renal cell, haemangioblastoma, phaeochromocytoma) - SMAD4 (DPC4): TGF-β signalling pathway — colorectal, pancreatic cancers - CDKN2A (p16/INK4a): CDK inhibitor — melanoma, pancreatic, lung, cervical (HPV integration → p16 upregulation — paradoxically high p16 = surrogate marker for HPV-related cervical cancer) - LKB1/STK11: Peutz-Jeghers syndrome → hamartomatous polyps, increased risk of gynaecological cancers (sex cord-stromal tumours, cervical adenoma malignum, breast, pancreatic)

DNA Repair Genes — Defects in DNA Repair

• Mismatch Repair (MMR) Genes: MLH1, MSH2, MSH6, PMS2
• Function: correct single-base mismatches and insertion-deletion loops that escape DNA polymerase proofreading
• Deficiency → microsatellite instability (MSI) — expansion/contraction of short tandem repeats (microsatellites)
• Hereditary Non-Polyposis Colorectal Cancer (HNPCC / Lynch Syndrome): germline mutation in one MMR gene (MLH1 or MSH2 → 90%; MSH6, PMS2 → 10%)
  • Lifetime risks: colorectal (60-80%), endometrial (40-60% — highest risk after colorectal in women), ovarian (10-15%), stomach, small bowel, urinary tract, hepatobiliary, brain
  • Lynch-related endometrial cancer: more often lower uterine segment, endometrioid histology (but also clear cell, serous), MMR-deficient by IHC, MSI-high, better prognosis stage-for-stage
  • Amsterdam II criteria / Revised Bethesda guidelines for screening
  • Universal screening: all endometrial and colorectal cancers should be tested for MMR deficiency (IHC for MLH1, MSH2, MSH6, PMS2 ± MSI testing)

• MLH1 promoter hypermethylation — sporadic silencing (most common cause of MSI in sporadic colorectal and endometrial cancers) — NOT hereditary

• Nucleotide Excision Repair (NER): Xeroderma Pigmentosum — defective UV damage repair → extreme photosensitivity → 1000x ↑ risk of skin cancers

Tumour Angiogenesis (VEGF)

• Tumours cannot grow >1-2 mm³ without new blood vessels
• Angiogenic switch: tumour cells + microenvironment shift balance from anti-angiogenic to pro-angiogenic factors
• Key pro-angiogenic factors:
• VEGF (VEGF-A): most important — induced by hypoxia (HIF-1α), also by oncogenes (Ras, Myc, p53 loss)
• FGF-2 (bFGF): endothelial cell proliferation
• PDGF: pericyte recruitment → vessel maturation
• Angiopoietins (Ang-1, Ang-2): vessel stability vs destabilisation
• IL-8, TGF-β, PGE₂, MMPs
• Anti-angiogenic factors:
• Thrombospondin-1 (TSP-1): inhibited by p53 loss and Myc activation
• Endostatin, angiostatin, tumstatin — derived from ECM cleavage
• Tumour vessels are abnormal: tortuous, leaky, irregularly shaped, haphazard branching, loss of pericyte coverage → increased permeability (provides route for metastasis)
• Clinical relevance — Anti-VEGF therapy:
• Bevacizumab (Avastin): humanised anti-VEGF monoclonal antibody — used in ovarian (advanced/recurrent), colorectal, lung, glioblastoma, renal cancers
• VEGF-Trap (aflibercept): soluble decoy receptor
• Tyrosine kinase inhibitors: sunitinib, sorafenib, pazopanib (target VEGFR, PDGFR, etc.)
• Side effects: hypertension, proteinuria, impaired wound healing, bleeding, thrombosis, GI perforation

3.3 Invasion and Metastasis

The Metastatic Cascade

1. Local invasion — penetration of basement membrane and invasion of stroma
2. Intravasation — entry into blood/lymphatic vessels
3. Survival in circulation — protection from anoikis (apoptosis due to loss of cell-matrix attachment), evasion of immune cells
4. Extravasation — exit from vessels into distant organ parenchyma
5. Metastatic colonisation — survival and proliferation in new microenvironment

Epithelial-Mesenchymal Transition (EMT)

• Key process enabling invasion and metastasis in carcinomas
• Epithelial cells lose polarity → acquire mesenchymal (fibroblast-like) properties
• Changes:
• ↓ E-cadherin (loss of intercellular adhesion) — most important change. E-cadherin is a tumour/metastasis suppressor
• ↑ N-cadherin, vimentin — mesenchymal markers
• ↑ MMP secretion → basement membrane degradation
• ↑ Cell motility (actin cytoskeleton rearrangement)
• ↑ Resistance to apoptosis
• Transcriptional repressors of E-cadherin: Snail, Slug, Twist, ZEB1, ZEB2 — key EMT-inducing transcription factors
• Inducers: TGF-β, Wnt, Notch, Hedgehog, hypoxia, inflammatory signals, growth factors
• EMT is reversible — at metastatic site, cells may undergo mesenchymal-epithelial transition (MET) to re-form epithelial structures

Basement Membrane Degradation — Role of MMPs

• Matrix Metalloproteinases (MMPs): zinc-dependent endopeptidases
• Collagenases: MMP-1, MMP-8, MMP-13 (cleave fibrillar collagens I, II, III)
• Gelatinases: MMP-2 (gelatinase A), MMP-9 (gelatinase B) — cleave type IV collagen (basement membrane) and denatured collagen (gelatin)
• Stromelysins: MMP-3, MMP-10, MMP-11 — degrade proteoglycans, laminin, fibronectin
• Membrane-type MMPs (MT-MMPs): MMP-14, -15, -16, -24 — anchored to cell surface
• Regulation: secreted as inactive pro-MMPs → cleaved by other proteases (plasmin, trypsin, other MMPs). TIMPs (TIMP-1, -2, -3, -4) inhibit MMPs
• Tumour cells upregulate MMPs (via growth factors, cytokines, oncogenic signals) and/or recruit stromal cells (fibroblasts, inflammatory cells) to produce MMPs
• Balance of MMPs > TIMPs → tumour invasion
• Other proteases: uPA/uPAR system (plasminogen activator cascade → plasmin → degrades ECM, activates MMPs)

Lymphovascular Invasion

• Tumour cells enter lymphatic vessels → travel to sentinel lymph node (first node in regional basin)
• Lymphatic spread is the most common route for carcinomas (epithelial tumours)
• Haematogenous spread is more common for sarcomas, but carcinomas also use it
• Venous invasion → systemic dissemination (liver, lungs, brain, bone)
• Perineural invasion — tumour cells wrapping around or infiltrating nerve sheaths (e.g., pancreatic cancer, vulvar cancer)
• Histological identification: tumour cell emboli within lymphatic (no RBCs, thin endothelium) or blood vessel (RBCs present, thicker wall)
• D2-40 — immunohistochemical marker for lymphatic endothelium
• CD31, CD34 — pan-endothelial markers (blood vessels)
• Elastic van Gieson (EVG) stain — highlights vessel walls

Lymphatic vs Haematogenous Spread

Lymphatic Spread: - Most common for carcinomas (epithelial tumours) - Tumour cells → lymphatic channels → regional lymph nodes → thoracic duct → bloodstream - Sentinel lymph node concept — first node in the lymphatic basin draining the tumour. Biopsy of sentinel node determines if nodal involvement present (avoids full lymphadenectomy if negative) - Gynae applications: sentinel lymph node biopsy in vulvar, cervical, and endometrial cancer - Patterns: may skip a node directly to higher echelon (skip metastasis) - Tumour cells may be arrested in subcapsular sinus of node → proliferate → enlarge node → eventually efface node architecture → extra nodal extension

Haematogenous Spread: - Most common for sarcomas (mesenchymal tumours) and some carcinomas (renal cell, HCC, follicular thyroid, choriocarcinoma) - Entry: tumour cells invade thin-walled venules (easier than arteries) → venous system - Pattern determined by vascular drainage: - Portal vein drainage (GI cancers) → liver first - Caval drainage → lungs first - Batson's vertebral venous plexus — bypasses caval/pulmonary filtration → allows metastasis to spine/brain without lung involvement (e.g., prostate cancer → lumbar spine; breast cancer → thoracic spine) - Seed and soil hypothesis (Paget, 1889): metastases do not occur randomly. Certain tumours preferentially metastasise to certain organs based on favourable microenvironment (soil) for the tumour cells (seed) - Breast → bone, brain, liver, lung - Prostate → bone (osteoblastic) - Lung → brain, bone, adrenal - Colorectal → liver (portal drainage) - Ovarian → peritoneum (transcoelomic) - Uveal melanoma → liver

Sentinel Lymph Node Concept

• First lymph node that receives lymphatic drainage from a tumour
• Clinical utility: if sentinel node is tumour-negative → skip full lymphadenectomy (reduced morbidity — lymphoedema, nerve injury)
• Technique: peritumoural injection of blue dye (isosulfan blue, methylene blue) +/− radio-labelled colloid (technetium-99m) → identify blue/hot node(s) → sentinel node biopsy
• Indications in gynaecology:
• Vulvar cancer: sentinel node biopsy standard for early-stage (unifocal, <4 cm, clinically node-negative) — reduces groin lymphadenectomy morbidity
• Cervical cancer: early-stage (IA2-IB1) — sentinel node biopsy increasingly used
• Endometrial cancer: sentinel node mapping for staging (especially high-intermediate risk)
• Limitations: false-negative rate, need for experienced surgeon/pathologist, micrometastases detection requires ultrastaging (serial sections + IHC)

3.4 Tumour Grading vs Staging

Grading

• Histological assessment of differentiation — how closely tumour cells resemble the parent tissue
• Determined by: degree of gland formation (adenocarcinoma), nuclear atypia, mitotic activity
• WHO/FIGO grades:
• Grade 1 (well-differentiated): >95% glandular (Endometrioid) — low grade
• Grade 2 (moderately differentiated): 50-95% glandular
• Grade 3 (poorly differentiated): <50% glandular — high grade
• Nuclear grading: based on nuclear pleomorphism, nucleoli, chromatin pattern
• Nottingham (Elston-Ellis) grade for breast: tubule formation + nuclear pleomorphism + mitotic count → grade 1-3
• Clinical importance: grade correlates with prognosis (higher grade → worse outcome)
• Limitations: inter-observer variability, sampling issues (heterogeneous tumours), grading may change during progression

Staging

• Extent of tumour spread at diagnosis — most important prognostic factor
• Anatomic basis: primary tumour (T), regional nodes (N), distant metastasis (M)
• Staging is clinical + pathological (pathological staging requires surgical examination of tissues)

TNM System (American Joint Committee on Cancer — AJCC/UICC)

• T: size and extent of primary tumour (T0 → T4)
• Tis = carcinoma in situ
• T1-4 increasing size/invasion
• N: regional lymph node involvement (N0 → N3)
• N0 = no nodal involvement
• N1-3 based on number, size, location of involved nodes
• Nx = cannot be assessed
• M: distant metastasis (M0 = absent, M1 = present)
• Prefixes: cTNM (clinical), pTNM (pathological), yTNM (after neoadjuvant therapy), rTNM (recurrence)

FIGO Staging (Gynaecological Cancers)

• International Federation of Gynecology and Obstetrics staging system
• Surgicopathological — requires surgical evaluation
• Key principles:
• Stage I: confined to primary organ
• Stage II: spread within pelvis
• Stage III: spread beyond pelvis or to regional nodes
• Stage IV: distant metastasis (IVB) or bladder/rectal involvement (IVA)
• Specific FIGO stages differ for each site (cervix, endometrium, ovary, vulva, vagina, fallopian tube)
• See Section 4 for detailed FIGO staging of each gynaecological cancer

Prognostic Factors

• Stage — most important
• Grade
• Histological subtype (e.g., serous vs endometrioid endometrial cancer)
• Lymphovascular space invasion (LVSI)
• Residual disease after surgery (especially ovarian cancer)
• Molecular markers: p53 status, hormone receptor status, HER2, MMR status
• Age and performance status
• Completeness of cytoreduction (ovarian cancer)

3.5 Paraneoplastic Syndromes

Definition

• Symptom complexes occurring in cancer patients that are NOT directly due to the primary tumour, invasion, or metastasis
• Caused by: hormones, cytokines, or immune cross-reactivity
• Seen in ~10-15% of cancer patients
• Clinical importance: (1) May be presenting feature → lead to cancer diagnosis. (2) May mimic metastatic disease. (3) May cause significant morbidity. (4) May be monitored as tumour markers

Gynaecological Relevance

Hypercalcaemia

• Mechanism: tumour secretion of parathyroid hormone-related protein (PTHrP)
• Most common paraneoplastic syndrome
• Cancers: Squamous cell carcinoma of lung (most classic), renal cell carcinoma, breast cancer, ovarian SCC, endometrial cancer (rare), vulvar SCC, head and neck SCC, bladder cancer, multiple myeloma
• Symptoms: bone pain, nausea/vomiting, constipation, polyuria, confusion, shortened QT interval on ECG, renal stones
• Treatment: IV fluids, bisphosphonates, denosumab, calcitonin

SIADH (Syndrome of Inappropriate Antidiuretic Hormone)

• Mechanism: tumour (usually SCLC) produces ADH (vasopressin) → water reabsorption → hyponatraemia
• Cancers: Small cell lung carcinoma (SCLC) — most common. Also head and neck, gynaecological (rare)
• Symptoms: lethargy, confusion, headache, seizures, coma (depending on severity and speed of onset of hyponatraemia)
• Diagnosis: hyponatraemia, low serum osmolality, inappropriately concentrated urine (>100 mOsm/kg), urine Na >20 mEq/L, normal renal/thyroid/adrenal function
• Treatment: fluid restriction, demeclocycline, vasopressin receptor antagonists (tolvaptan, conivaptan)

Cushing's Syndrome (Ectopic ACTH)

• Mechanism: tumour secretes ACTH → adrenal hypercortisolism
• Cancers: Small cell lung carcinoma (SCLC) — most common (~50% of ectopic ACTH). Also bronchial carcinoid, pancreatic carcinoid, medullary thyroid, thymic carcinoid, ovarian carcinoid (strumal carcinoid)
• Features: weakness (hypokalaemia), hypertension, hyperglycaemia, oedema, moon facies, central obesity, striae (but onset often rapid/fulminant → classic Cushingoid features may be absent), pigmentation (ACTH also stimulates melanocytes)
• Biochemistry: high ACTH, high cortisol (not suppressed by high-dose dexamethasone), hypokalaemia, metabolic alkalosis
• Treatment: tumour resection, ketoconazole, metyrapone

Eaton-Lambert Myasthenic Syndrome (LEMS)

• Mechanism: autoantibodies against presynaptic voltage-gated calcium channels (VGCC) at neuromuscular junction → impaired ACh release
• Cancers: Small cell lung carcinoma (SCLC) — 60% of LEMS cases are paraneoplastic
• Features: proximal muscle weakness (especially legs), improves with exertion (unlike myasthenia gravis which worsens), autonomic dysfunction (dry mouth, impotence, blurred vision), hyporeflexia
• Electrophysiology: low compound muscle action potential (CMAP) amplitude at rest; incremental response on repetitive nerve stimulation (facilitation) — opposite to myasthenia gravis (decremental)
• Treatment: treat underlying cancer, 3,4-diaminopyridine (blocks K⁺ channels → prolongs AP → ↑ Ca²⁺ influx), IVIG, immunosuppression

Trousseau's Syndrome (Migratory Thrombophlebitis)

• Mechanism: tumour-associated hypercoagulable state — tumour cells express tissue factor (TF) and cancer procoagulant (cysteine protease) → activation of coagulation cascade → diffuse thrombosis
• Cancers: Pancreatic adenocarcinoma (most classic), ovarian cancer (especially serous), lung, breast, GI, brain (glioblastoma)
• Features: recurrent, migratory thrombophlebitis (superficial and deep veins), often at unusual sites (arms, chest wall), resistant to anticoagulation
• Also: Non-bacterial thrombotic endocarditis (NBTE) — sterile vegetations on heart valves → emboli → strokes, MI
• Note: Trousseau's sign = carpopedal spasm in hypocalcaemia (NOT the same)
• Treatment: LMWH (unfractionated heparin may be required — warfarin often ineffective)

Acanthosis Nigricans

• Mechanism: tumour secretion of TGF-α (and possibly other growth factors) that bind to EGFR in skin → epidermal hyperplasia
• Cancers: Gastric adenocarcinoma (most common), also pancreatic, lung, breast, ovarian cancer, endometrial cancer
• Features: velvety, hyperpigmented, thickened skin plaques in flexural areas (neck, axillae, groin, areo) — symmetrical
• Benign acanthosis nigricans: associated with insulin resistance/obesity (much more common)
• Malignant acanthosis nigricans: rapid onset, extensive, may involve mucosal surfaces, often accompanied by sign of Leser-Trélat (sudden eruption of multiple seborrhoeic keratoses)

Other Paraneoplastic Syndromes

Syndrome	Mechanism	Associated Cancers
Polycythaemia	Erythropoietin secretion	Renal cell, HCC, cerebellar haemangioblastoma
Hypertrophic pulmonary osteoarthropathy (HPOA)	Unknown (likely VEGF, PDGF)	Lung cancer (especially NSCLC) — clubbing + periosteal new bone formation
Dermatomyositis	Autoimmune — cross-reacting antibodies?	Ovarian, lung, pancreatic, stomach, breast — Gottron's papules, heliotrope rash, proximal myopathy
Nephrotic syndrome	Immune complex deposition (membranous nephropathy)	Lung, colon, breast
Hypoglycaemia	IGF-II secretion (non-islet cell tumour hypoglycaemia — NICTH)	Large mesenchymal tumours (fibrosarcoma, leiomyosarcoma), HCC, adrenal
Carcinoid syndrome	Serotonin, bradykinin, histamine secretion	Carcinoid tumour (especially with liver metastases → bypasses hepatic metabolism) — flushing, diarrhoea, wheeze, right-sided heart valve disease

3.6 Tumour Markers

Definition

• Substances produced by tumour cells (or by host in response to tumour) that can be measured in blood, urine, or tissues
• Uses: screening (limited), diagnosis, prognosis, monitoring response to therapy, detecting recurrence

Key Tumour Markers in Gynaecological Oncology

Marker	Cancer	Notes
CA-125	Ovarian (especially serous)	Most used ovarian cancer marker. Elevated in ~80% of advanced serous ovarian cancers. Not specific — also elevated in endometriosis, PID, pregnancy, fibroids, menstruation, liver disease, other cancers (pancreatic, breast, lung). Used for monitoring treatment response and detecting recurrence. Cut-off usually 35 U/mL. Screening (UKCTOCS) showed CA-125 + transvaginal US can detect early-stage but mortality benefit is modest
HE4	Ovarian (especially serous, endometrioid)	Human epididymis protein 4. Less elevated in benign gynaecological conditions (more specific than CA-125 for malignant vs benign pelvic mass). Combined with CA-125 in ROMA index
ROMA Index	Ovarian	Risk of Ovarian Malignancy Algorithm. Uses CA-125 + HE4 + menopausal status to classify risk (pre- vs postmenopausal). Improves sensitivity and specificity over CA-125 alone
CEA	Colon, gastric, pancreatic, breast, ovarian (mucinous)	Carcinoembryonic antigen. Non-specific. Mainly used for colorectal cancer monitoring. Elevated in mucinous ovarian tumours
AFP	Ovarian yolk sac tumour, HCC, germ cell tumours	Alpha-fetoprotein. Elevated in yolk sac tumour (endodermal sinus tumour) of ovary. Also in hepatocellular carcinoma, hepatitis, pregnancy
β-hCG	Choriocarcinoma, gestational trophoblastic neoplasia, germ cell tumours	Human chorionic gonadotropin (β-subunit). Elevated in choriocarcinoma, invasive mole, mixed germ cell tumours (with choriocarcinoma component). Used for monitoring GTD. Also in pregnancy
Inhibin	Granulosa cell tumour, mucinous ovarian tumours	Granulosa cell tumour marker (inhibin A and B, especially inhibin B). Also positive in some mucinous ovarian tumours. Used for monitoring
SCC Antigen	Cervical SCC, vulvar SCC, head and neck SCC	Squamous cell carcinoma antigen. Useful for monitoring cervical SCC (follow-up after treatment). Elevation correlates with tumour burden
LDH	Dysgerminoma, SCLC, lymphomas, other	Lactate dehydrogenase. Elevated in dysgerminoma (ovarian germ cell). Also in liver disease, haemolysis, many cancers. Non-specific but useful as tumour marker in seminoma/dysgerminoma
CA 19-9	Pancreatic, gastric, colorectal, ovarian (mucinous)	Also elevated in benign pancreatic/biliary disease. Associated with mucinous ovarian tumours
CA 15-3	Breast cancer	Used for monitoring advanced breast cancer. Not sensitive for early detection
PLAP	Germ cell tumours (seminoma/dysgerminoma)	Placental alkaline phosphatase. Elevated in dysgerminoma and seminoma

Limitations of Tumour Markers

• False positives: many markers elevated in benign conditions
• Poor sensitivity for early-stage disease (CA-125 normal in ~50% of stage I ovarian cancer)
• Not specific enough for screening (except β-hCG in GTD surveillance)
• Organ-specificity is limited
• Levels affected by: renal function, liver disease, pregnancy, menstruation

3.7 Principles of Cancer Therapy

Surgery

• Primary treatment for most solid tumours (early-stage)
• Debulking/cytoreduction — especially in ovarian cancer (optimal = <1 cm residual disease)
• Staging — lymphadenectomy, omentectomy, peritoneal biopsies

Chemotherapy

• Adjuvant: after surgery (eliminate micrometastases)
• Neoadjuvant: before surgery (downstage, improve resectability)
• Palliative: advanced/metastatic disease
• Common gynaecological agents:
• Platinum agents — cisplatin, carboplatin (DNA cross-linking → apoptosis). Mainstay of ovarian cancer treatment
• Taxanes — paclitaxel, docetaxel (microtubule stabilisers → mitotic arrest). Ovarian, endometrial, cervical
• Anthracyclines — doxorubicin (topoisomerase II inhibitor, free radical generation). Endometrial, ovarian
• Alkylating agents — cyclophosphamide, ifosfamide (DNA alkylation)
• Antimetabolites — methotrexate (GTD), 5-FU, gemcitabine
• Topoisomerase inhibitors — irinotecan, topotecan (topoisomerase I poisons)
• Antibiotics — bleomycin, dactinomycin, mitomycin
• Vinca alkaloids — vincristine, vinblastine (microtubule inhibitors)

Molecular Targeted Therapy

• PARP inhibitors: olaparib, niraparib, rucaparib — exploit synthetic lethality in BRCA-mutated/HDR-deficient tumours (ovarian cancer maintenance therapy)
• Anti-VEGF: bevacizumab — anti-angiogenic. Used in advanced ovarian, cervical
• Anti-HER2: trastuzumab, pertuzumab, T-DM1 — HER2+ breast and endometrial serous
• EGFR inhibitors: cetuximab, gefitinib, erlotinib
• mTOR inhibitors: everolimus, temsirolimus
• Tyrosine kinase inhibitors: imatinib (BCR-ABL), sunitinib (VEGFR, PDGFR, KIT)

Immunotherapy

• Immune checkpoint inhibitors:
• Anti-PD-1: pembrolizumab, nivolumab
• Anti-PD-L1: atezolizumab, durvalumab
• Anti-CTLA-4: ipilimumab
• Indications in gynaecology:
• MSI-H/dMMR tumours — pembrolizumab approved for any MSI-H solid tumour (including endometrial)
• Cervical cancer — PD-L1+ advanced/recurrent (pembrolizumab)
• Mechanism: removes tumour-induced immune suppression → reactivates cytotoxic T cells

Hormonal Therapy

• Breast cancer: tamoxifen (SERM), aromatase inhibitors (letrozole, anastrozole, exemestane), ovarian suppression, fulvestrant (SERD)
• Endometrial cancer: progestogens (medroxyprogesterone acetate, megestrol acetate) — for early-stage low-grade endometrioid (fertility-sparing) or advanced disease

Resistance Mechanisms

Chemoresistance

1. Pre-existing heterogeneity — subclones with intrinsic resistance survive selection
2. Drug inactivation — glutathione conjugation (glutathione S-transferase), metallothioneins
3. Drug efflux — MDR phenotype (P-glycoprotein / MDR1/ABCB1, MRP, BCRP)
4. Altered drug target — topoisomerase II downregulation, β-tubulin mutations (taxane resistance)
5. Enhanced DNA repair — platinum resistance through increased NER, homologous recombination (reversion mutations restoring BRCA function)
6. Apoptosis evasion — Bcl-2 overexpression, p53 mutation, upregulation of IAPs
7. Epithelial-mesenchymal transition (EMT)
8. Tumour microenvironment — hypoxia, stromal cells, extracellular matrix
9. Cancer stem cells — quiescent, self-renewing, resistant population

MDR Phenotype (Multidrug Resistance)

• Overexpression of ATP-binding cassette (ABC) transporters that efflux chemotherapeutic drugs
• Key transporter: P-glycoprotein (P-gp / MDR1 / ABCB1) — broad substrate specificity for lipophilic drugs (anthracyclines, taxanes, vinca alkaloids, colchicine, actinomycin D, etoposide)
• Other transporters: MRP1 (ABCC1 — also transports organic anions, glutathione conjugates), BCRP (ABCG2 — mitoxantrone, topotecan, methotrexate)
• Mechanism: drugs enter cell → P-gp effluxes them out → reduced intracellular concentration → resistance
• Overexpressed in: many cancers (intrinsic resistance or induced by chemotherapy)
• Clinical: attempts to develop P-gp inhibitors have been largely unsuccessful due to toxicity

Cancer Cachexia

• Multifactorial wasting syndrome — loss of skeletal muscle (sarcopenia) ± adipose tissue
• Not simply starvation — cannot be reversed by nutritional support alone
• Mechanisms:
• Pro-inflammatory cytokines: TNF-α (cachectin — suppresses appetite, induces muscle proteolysis), IL-1, IL-6, IFN-γ
• Tumour-derived factors: PIF (proteolysis-inducing factor) — activates ubiquitin-proteasome pathway in muscle. LMF (lipid-mobilising factor)
• Hypermetabolism — increased resting energy expenditure
• Anorexia — due to cytokines, tumour products, side effects of treatment
• Insulin resistance
• Clinical: severe weight loss, muscle wasting, weakness, fatigue, anorexia, hypoalbuminaemia, impaired immune function, poor response to treatment
• Most common in: pancreatic, gastric, lung, oesophageal, ovarian (advanced)

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4. Gynaecological Pathology

4.1 Vulva

Anatomy

• Vulva includes: labia majora, labia minora, clitoris, vestibule, introitus, Bartholin's glands, Skene's glands
• Epithelium: keratinised stratified squamous (labia majora/minora), non-keratinised stratified squamous (vestibule)
• Hair follicles and sebaceous/sweat glands in labia majora

Non-Neoplastic Epithelial Disorders (Formerly "Vulvar Dystrophies")

Lichen Sclerosus

• Chronic inflammatory dermatosis of unknown aetiology (autoimmune component — associated with other autoimmune diseases: thyroiditis, vitiligo, alopecia areata)
• Most common in: postmenopausal women (but can occur at any age, including children — childhood lichen sclerosus)
• Symptoms: itching, soreness, dyspareunia, white plaques
• Gross appearance: white, atrophic, "cigarette paper" wrinkled skin, often perianal involvement ("figure of 8" or keyhole distribution). Fissures, purpura, and excoriations
• Microscopy:
• Thinned epidermis (atrophy) with flattening of rete ridges
• Homogenised, eosinophilic, hyalinised collagen in upper dermis (band-like)
• Chronic inflammatory infiltrate beneath the hyalinised zone (lymphocytes, plasma cells)
• Hyperkeratosis (orthokeratotic — anuclear keratin)
• Follicular plugging (dilated hair follicle with keratin plug)
• Early lesions may show basal cell vacuolation and hydropic degeneration
• Risk: Increased risk of squamous cell carcinoma (2-5% lifetime risk — small but significant). SCC arises in the background of lichen sclerosus, especially in untreated cases
• Treatment: ultra-potent topical steroids (clobetasol propionate). Regular follow-up for early detection of malignancy

Lichen Planus

• Autoimmune T-cell-mediated inflammatory disorder — can affect skin, mucous membranes, nails, scalp
• Vulvar involvement: erosive (most common in vulva) or papulosquamous
• Symptoms: pain, burning, dyspareunia, vaginal discharge (if mucosal involvement)
• Gross appearance: Erosive form — red, raw, glazed erosions with white lacy pattern at margins (Wickham's striae). Papular form — purple, pruritic, polygonal papules
• Often involves vagina — desquamative inflammatory vaginitis (diffuse erythema, purulent discharge)
• Histology:
• Hyperkeratosis, hypergranulosis, irregular acanthosis
• Saw-tooth rete ridges
• Lichenoid lymphocytic infiltrate at dermo-epidermal junction (band-like)
• Basal cell degeneration (Civatte bodies — apoptotic keratinocytes, colloid bodies)
• Max Joseph spaces (cleft between epidermis and dermis due to basal layer destruction)
• Risk of malignant transformation: small but increased (especially erosive form → SCC)
• Association: hepatitis C infection (oral lichen planus)
• Treatment: topical steroids, calcineurin inhibitors (tacrolimus)

Squamous Cell Hyperplasia (Formerly Hyperplastic Dystrophy)

• Non-specific thickening of vulvar epithelium due to chronic scratching/rubbing
• Gross appearance: thickened, white, leathery plaques (lichenification)
• Histology:
• Acanthosis (thickened spinous layer)
• Hyperkeratosis
• No atypia (no dysplasia)
• Chronic inflammation in dermis
• Benign condition — no increased malignant risk
• Treatment: remove irritants, topical steroids, emollients

Vulvar Intraepithelial Neoplasia (VIN)

Classification (Latest WHO / ISSVD)

Usual-type VIN (uVIN): - HPV-related (high-risk HPV 16, 33, 18) - Younger women (40-50 years) - Multifocal disease - Histology: Bowenoid — full-thickness atypia with koilocytes (HPV cytopathic effect) - Increased N:C ratio, hyperchromatic nuclei, dyskeratosis, abnormal mitoses throughout epithelium - p16INK4a: strong diffuse block-positive (surrogate marker for HPV integration) - p53: wild-type (not mutated) - Subtypes: - VIN, usual type (warty/basaloid): warty has koilocytosis + parakeratosis; basaloid has smaller, more uniform cells - Previous term: VIN 1/2/3 (now VIN usual type subdivides into high-grade — moderate/severe dysplasia — VIN 2/3 equivalent) - Risk of progression to invasion: 3-5% if treated; up to 10% if untreated (especially in immunocompromised) - Treatment: surgical excision, laser ablation, imiquimod (topical immune modulator)

Differentiated-type VIN (dVIN): - NOT HPV-related (HPV-negative) - Associated with lichen sclerosus (background) - Older women (60+) - Often unifocal - Histology: Highly differentiated atypia — subtle, easy to miss! - Elongated, anastomosing rete ridges - Abnormal keratinisation — keratin pearls in deep epithelium (abnormal) - Pale/pink eosinophilic cytoplasm (abnormal maturation/differentiation) - Basal layer atypia — large vesicular nuclei, prominent nucleoli, increased mitoses in basal layer - No koilocytes - p16: negative or patchy (not block-positive) - p53: strong diffuse or null pattern (p53 mutation — 90% of dVIN) - Ki-67: high in basal/parabasal layers - Risk: HIGH RISK of rapid progression to SCC — higher than uVIN. Up to 30-50% of dVIN progresses to invasive SCC - Treatment: wide local excision (cannot treat with imiquimod or laser — not HPV-related)

Paget's Disease of the Vulva

• Intraepithelial adenocarcinoma — presents as eczematous, red, scaly, weeping plaque on vulva (often labia majora)
• Symptoms: pruritus, burning, pain (often mistaken for dermatitis — delayed diagnosis)
• Peak age: 60-80 years
• Histology:
• Paget cells — large, round cells with abundant pale/clear cytoplasm, large vesicular nuclei, prominent nucleoli
• Cells scattered singly or in nests within epidermis (often at all levels)
• Cells may be compressed at basal layer (but not invading dermis)
• Glandular/luminal differentiation may be present
• Immunohistochemistry:
• CK7+ (strong, diffuse)
• CK20− (usually negative — helps distinguish from urothelial carcinoma in situ)
• MUCA1 (EMA)+
• CEA+, HER2+ (in ~50%)
• GCDFP-15 (BRST-2)+ (marker of apocrine differentiation)
• S100−, HMB45− (excludes melanoma)
• p63− (excludes squamous differentiation)
• Subtypes:
• Primary Paget's (90%): intraepithelial adenocarcinoma of vulvar skin apocrine glands. Not associated with underlying adenocarcinoma in most cases
• Secondary Paget's (10%): due to underlying adenocarcinoma — either vulvar (Bartholin's, sweat gland) or distant (rectal, bladder, cervical, endometrial, ovarian) — Paget cells extend into vulvar epidermis from adjacent carcinoma
• Immunostaining of special stains for secondary Paget's:
• Urothelial origin → CK7+, CK20+, uroplakin+, GATA3+
• Colorectal origin → CK20+, CDX2+, CK7-
• Anogenital mammary-like gland origin → CK7+, CK20-, GCDFP-15+, ER+, PR+, HER2+
• Treatment: wide local excision with margin assessment (high recurrence rate — 30-50% due to occult extension beyond visible margins, multifocality). Topical imiquimod (some success). Check for underlying malignancy
• Prognosis: if primary (intraepithelial only) → excellent. If underlying adenocarcinoma → poor

Squamous Cell Carcinoma of Vulva

• ~90% of vulvar malignancies
• Peak age: 65-75 years
• Two aetiologic pathways:
• HPV-related (younger, 40-60%) — usual-type VIN → SCC. HPV 16/33. p16+, p53 wild-type. Often multifocal, basaloid/warty morphology. Less aggressive overall
• HPV-independent (older, 40-60%) — lichen sclerosus → differentiated VIN → SCC. p16−, p53 mutant. Usually unifocal, keratinising SCC. More aggressive
• Histologic subtypes: keratinising (most common), non-keratinising, basaloid, warty (condylomatous), verrucous (well-differentiated, exophytic, pushing border — very low malignant potential)
• Spread:
• Lymphatic → inguinal and femoral nodes (superficial → deep)
• Direct extension → vagina, perineum, urethra, anus
• Haematogenous — late
• FIGO Staging (Vulvar Cancer):
• Stage I: Tumour confined to vulva
  • IA: ≤2 cm, stromal invasion ≤1 mm
  • IB: >2 cm OR stromal invasion >1 mm
• Stage II: Tumour extends to lower perineal structures (vagina, urethra, anus) regardless of size
• Stage III: Involvement of inguinofemoral nodes
  • IIIA: 1 node ≥5 mm OR 1-2 nodes <5 mm
  • IIIB: ≥2 nodes ≥5 mm OR ≥3 nodes <5 mm
  • IIIC: node with extracapsular spread
• Stage IV: Tumour invades upper urethra/bladder/rectum/pelvic bone (IVA) OR distant metastasis (IVB)
• Prognostic factors: stage (nodal status most important), depth of invasion, LVSI, perineural invasion, margin status
• Sentinel node biopsy: standard for early-stage (unifocal, <4 cm, clinically node-negative)

Other Vulvar Malignancies

Malignant Melanoma: - Second most common vulvar malignancy (5-10%) - Most common site: labia minora, clitoris - Histology: nested epithelioid/spindled cells, melanin pigment, pagetoid spread - IHC: S100+, SOX10+, HMB45+, Melan-A/MART-1+ - Very aggressive — 5-year survival ~30% - Treatment: wide excision + sentinel node biopsy. No role for radical vulvectomy (does not improve survival). Immunotherapy (checkpoint inhibitors) used

Bartholin's Gland Carcinoma: - Rare (<5% of vulvar malignancies) - Histology: SCC (most common), adenocarcinoma (second), adenoid cystic, adenosquamous, transitional - Presentation: Bartholin's gland mass in postmenopausal woman (>90% of Bartholin's gland masses in women >40 are benign cysts; in >50, malignant risk rises) - Treatment: radical hemivulvectomy + ipsilateral inguinofemoral lymphadenectomy ± radiotherapy

Paget's Disease — discussed above

Basal Cell Carcinoma: - Rare on vulva (<1%) - Indolent, locally invasive - Treatment: wide local excision

Benign Vulvar Lesions

Bartholin's Cyst: - Most common vulvar cyst - Due to: obstruction of Bartholin's duct (not gland) - Lined by: transitional/columnar epithelium (may be squamous if chronically inflamed) - Contents: mucoid - Size: 1-3 cm, may enlarge with sexual arousal - Infected → Bartholin's abscess: polymicrobial (E. coli, Bacteroides, Neisseria gonorrhoeae, Chlamydia trachomatis, anaerobes) - Treatment: asymptomatic → observation. Symptomatic → marsupialisation (incision + suturing edges to keep open) or Word catheter (balloon-tipped). Recurrent → excision of gland

Other benign vulvar cysts: - Epidermal inclusion cyst — lined by stratified squamous with keratin contents - Pilonidal sinus — in clitoral area/mons pubis, associated with hair - Mucinous cyst — lined by mucinous epithelium (vestibule) - Gartner's duct cyst — mesonephric remnant (Wolfian), lateral vaginal wall

4.2 Vagina

Anatomy and Histology

• Epithelium: non-keratinised stratified squamous
• No glands — lubrication from cervical mucus and Bartholin's glands
• Layers: epithelium → lamina propria (rich in elastic fibres) → muscularis (smooth muscle) → adventitia

Vaginal Adenosis

• Presence of mucinous (endocervical-type) or tubo-endometrioid (ciliated) epithelium in the vagina (replacing normal squamous epithelium)
• Location: upper 1/3 vagina (most common), can extend to lower vagina
• Classic association: Diethylstilbestrol (DES) exposure in utero (women born 1940-1971 whose mothers took DES to prevent miscarriage)
• Sporadic adenosis also occurs
• Complications: may be asymptomatic (incidental), or cause mucoid discharge, postcoital bleeding. Risk of clear cell adenocarcinoma (small but significant — 1/1000 in DES-exposed). Also associated with cervical structural abnormalities (cockscomb cervix, cervical collar, T-shaped uterus)
• Histology: glands lined by columnar mucinous/ciliated epithelium in vaginal stroma. May undergo squamous metaplasia (glands replaced by squamous) which is a normal maturation process
• Colposcopy: red, granular patches in vagina

Vaginal Intraepithelial Neoplasia (VAIN)

• Pre-invasive squamous dysplasia of vagina — analogous to CIN
• Usually HPV-related (HPV 16)
• Often multifocal and associated with CIN/VIN (field effect)
• Histology: increased N:C ratio, nuclear hyperchromasia, abnormal mitoses, koilocytes
• VAIN 1 (low-grade): lower 1/3 of epithelium
• VAIN 2 (moderate): lower 2/3
• VAIN 3 (high-grade/CIS): full-thickness involvement
• p16INK4a: positive in high-grade VAIN
• Treatment: laser ablation, excision (upper vaginectomy), topical 5-FU, imiquimod

Squamous Cell Carcinoma of Vagina

• Primary vaginal SCC — rare (<2% of gynaecological malignancies)
• Diagnosis requires: no evidence of CIN or vulvar cancer within 5 years (most "vaginal" SCC is extension from cervix or vulva)
• Risk factors: HPV (40-60%), previous CIN/vulvar cancer, immunosuppression, chronic irritation (pessary use)
• Location: upper 1/3 of posterior wall (most common)
• Histology: similar to cervical SCC — keratinising or non-keratinising
• Spread: direct extension to bladder/rectum, lymphatic to pelvic nodes (upper vagina → pelvic nodes; lower vagina → inguinal nodes)
• FIGO Staging (Vaginal Cancer):
• Stage I: Limited to vaginal mucosa
• Stage II: Submucosal extension into paravaginal tissues, not to pelvic wall
• Stage III: Extension to pelvic wall
• Stage IVA: Bladder/rectal mucosa involvement, extension beyond true pelvis
• Stage IVB: Distant metastasis
• Treatment: radiotherapy (± chemo) — primary. Surgery for stage I-II (upper vaginectomy, radical hysterectomy). Very poor prognosis if recurrent

Clear Cell Adenocarcinoma of Vagina

• Rare — classic association with in utero DES exposure
• Peak incidence: 19 years (range 7-30)
• Location: upper anterior vaginal wall (most common)
• Histology: tubulocystic, papillary, or solid patterns. Clear cells (glycogen-rich) with hobnail nuclei (clear cells with large hyperchromatic nuclei protruding into lumen — also in ovarian clear cell carcinoma)
• IHC: CK7+, EMA+, HNF1B+, p53 wild-type, ER/PR usually negative
• Prognosis: better than non-DES-related clear cell ca. Dependent on stage
• Treatment: radical hysterectomy + vaginectomy, or radiation
• Screening: DES-exposed daughters should have annual vaginal/cervical examination starting at menarche or age 14

Rhabdomyosarcoma (Sarcoma Botryoides)

• Most common vaginal malignancy in infants/children (<6 years)
• Gross appearance: "Grapelike" (botryoid = bunch of grapes) — polypoid, oedematous, exophytic mass protruding from vagina
• Histology:
• Cambium layer — dense band of rhabdomyoblasts (primitive skeletal muscle cells) beneath vaginal epithelium
• Cross-striations in rhabdomyoblasts (may be hard to find)
• Myxoid stroma
• IHC: Desmin+, MyoD1+, Myogenin+, vimentin+, CK−
• Subtype of embryonal rhabdomyosarcoma — botryoid variant
• Genetics: loss of heterozygosity at 11p15.5 (IGF2 locus)
• Treatment: multimodal — surgery (conservative), chemotherapy (VAC — vincristine, actinomycin D, cyclophosphamide), radiotherapy. Survival improved dramatically (now >80% with modern protocols)
• Prognostic factors: embryonal/botryoid → good prognosis. Alveolar (PAX3/7-FOXO1 fusion) → worse

4.3 Cervix

Anatomy and Histology

• Ectocervix: non-keratinised stratified squamous epithelium
• Endocervix: single layer of columnar mucus-secreting epithelium with glands (crypts)
• Squamocolumnar junction (SCJ): junction between ectocervical squamous and endocervical columnar epithelium
• Transformation zone (TZ): area between original SCJ and current SCJ — where squamous metaplasia occurs (columnar → squamous under hormonal influence)
• TZ is the site of highest risk for cervical carcinogenesis — HPV preferentially infects metaplastic epithelium
• Cervical stroma: dense fibromuscular connective tissue (smooth muscle + collagen)

Normal Squamous Metaplasia of Cervix

• Physiological process — endocervical columnar epithelium is replaced by squamous epithelium through proliferation of reserve cells (subcolumnar pluripotent cells)
• Stimulated by: oestrogen (especially at puberty, first pregnancy)
• Stages: reserve cell hyperplasia → immature squamous metaplasia (no glycogen, no maturation) → mature squamous metaplasia (glycogenated cells, full maturation)
• Immature metaplasia may mimic dysplasia — but lacks nuclear atypia, has no abnormal mitoses, p16 negative
• Cervical "ectropion"/"erosion": visible columnar epithelium on ectocervix (normal in young women, pregnancy, OCP users) — NOT pathological

Cervical Intraepithelial Neoplasia (CIN)

Classification

CIN 1 (Low-grade — mild dysplasia): - Atypia limited to lower 1/3 of epithelium - Koilocytes present (HPV effect) - Nuclear enlargement, hyperchromasia, irregularity - Mitoses in lower 1/3 - Most (60-70%) regress spontaneously within 1-2 years - p16: negative or patchy (no block positivity)

CIN 2 (Moderate dysplasia): - Atypia involves lower 2/3 of epithelium - Koilocytes may still be present - Mitoses present in middle third - p16: positive (block) in HPV-driven cases - Majority of CIN2 is high-risk HPV driven — management similar to CIN3

CIN 3 (Severe dysplasia / Carcinoma in situ): - Full-thickness atypia (>2/3 to full thickness) - No surface maturation - Abnormal mitoses throughout all layers - p16: strong diffuse block-positive in HPV-driven cases - High risk of progression to invasion: ~30% over 10-20 years if untreated

Natural History of HPV → CIN → Invasive Cancer

HPV Infection (high-risk types): - Most sexually active women acquire HPV at some point - 90% clear spontaneously (immune-mediated) within 2 years - Persistent infection with high-risk HPV → risk of CIN/progression

HPV → CIN1: - Productive HPV infection (viral replication in differentiated squamous cells) - High viral load, koilocytes visible - Most clear spontaneously

CIN1 → CIN2/3: - HPV integration into host genome — loss of E2 → increased E6/E7 expression - E6 → p53 degradation (loss of apoptosis, DNA repair) - E7 → Rb degradation (loss of cell cycle control) - CIN2/3 shows transforming infection — cells proliferate despite differentiation - p16INK4a overexpression — negative feedback loop: Rb loss → p16 upregulation (paradox: p16=surrogate marker for high-risk HPV integration)

CIN3 → Invasive SCC: - Accumulation of additional mutations (genomic instability) - Invasion through basement membrane into stroma - Depth of invasion determines stage

Koilocytes

• HPV cytopathic effect — hallmark of low-grade CIN/productive HPV infection
• Features:
• Perinuclear clearing (halo) — clear zone around nucleus
• Irregular, raisinoid, hyperchromatic nucleus (wrinkled, degenerated appearance)
• Binucleation common
• Perinuclear condensation of cytoplasm — thickened rim
• Location: upper 2/3 of epithelium (differentiating compartment)
• Best seen in: CIN1 (low-grade). May be absent in high-grade CIN (transforming infection — no viral production)
• Not pathognomonic — similar changes can be seen in reactive conditions (but rarely so well-formed)

p16INK4a Immunostaining

• Surrogate marker for high-risk HPV E7-mediated Rb inactivation
• Pattern: Strong diffuse nuclear + cytoplasmic block positivity
• Uses:
• Distinguish CIN2/3 from benign mimics (immature metaplasia, reactive changes, atrophy)
• Confirm HPV causality in CIN/SCC
• Help diagnose CIN2 in borderline cases
• Triage of HPV-positive women (p16+ CIN2/3 = treatment)
• p16+ in cervical adenocarcinoma (CGIN) as well
• Controls: p16+ in high-grade CIN → block positive; in normal/reactive → negative or patchy; p16+ also in usual-type VIN, VAIN, AIN, HPV-related vulvar SCC, HPV-related oropharyngeal SCC
• Note: p16 can also be positive in some p53-mutated serous carcinomas (endometrial, ovarian) — different context, not HPV-related

Cervical Glandular Intraepithelial Neoplasia (CGIN)

• Pre-invasive lesion of endocervical glandular epithelium
• Less common than CIN (~10-15% of pre-invasive lesions)
• HPV-related (HPV 18 more common than 16 — different from SCC where HPV 16 dominates)
• Rising incidence (not clear if real or better detection)
• Histology:
• Stratification of glandular nuclei (pseudostratified, cigar-shaped)
• Nuclear enlargement, hyperchromasia, pleomorphism
• Increased mitotic activity (including atypical mitoses)
• Apical cytoplasmic budding (apoptotic bodies)
• Loss of mucin (cytoplasmic mucin decreased)
• Grading: Low-grade CGIN (rarely diagnosed) vs High-grade CGIN (usual diagnosis — analogous to CIN3)
• Architecture: may be flat (surface epithelium) or involve crypts/glands
• IHC: p16+ (block), Ki-67 high, ER− (normal endocervical glands are ER+), CEA+ (aberrant cytoplasmic expression in CGIN/invasive adenocarcinoma)
• Subtypes:
• Usual (endocervical) type — most common
• Intestinal type — goblet cells, Paneth cells
• Tubal/endometrioid type — less common
• Associated with invasive adenocarcinoma — risk of progression
• Treatment: excisional (LLETZ, cone biopsy). Adenocarcinoma in situ is not adequately treated by ablation (cannot see crypt involvement depth)
• Important: Skip lesions can occur — ensure cone margins are clear (recurrence risk if positive margins)

Cervical Cancer — Invasive

Squamous Cell Carcinoma (80%)

• Most common cervical cancer (though proportion of adenocarcinoma rising)
• Peak age: 45-55 years
• Risk factors: HPV (16 most common), smoking (synergistic with HPV), immunosuppression (HIV), high parity, long-term OCP use, early sexual debut, multiple partners, low socioeconomic status
• HPV types: HPV 16 (50-60%) , HPV 18 (10-15%), HPV 31/33/45/52/58 (remaining)
• Histologic subtypes:
• Keratinising: keratin pearls, intercellular bridges, abundant eosinophilic cytoplasm, well-defined cell borders
• Non-keratinising (most common): sheets/nests of squamous cells, no keratin, may have high mitotic activity
• Basaloid (small cell): small cells, high N:C ratio, hyperchromatic — aggressive
• Verrucous: very well-differentiated, exophytic, pushing border — low malignant potential
• Warty (condylomatous): HPV-related — koilocytes, papillary architecture
• Spread:
• Direct extension: into parametria → pelvic wall; down vagina; up to uterine isthmus; anterior → bladder; posterior → rectum
• Lymphatic: parametrial → obturator → internal/external iliac → common iliac → para-aortic nodes
• Haematogenous: late — lung, liver, bone

Adenocarcinoma (15-20%)

• Rising incidence (especially in younger women) — relative increase due to screening more effective for SCC
• HPV 18 most common (50-60%), HPV 16 (20-30%)
• Subtypes:
• Usual (endocervical) type: complex glandular patterns, mucin depletion, eosinophilic cytoplasm
• Mucinous (including minimal deviation adenocarcinoma/adenoma malignum):
  • Minimal deviation (adenoma malignum): well-differentiated glands that mimic normal endocervical glands — diagnostic pitfall! Glands are irregular, deep, some with abnormal shapes. Associated with Peutz-Jeghers syndrome (STK11 mutation). IHC: p53+, increased Ki-67
• Villoglandular: papillary architecture, often in younger women, good prognosis
• Endometrioid, clear cell, serous — rarer
• Mesonephric: rare, arises from mesonephric remnants (lateral cervix)
• Screening: can be detected by cytology (glandular cells abnormal) but harder than SCC
• Prognosis: similar to SCC stage-for-stage

Adenosquamous Carcinoma

• Mixed squamous and glandular differentiation (~5-10%)
• Aggressive — worse prognosis than pure SCC or adenocarcinoma
• IHC: p63+ (squamous), CK7+/CEA+ (glandular)

Neuroendocrine Carcinoma (Small Cell/Large Cell)

• Rare, very aggressive
• Associated with HPV 18
• Histology: small to medium cells with high N:C, salt-and-pepper chromatin, nuclear moulding, high mitotic rate
• IHC: chromogranin+, synaptophysin+, CD56+
• Behaviour: early lymphatic/hematogenous spread, poor prognosis
• Treatment: multimodal — chemo (platinum/etoposide), radiotherapy, ± surgery

FIGO Staging of Cervical Cancer (2018 Revised)

Stage	Description
I	Carcinoma confined to cervix (extension to corpus disregarded)
IA	Invasive carcinoma diagnosed by microscopy only
IA1	Stromal invasion ≤3 mm in depth
IA2	Stromal invasion >3 mm but ≤5 mm in depth
IB	Clinically visible lesion confined to cervix
IB1	≥4 cm (size removed from staging — any clinically visible lesion ≤4 cm is IB1) — Actually revised: Invasive carcinoma with deepest invasion >5 mm (depth) and horizontal spread >7 mm
II	Carcinoma extends beyond uterus but not to pelvic wall or lower 1/3 vagina
IIA	Without parametrial involvement
IIB	With parametrial involvement
III	Extension to pelvic wall AND/OR lower 1/3 vagina AND/OR causing hydronephrosis
IIIA	Involves lower 1/3 vagina, not pelvic wall
IIIB	Pelvic wall extension AND/OR hydronephrosis/non-functioning kidney
IIIC	Lymph node involvement (pelvic or para-aortic) — imaging or pathology
IV	Extension beyond true pelvis OR involvement of bladder/rectal mucosa
IVA	Bladder/rectal mucosa involvement
IVB	Distant metastasis

• Key changes in 2018 revision: Stage IIIC added (lymph node status can be designated from imaging [r] or pathology [p]). Stage IA now uses only depth of invasion (horizontal spread removed)

Pathophysiology of Cervical Carcinogenesis

The central role of HPV:

1. HPV genome: double-stranded circular DNA virus
2. Early regions (E): E1 (replication), E2 (transcription regulator), E4 (late gene expression), E5 (transforming), E6 (binds p53 → degradation), E7 (binds Rb → release E2F), E6/E7 = major oncoproteins
3. Late regions (L): L1 (major capsid protein — target of HPV vaccine), L2 (minor capsid)

4. Long control region (LCR): regulatory region

5. HPV integration into host genome:

6. Loss of E2 (E2 normally represses E6/E7 transcription) → E6/E7 overexpressed
7. Integration sites often near common fragile sites, may disrupt host genes
8. E6 → ubiquitin-mediated degradation of p53 → loss of apoptosis, DNA repair, cell cycle arrest
9. E7 → ubiquitin-mediated degradation of Rb → release E2F → cell cycle progression, S-phase entry

10. E7 also activates p16INK4a through Rb loss → p16 as surrogate marker

11. HPV vaccines:

12. Cervarix (bivalent): HPV 16, 18 (L1 virus-like particles)
13. Gardasil (quadrivalent): HPV 6, 11, 16, 18
14. Gardasil 9 (nonavalent): HPV 6, 11, 16, 18, 31, 33, 45, 52, 58
15. Mechanism: L1 VLP vaccine → neutralising antibodies → prevent infection

16. Therapeutic vaccines: under development (target E6/E7 to treat existing CIN/cancer)

17. Screening: Cervical cytology (Pap smear) ± HPV testing

18. Cytology: detection of dysplastic cells (high N:C, hyperchromatic, abnormal chromatin, koilocytes)
19. Liquid-based cytology (ThinPrep): reduces obscuring blood/inflammation
20. HPV testing: detects high-risk HPV DNA/mRNA
21. Co-testing (cytology + HPV): highest sensitivity
22. Triage: HPV-positive + abnormal cytology → colposcopy; HPV-positive + normal cytology → repeat in 1 year

4.4 Endometrium

Normal Endometrial Histology

• Two layers:
• Functional layer (upper 2/3): shed during menstruation. Responsive to hormones
• Basal layer (lower 1/3): not shed — regenerates functional layer each cycle. Less hormone-responsive
• Glands and stroma — both respond to cyclical hormonal changes

Proliferative Phase (Days 1-14, Oestrogen-dominant): - Early: narrow, straight glands, tubular - Mid: glands slightly curved, pseudostratified nuclei, abundant mitoses (glands and stroma) - Late: glands become more tortuous, taller columnar cells - Stroma: compact, cellular, spindle-shaped cells, mitotically active - Spiral arterioles: straight, reach only upper 1/3 of endometrium

Secretory Phase (Days 15-28, Progesterone-dominant): - Day 16-17: Subnuclear vacuoles (glycogen) — hallmark of early secretory phase - Day 18-21: vacuoles move to apical (supranuclear) location, secretory exhaustion - Day 22-23: oedematous stroma, glands tortuous with saw-tooth appearance - Day 24-25: Pre-decidual reaction around spiral arterioles (stromal cells become plump, eosinophilic) - Day 26-27: prominent decidual reaction in superficial stroma, granular lymphocytes appear - Day 28: glandular breakdown, stromal haemorrhage, neutrophil infiltration

Menstrual Phase (Days 1-4): - Fragmented glands, stromal breakdown, haemorrhage, blood, fibrin - Neutrophils, apoptotic bodies - Condensed stroma with predecidual cells

Menstrual Dating (Noyes criteria): - Based on glandular morphology, stromal changes, mitotic activity, vacuoles, secretions, decidual change - Clinical utility limited — inter-observer variability. Used in infertility workup for luteal phase assessment - More reliable: mid-luteal endometrial biopsy + serum progesterone

Endometrial Hyperplasia

Classification (WHO 2014/2020)

Based on glandular architecture AND cytological atypia:

Category	Architecture	Cytological Atypia	Risk of Concurrent/Progression to Carcinoma
Hyperplasia without atypia	Simple (dilated, irregular glands) OR Complex (crowded, branching)	Absent	Low (~1% over 20 years)
Atypical hyperplasia (Endometrial Intraepithelial Neoplasia — EIN)	Simple or Complex (usually complex)	Present	High (~30-50% concurrent ca or progression over 5-10 years)

Endometrial Hyperplasia without Atypia: - Cause: unopposed oestrogen (anovulation, PCOS, obesity, oestrogen-only HRT, tamoxifen, oestrogen-producing ovarian tumours) - Histology: - Simple: dilated, irregular, branching glands, abundant stroma, "Swiss cheese" pattern. No atypia - Complex: crowded, back-to-back glands, little intervening stroma. Glands irregular with buds. No atypia - Management: progestogens (oral, Mirena IUS), treat underlying cause, repeat biopsy in 3-6 months

Atypical Hyperplasia / Endometrial Intraepithelial Neoplasia (EIN): - Cytological atypia (essential diagnostic criterion): - Enlarged, round (rather than elongated) nuclei - Prominent nucleoli - Chromatin clearing/clumping - Loss of polarity - Increased N:C ratio - Architecture: gland crowding (stroma <50%), irregular outlines, branching - Differential diagnosis: well-differentiated endometrioid adenocarcinoma (invasion vs back-to-back glands — distinction can be very difficult in curettings) - Management: Total hysterectomy + BSO (standard for postmenopausal women). For young women who want fertility: high-dose progestogens (megestrol acetate, Mirena IUS) + close follow-up with biopsies q3-6 months. Response rate ~70-80% with progestogens - Molecular: PTEN mutation (most common — early event), KRAS mutations, ARID1A mutations, PIK3CA mutations, MSI (microsatellite instability)

Endometrial Carcinoma

• Most common gynaecological malignancy in developed countries
• Peak age: 55-65 years
• ~40,000 new cases/year in the UK
• ~90% are sporadic; ~10% hereditary (Lynch syndrome)

Type I vs Type II (Bokhman — Dualistic Model)

Feature	Type I (Endometrioid)	Type II (Serous, Clear Cell)
Frequency	~80%	~15-20%
Histology	Endometrioid (grades 1-2)	Serous, clear cell, grade 3 endometrioid, carcinosarcoma
Oestrogen association	Strong — unopposed oestrogen (obesity, anovulation, PCOS, tamoxifen)	Minimal — arises in atrophic endometrium
Precursor	Atypical hyperplasia / EIN	Serous endometrial intraepithelial carcinoma (SEIC)
Genetics	PTEN mutation (40-80%), PIK3CA (30-50%), KRAS (15-30%), ARID1A, MSI (20-40%), β-catenin/CTNNB1 (25% — low-grade)	p53 mutation (80-90%), HER2 amplification (25-30%), chromosomal instability; few PTEN mutations
Clinical	Younger, obese, good prognosis	Older, thin, aggressive, poor prognosis
Myometrial invasion	Usually superficial	Often deep
Spread	Generally slower	Early lymphatic/peritoneal spread
Prognosis	Good (5-year survival ~85-90% for low-grade)	Poor (5-year survival ~40-60% for serous)

Endometrioid Adenocarcinoma (Type I)

• Most common endometrial cancer
• Risk factors:
• Obesity (↑ peripheral aromatisation of androstenedione to oestrone)
• Nulliparity, infertility, anovulation (PCOS)
• Early menarche, late menopause
• Unopposed oestrogen therapy (without progestogen)
• Tamoxifen (partial agonist at endometrium)
• Lynch syndrome (MMR mutation)

• Diabetes, hypertension

• Histology:

• Grade 1 (FIGO): >95% glandular differentiation (well-formed glands, complex architecture, no solid areas)
• Grade 2: 50-95% glandular (solid areas 5-50%)
• Grade 3: <50% glandular (solid areas >50%, poor differentiation)
• Other features: squamous differentiation (mortules, pearls), mitotic activity
• Myometrial invasion: invasive glands have desmoplastic stromal response (fibrotic, cellular stroma)

• LVSI: important prognostic factor

• Differential:

• Atypical hyperplasia: requires demonstration of invasion (myometrial or desmoplastic stroma) or complex cribriform architecture with confluence

• Cytological diagnosis in curettings: biopsies may not show invasion — final diagnosis requires hysterectomy specimen

• Variants:

• Villoglandular: papillary architecture, good prognosis
• Secretory: glycogen-rich, resembles secretory endometrium — good prognosis (almost always low-grade)
• Ciliated: abundant ciliated cells — often low-grade
• With squamous differentiation: keratin pearls (morules). Usually low-grade. Nuclear grade determines aggressiveness, not squamous component

Serous Carcinoma (Type II)

• Aggressive — presents at advanced stage even without myometrial invasion
• Precursor: Serous Endometrial Intraepithelial Carcinoma (SEIC) — malignant cells replace surface endometrium/glands WITHOUT stromal invasion — but can shed malignant cells → peritoneal spread even without invasion
• Histology:
• Complex papillary architecture (hierarchical branching, fibrovascular cores)
• Marked nuclear atypia — large, pleomorphic, hyperchromatic nuclei, prominent nucleoli
• High mitotic activity including abnormal forms
• Psammoma bodies (calcified concretions) — 50%
• Hobnail cells
• May arise in endometrial polyp (especially in older women)
• IHC:
• p53: Strong diffuse nuclear positivity (overexpression) or complete null pattern — surrogate for TP53 mutation
• p16: Strong diffuse positive (but NOT HPV-related — due to Rb loss, not E7)
• ER/PR: usually negative or weak
• WT1: negative (helps distinguish from ovarian serous — WT1+)
• HER2: amplified/overexpressed in 25-30% (targetable with trastuzumab)

Clear Cell Carcinoma

• Rare (~5%)
• Aggressive — similar prognosis to serous
• Histology:
• Clear cells (glycogen-rich, clear cytoplasm) and/or hobnail cells
• Architectures: tubulocystic, papillary, solid
• Pink hyaline globules (extracellular)
• IHC: HNF1B+, Napsin A+, p53 mutated (40-60%), ER/PR often negative

Carcinosarcoma (Malignant Mixed Müllerian Tumour — MMMT)

• Biphasic tumour — both carcinoma (epithelial) and sarcoma (mesenchymal) components
• Previously called "mixed mesodermal tumour"
• Aetiology: Monoclonal origin — carcinoma is the driving component; sarcoma arises from carcinoma through EMT-like dedifferentiation (same p53 mutation in both)
• Histology:
• Carcinomatous component: usually serous or endometrioid (high-grade); sometimes clear cell, squamous, undifferentiated
• Sarcomatous component:
  • Homologous (tissues native to uterus): endometrial stromal sarcoma, fibrosarcoma, leiomyosarcoma
  • Heterologous (non-native tissues): rhabdomyosarcoma (most common heterologous), chondrosarcoma, osteosarcoma, liposarcoma
• IHC: CK+ (carcinoma), vimentin+, desmin+ (rhabdomyosarcoma), myogenin+ (rhabdomyoblasts)
• Behaviour: Very aggressive — presents at advanced stage, high recurrence rate
• Prognosis: poor — 5-year survival ~30-50%
• Treatment: staging laparotomy + BSO + omentectomy + lymphadenectomy. Adjuvant chemo (platinum/taxane) ± radiation

FIGO Grading of Endometrioid Adenocarcinoma

• Grade 1: ≤5% solid non-squamous growth
• Grade 2: 6-50% solid non-squamous growth
• Grade 3: >50% solid non-squamous growth
• Nuclear grade upgrade: if severe nuclear atypia is present (grade 1 or 2 → grade 3)

FIGO Staging of Endometrial Cancer (2009/2023)

Stage	Description
I	Confined to uterine corpus
IA	No myometrial invasion or <50% invasion
IB	≥50% myometrial invasion
II	Cervical stromal invasion (not just glandular)
III	Local and/or regional spread
IIIA	Involvement of uterine serosa and/or adnexae
IIIB	Vaginal and/or parametrial involvement
IIIC1	Pelvic node involvement
IIIC2	Para-aortic node involvement (± pelvic nodes)
IV	Invasion of bladder/rectum (IVA) or distant metastasis (IVB)

Molecular Classification (TCGA / ProMisE)

The Cancer Genome Atlas (TCGA) identified 4 molecular subtypes with prognostic significance:

Subtype	Frequency	Molecular Features	Prognosis
POLE-ultramutated	~7-10%	POLE exonuclease domain mutations → very high mutation rate. Young, low-stage, often high-grade histology (G3)	Excellent (despite high-grade histology)
MSI-hypermutated	~20-30%	Microsatellite instability (MLH1 methylation in sporadic, MMR mutation in Lynch). Associated with endometrioid, LVSI, lower uterine segment involvement	Intermediate
Copy-number low (p53 wild-type, endometrioid)	~40-50%	Low mutation rate, few CNVs. PTEN, PIK3CA, ARID1A, KRAS mutations. Mostly low-grade endometrioid	Favourable
Copy-number high (p53 mutant, serous-like)	~15-20%	TP53 mutations, extensive CNVs. Most serous, clear cell, high-grade endometrioid, carcinosarcoma	Poor

Clinical utility: - POLE-mutated: may be candidates for treatment de-escalation (excellent prognosis) - MSI-H/dMMR: candidates for immunotherapy (pembrolizumab) - p53 mutant: need aggressive treatment (chemo-radiation) - Clinical implementation: surrogate markers (IHC for p53 and MMR proteins + POLE sequencing) → ProMisE classification

Tamoxifen-Related Endometrial Pathology

• Tamoxifen: Selective oestrogen receptor modulator (SERM) — antagonist in breast, agonist in endometrium
• Risk: 2-3 fold increased risk of endometrial cancer (especially after 5+ years of use)
• Most common: endometrioid adenocarcinoma (low-grade, good prognosis)
• Also: increased risk of serous carcinoma, carcinosarcoma, uterine sarcomas
• Benign effects: endometrial hyperplasia, polyps (often multiple, large), cystic atrophy, adenomyosis
• Screening: NOT routinely recommended — annual gynaecological assessment if symptomatic (bleeding) → ultrasound + biopsy
• Prophylaxis: if tamoxifen indicated, consider Mirena IUS to protect endometrium

Lynch Syndrome (HNPCC) Related Endometrial Cancer

• Lifetime risk of endometrial cancer in women with Lynch: 40-60% (higher than colorectal risk in women)
• Age: younger (mean 45-55 years)
• Histology: endometrioid (most common), also clear cell, serous; MSI-high, MMR-deficient
• Location: often lower uterine segment (isthmus/cervix)
• Features: synchronous/metachronous ovarian cancer common; better prognosis stage-for-stage than sporadic MSI-stable
• Screening (controversial): annual transvaginal ultrasound + endometrial biopsy starting age 35
• Risk-reducing surgery: total hysterectomy + BSO after childbearing (age 40-45)
• Universal screening: All endometrial cancers should be tested for MMR deficiency (IHC for MLH1, MSH2, MSH6, PMS2 ± MSI testing) — if abnormal, refer for genetic counselling and germline testing

4.5 Myometrium

Leiomyoma (Uterine Fibroid)

• Benign smooth muscle tumour — most common uterine neoplasm (20-40% of reproductive-age women)
• Origin: myometrial smooth muscle cell (monoclonal)
• Oestrogen and progesterone-dependent — grow during reproductive years, grow in pregnancy (especially first trimester), regress after menopause
• Gross: white, whorled, firm, well-circumscribed, bulging on cut surface. Usually multiple
• Locations:
• Subserosal (most common) — may become pedunculated
• Intramural — within myometrium
• Submucosal — beneath endometrium, may cause bleeding, infertility
• Cervical — rare
• Secondary changes:
• Hyaline degeneration (most common) — glassy, eosinophilic
• Cystic degeneration — liquefaction
• Red (carneous) degeneration — acute ischaemic necrosis, often in pregnancy — severe pain, fever. Gross: soft, red, beefy
• Calcification — postmenopausal (dystrophic)
• Fatty degeneration (lipoleiomyoma) — adipocytes within leiomyoma
• Infection — especially submucosal (endometritis)
• Sarcomatous change — EXTREMELY RARE (<0.1%). Controversial — most leiomyosarcomas arise de novo, not from pre-existing leiomyoma
• Histology:
• Fascicles of smooth muscle cells intersecting at right angles
• Spindle-shaped cells — cigar-shaped nuclei, eosinophilic cytoplasm
• No cytologic atypia, low mitotic activity (<5 MF/10 HPF)
• Whorled pattern
• Variants:
• Cellular leiomyoma: hypercellular, but no atypia, low mitoses. Distinguish from endometrial stromal tumour (CD10 IHC: EST+ vs SMA+)
• Bizarre (symplastic/atypical) leiomyoma: scattered markedly atypical cells (large, hyperchromatic, bizarre nuclei) — but low mitotic activity and no coagulative necrosis. BENIGN
• Mitotically active leiomyoma: increased mitoses (5-15/10 HPF) but no atypia and no coagulative necrosis. Seen in pregnancy/progesterone users. BENIGN
• Lipoleiomyoma: contains mature adipose tissue
• Hydropic leiomyoma: oedematous stroma
• Epithelioid leiomyoma: cells with epithelioid appearance
• Intravenous leiomyomatosis: benign smooth muscle proliferating within uterine/iliac veins — histologically benign but can extend into inferior vena cava → heart. Recurrent
• Disseminated peritoneal leiomyomatosis: multiple benign leiomyoma-like nodules on peritoneal surfaces — rare, associated with pregnancy/progesterone
• Benign metastasising leiomyoma: rare — histologically benign smooth muscle tumours in lungs/lymph nodes in women with uterine leiomyomas — thought to be embolic

Leiomyosarcoma

• Rare — 1-2% of uterine malignancies
• Incidence: ~0.5-1 per 100,000 women
• Arises de novo — NOT from malignant transformation of leiomyoma (though about 30% of patients have concurrent leiomyomas)
• Presentation: rapidly growing pelvic mass, postmenopausal bleeding, pelvic pain (often misdiagnosed as fibroid)
• Gross: soft, fleshy, yellow/tan, necrotic, haemorrhagic — poor circumscription, infiltrative borders
• Diagnostic criteria (Stanford criteria — need ALL three for definitive diagnosis in most cases):
• Significant cytologic atypia (moderate to severe, at least 2+ on scale)
• Mitotic activity ≥10 MF/10 HPF (in most cases; certain variants may have lower)
• Tumour cell necrosis (coagulative) — geographic zones of necrosis with abrupt transition from viable cells
• Note: smooth muscle tumours that do not meet all three criteria → classified as smooth muscle tumour of uncertain malignant potential (STUMP)
• Histologic subtypes:
• Spindle cell (most common)
• Epithelioid — more aggressive
• Myxoid — may have lower mitotic count but aggressive behaviour
• IHC: desmin+, SMA+, h-caldesmon+, p53 often overexpressed, ER/PR may be positive, Ki-67 high
• Genetics: complex karyotype, TP53 mutation, RB1 loss, ATRX mutations, MED12 mutations NOT found (MED12 mutation common in benign leiomyomas)
• Prognosis: Very poor — 5-year survival ~30-50% (depends on stage)
• Stage I disease — ~50% 5-year survival
• Advanced disease — <15% 5-year survival
• Prognostic factors:
• Stage — most important
• Mitotic index — >20/10 HPF → worse
• Tumour size — >5 cm → worse
• Degree of atypia
• Necrosis
• LVSI
• Residual disease after surgery
• Treatment: Total hysterectomy + BSO (no role for myomectomy). Lymphadenectomy not clearly beneficial. Doxorubicin-based chemotherapy for metastatic/recurrent. If confined to uterus, prognosis is better but still guarded
• Uterine sarcomas: also include endometrial stromal sarcoma (low-grade — ESS; high-grade — HGESS), undifferentiated uterine sarcoma (UUS), adenosarcoma (biphasic, low malignant potential)

4.6 Fallopian Tube

Serous Tubal Intraepithelial Carcinoma (STIC)

• The "fimbrial endocrine hypothesis" — STIC in the fimbrial end of the fallopian tube is now widely accepted as the precursor lesion for most high-grade serous "ovarian" carcinomas (especially in BRCA mutation carriers)
• Location: Fimbriae (most common), also ampulla/isthmus
• Gross: usually no visible lesion (incidental finding) or subtle papillary/friable area at fimbrial end
• Protocol: SEE-FIM protocol (Sectioning and Extensively Examining the FIMbriae) — complete sectioning of fimbriae to detect occult STIC → routine for risk-reducing salpingo-oophorectomies in BRCA carriers, and for all "ovarian" HGSOC cases
• Histology:
• Malignant epithelial cells lining tubal mucosa (usually papillary or flat)
• Nuclear atypia: pleomorphism, hyperchromasia, prominent nucleoli
• Loss of polarity
• High mitotic activity (including abnormal mitoses)
• No stromal invasion (by definition — if invasion present, it's tubal carcinoma)
• IHC: p53: strong diffuse or null (mutant pattern), p16: strong diffuse (not HPV-related), Ki-67: high (>50%), WT1+, PAX8+, ER+ (usually)
• Clinical significance:
• In BRCA carriers, RRSO identifies occult STIC in 2-10% of cases
• STIC can shed cells → peritoneal carcinomatosis even without invasion
• Detection of STIC → complete staging (to rule out occult invasive disease)
• Supports the theory that many "primary peritoneal" and "ovarian" high-grade serous carcinomas actually originate from tubal epithelium

Fallopian Tube Carcinoma

• Rare — <1% of gynaecological malignancies
• Most common: high-grade serous carcinoma (often associated with STIC)
• Less common: endometrioid, transitional, clear cell
• Usually diagnosed at advanced stage (peritoneal spread)
• Diagnostic criteria (Hu et al.): tumour arises from endosalpinx, histology recapitulates tubal epithelium, transition from benign to malignant epithelium demonstrated
• Treatment: similar to ovarian cancer — staging, cytoreduction, platinum-based chemotherapy

4.7 Ovary

Overview

• Ovary is the most common site of gynaecological cancer death (poor survival due to late presentation)
• Most ovarian masses in reproductive age are benign (functional cysts, endometriomas, mature teratomas, cystadenomas)
• Ovarian malignancies are classified by cell of origin:

WHO Classification of Ovarian Tumours

1. Surface Epithelial Tumours (~60-70% of all ovarian tumours, ~90% of malignant)

Serous Tumours: - Benign: serous cystadenoma (unilocular, thin-walled, lined by ciliated tubal-type epithelium) - Borderline (LMP — low malignant potential): atypical epithelial proliferation without stromal invasion (complex papillae, tufting). Excellent prognosis (5-year survival >95% when stage I). Micropapillary pattern → more aggressive - Malignant: - Low-grade serous carcinoma (LGSC): micropapillary architecture, KRAS/BRAF mutations, p53 wild-type, indolent but resistant to platinum - High-grade serous carcinoma (HGSOC): most common (>80%) and most lethal ovarian cancer. Complex papillary/solid architecture, slit-like spaces (fenestrated pattern), >95% p53 mutation, BRCA1/2 pathway dysfunction (50% — 20% germline, 30% somatic), extensive genomic instability. WT1+, PAX8+, ER+, PR+, p53 mutant pattern - Psammoma bodies — concentrically laminated calcifications — seen in ~60% of serous carcinomas

Mucinous Tumours: - Benign: mucinous cystadenoma (multiloculated, lined by endocervical/gastric-type epithelium) - Borderline: intestinal-type (goblet cells) or endocervical-type. Stromal invasion absent. Excellent prognosis - Malignant (mucinous adenocarcinoma): Rare — true primary ovarian mucinous carcinomas are uncommon. Most mucinous carcinomas in ovary are METASTATIC from GI tract (appendix, colon, stomach, pancreas). Primary ovarian mucinous carcinoma is usually large (>10-15 cm), unilateral, stage I - Pseudomyxoma peritonei: massive mucinous ascites with peritoneal implants — almost always from appendiceal low-grade mucinous neoplasm (LAMN) , NOT from ovarian primary. The ovary is secondarily involved (surface implants, not invasive). Important distinction for treatment

Endometrioid Tumours: - Benign: endometrioid cystadenoma (rare) - Borderline: atypical endometrioid epithelium, no invasion - Malignant (endometrioid adenocarcinoma): closely resembles endometrial endometrioid carcinoma. Often associated with endometriosis (~30-40%). Good prognosis (usually low-grade, early-stage, good response to platinum). WT1− (distinguishes from serous) - Synchronous endometrial and ovarian endometrioid carcinomas — two primaries vs metastatic? If both are low-grade, stage I, no LVSI, no deep myometrial invasion → likely independent primaries. Better prognosis than metastatic

Clear Cell Tumours: - Benign: clear cell adenofibroma - Borderline: rare - Malignant (clear cell carcinoma): strongly associated with endometriosis (>70% in same ovary). HNF1B+, Napsin A+, p53 wild-type (usually; some are p53 mutant). WT1−, ER− (usually). Resistant to platinum — poor prognosis in advanced stage - Architectural patterns: tubulocystic, papillary, solid. Clear cells (glycogen-rich) + hobnail cells (large, hyperchromatic nuclei protruding into lumen)

Brenner Tumours: - Benign: nests of transitional (urothelial-like) epithelium in abundant fibromatous stroma. Walthard rests — similar nests in fallopian tube/paratubal area (benign) - Borderline (proliferating): atypical Brenner tumour - Malignant: malignant Brenner tumour — rare, diagnosis requires benign/Brenner component plus invasive transitional cell carcinoma

Undifferentiated Carcinoma: - No clear differentiation — high-grade, poor prognosis

2. Sex Cord-Stromal Tumours (~5-10%)

Granulosa Cell Tumour: - Most common malignant sex cord-stromal tumour - Two types: - Adult (95%): postmenopausal. Indolent, low-grade malignant (late recurrence, >10 years). Inhibin+, FOXL2+ (mutation C134W — diagnostic, found in >95%). Call-Exner bodies (microfollicular pattern — small rosettes with central hyaline/fluid). Nuclear grooves (coffee bean nuclei). Produces oestrogen → endometrial hyperplasia, endometrioid adenocarcinoma - Juvenile (5%): <30 years. More aggressive. Call-Exner bodies rare. FOXL2 mutation uncommon - IHC: Inhibin (best marker) , calretinin, FOXL2, CD99, SF-1, WT1 - Treatment: surgical (TARBS — total abdominal radical BSO). Stage I → observation. Advanced → platinum-based chemo. Prognosis: very good overall (5-year >90%) but late recurrence is characteristic

Fibroma: - Benign — most common sex cord-stromal tumour - Spindle-shaped fibroblasts in whorls, collagen production - Macroscopic: firm, white, whorled - Meigs' syndrome: ovarian fibroma + ascites + pleural effusion (right > left). Resolves after tumour removal. Paraneoplastic phenomenon, not metastatic - Differential: thecoma (lipid-rich, more cellular, produces oestrogen)

Thecoma: - Benign — composed of theca cells (lipid-laden, round/oval nuclei) - Produces oestrogen → endometrial hyperplasia, endometrial carcinoma (in postmenopausal women) - IHC: inhibin+, calretinin+

Sertoli-Leydig Cell Tumour: - Androgen-producing → virilisation (hirsutism, voice deepening, clitoromegaly, male pattern balding, amenorrhea) - Histology: hollow tubules (Sertoli) + Leydig cells (eosinophilic, Reinke crystals — intracytoplasmic rods) - Grading: well-differentiated (good prognosis) → poorly differentiated (sarcomatoid — worse) - IHC: inhibin+, calretinin+, SF-1+, WT1+ - Associated with: Peutz-Jeghers syndrome (STK11 mutation) — some cases - Differential: granulosa cell tumour (oestrogen), thecoma (oestrogen)

3. Germ Cell Tumours (~10-15% — most common in children/adolescents)

Dysgerminoma: - Ovarian counterpart of testicular seminoma - Most common malignant germ cell tumour in young women - Histology: sheets of uniform cells with clear glycogen-rich cytoplasm, central round nucleus, prominent nucleolus. Lymphocytic infiltrate in fibrous septa. Granulomatous reaction (epithelioid macrophages) - IHC: PLAP+, OCT3/4+, SALI4+, CD117 (c-kit)+, D2-40+, CD30− (distinguishes from embryonal carcinoma) - Serum marker: ↑ LDH (often), β-hCG may be slightly elevated if syncytiotrophoblast present - Prognosis: excellent — >95% 5-year survival. Radiosensitive and chemosensitive - Treatment: unilateral salpingo-oophorectomy (fertility-sparing) ± chemo (BEP — bleomycin, etoposide, cisplatin)

Yolk Sac Tumour (Endodermal Sinus Tumour): - Second most common malignant germ cell tumour - Aggressive but very chemosensitive - Histology: Schiller-Duval bodies (glomeruloid structures — central fibrovascular core surrounded by malignant cuboidal/columnar cells projecting into a cystic space) — diagnostic - Patterns: reticular (microcystic), solid, glandular, polyvesicular vitelline - IHC: AFP+, SALI4+, Glypican-3+, CK+ - Serum marker: ↑ AFP (excellent for monitoring) - Prognosis: >90% cure with BEP

Immature Teratoma: - Malignant — contains immature (embryonal) tissue, most commonly immature neuroepithelium - Grading (Norris): based on amount of immature neuroectoderm - Grade 1: rare immature tissue (<1 low-power field per slide) → excellent prognosis - Grade 2: moderate (1-3 LPF/slide) - Grade 3: abundant (>3 LPF/slide) → higher risk of recurrence - IHC: SALI4+ (immature component), SOX2+, GFAP+ (glial) - Treatment: USO (fertility-sparing) + BEP (for grade 2-3 or advanced)

Mature Cystic Teratoma (Dermoid Cyst): - Most common ovarian germ cell tumour — BENIGN - All three germ layers: - Ectoderm: skin, hair, sebaceous glands, neural tissue (most prominent) - Mesoderm: bone, cartilage, fat, muscle - Endoderm: respiratory/gastrointestinal epithelium, thyroid (struma ovarii), salivary - Gross: cystic, filled with sebaceous material + hair. Rokitansky protuberance (solid nodule where teeth/bone often found) - Complications: torsion (most common — 15%), rupture (→ granulomatous peritonitis due to spilled keratin), malignant transformation (rare, <2% — most commonly SCC in wall of cyst in older women) - Struma ovarii: >50% of teratoma composed of thyroid tissue. May cause hyperthyroidism - Carcinoid tumour (strumal carcinoid): within teratoma — may cause carcinoid syndrome (if no liver metastases → syndrome bypasses hepatic metabolism via ovarian vein → direct systemic drainage)

Other Germ Cell Tumours: - Embryonal carcinoma: rarely pure in ovary (more common in testis). IHC: CD30+, OCT3/4+, SOX2+, SALI4+. ↑ β-hCG, ↑ AFP - Non-gestational choriocarcinoma: pure β-hCG-producing tumour in prepubertal girls (rare). Must exclude gestational choriocarcinoma (gonadotrophin-independent) - Polyembryoma: very rare — contains embryoid bodies (resemble early embryos) - Gonadoblastoma: mixed germ cell + sex cord-stromal elements. Associated with dysgenetic gonads (46,XY or 45,X/46,XY — mixed gonadal dysgenesis, Swyer syndrome). Precursor to dysgerminoma. Prophylactic gonadectomy indicated

4. Metastatic Tumours to Ovary (~5-10%)

Krukenberg Tumour: - Bilateral ovarian metastases from signet ring cell adenocarcinoma - Primary: Stomach (most common), also colon, breast, appendix - Histology: Signet ring cells (mucin-filled cytoplasm pushes nucleus to periphery) in a cellular, fibroblastic stroma (desmoplastic reaction) - Gross: solid, firm, often bilateral, bosselated, white/tan, may be large - IHC: CK7+, CK20+/−, CDX2+ (if GI primary), ER− (usually) - Pseudomyxoma peritonei — mucinous implants on ovarian surface — usually from appendix, NOT ovarian primary - Other metastases: breast (lobular carcinoma — single-file cells), colon, lung, melanoma, endometrial, cervical

FIGO Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma (2014)

Stage	Description
I	Tumour confined to ovaries/fallopian tubes
IA	Limited to one ovary/capsule intact, no surface tumour, no malignant cells in ascites/peritoneal washings
IB	Both ovaries/capsules intact, no surface tumour
IC	Tumour on surface, capsule ruptured, or malignant cells in ascites/washings
II	Tumour involves one or both ovaries with pelvic extension
IIA	Extension to uterus and/or tubes
IIB	Extension to other pelvic tissues
III	Spread to peritoneum beyond pelvis and/or retroperitoneal nodes
IIIA	Microscopic peritoneal metastases beyond pelvis
IIIB	Macroscopic peritoneal metastases ≤2 cm
IIIC	Macroscopic peritoneal metastases >2 cm AND/OR retroperitoneal node metastases
IV	Distant metastases (including liver/spleen parenchyma, pleural effusion with positive cytology, extra-abdominal nodes)
IVA	Pleural effusion with positive cytology
IVB	Parenchymal metastases (liver, spleen, lung)

Tumour Markers in Ovarian Cancer

Histology	Most Useful Markers
High-grade serous	CA-125 > 80% elevated. HE4 elevated. ROMA index positive
Low-grade serous	CA-125 (moderate elevation)
Mucinous	CA-125 (variable), CEA, CA 19-9, CA-72-4
Endometrioid	CA-125 (elevated), HE4
Clear cell	CA-125 (lower elevation), HNF1B (IHC)
Granulosa cell	Inhibin (A and B), AMH (Anti-Müllerian Hormone)
Sertoli-Leydig	Inhibin, Testosterone (serum androgens)
Dysgerminoma	LDH, PLAP, β-hCG (if syncytiotrophoblast present)
Yolk sac tumour	AFP
Immature teratoma	No specific serum marker (CA-125 may be elevated)
Choriocarcinoma	β-hCG
Struma ovarii	Thyroglobulin, T3/T4

ROMA (Risk of Ovarian Malignancy Algorithm): - Combines CA-125 + HE4 + menopausal status - Pre-menopausal cut-off: low risk <1/8; high risk ≥1/8 - Post-menopausal cut-off: low risk <1/4; high risk ≥1/4 - Sensitivity: ~90-95% for epithelial ovarian cancer (higher than CA-125 alone) - Specificity: ~75-85%

REAL (Risk of Endometrial and Ovarian Cancer) — IOTA ADNEX model: - Uses CA-125 + ultrasound features + age + number of papillary projections + size + bilaterality to differentiate benign vs borderline vs malignant

Ovarian Cancer — Genetic Predisposition Syndromes

Syndrome	Gene	Ovarian Cancer Risk	Other Cancer Risks
Hereditary Breast and Ovarian Cancer (HBOC)	BRCA1	20-45%	Breast (40-60%), fallopian tube, primary peritoneal
	BRCA2	10-20%	Breast (40-55%), male breast, pancreas, prostate
Lynch Syndrome (HNPCC)	MLH1, MSH2, MSH6, PMS2	10-15%	Endometrial (40-60%) , colorectal, stomach, small bowel
Peutz-Jeghers Syndrome	STK11 (LKB1)	~20% (sex cord-stromal tumours)	Breast, colon, pancreas, cervical (adenoma malignum)
Li-Fraumeni Syndrome	TP53	Variable (rare)	Breast, sarcoma, brain, adrenal, leukaemia
Cowden Syndrome	PTEN	Modestly increased	Breast, thyroid (follicular), endometrial
Ataxia Telangiectasia	ATM	Increased	Breast, leukaemia, lymphoma

Ovarian Tumour Classification by Behaviour

• Benign: cystadenomas, fibroma, thecoma, dermoid (mature teratoma), Brenner
• Borderline/LMP: serous borderline, mucinous borderline, endometrioid borderline, clear cell borderline (rare)
• Key: No stromal invasion. Atypical proliferative lesions. Can have peritoneal implants (non-invasive → good prognosis; invasive implants → worse)
• 5-year survival: Stage I >95%; Stage III ~65% (if non-invasive implants)
• Malignant: all invasive carcinomas, malignant germ cell, granulosa cell, Sertoli-Leydig

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5. Placental Pathology

5.1 Examination of the Placenta

Indications for Placental Pathology Examination

• Maternal: preeclampsia, gestational hypertension, diabetes (pre-existing or GDM), lupus, thrombophilia, abruption, placenta praevia, maternal infection, fever, prolonged rupture of membranes
• Fetal/Neonatal: IUGR, abnormal Doppler (umbilical artery), stillbirth, NICU admission, preterm delivery, congenital anomalies, low Apgar, meconium staining
• Placental: abnormal appearance, abnormal cord insertion (velamentous, marginal), single umbilical artery, signs of infection, infarction, retroplacental clot

Normal Placental Findings at Term

• Weight: ~450-550 g (placental:fetal weight ratio ~1:6)
• Cord: 2 arteries + 1 vein, central/eccentric insertion, 30-90 cm length, 3-8 spiral turns
• Membranes: translucent, intact, insertion marginal/normal
• Fetal surface (chorionic plate): smooth, shiny, transparent — vessels visible
• Maternal surface (basal plate): lobulated, cotyledons divided by septa, complete
• Cut surface: spongy, dark red, no pale areas, no cysts, no thrombosis

5.2 Important Placental Pathologies

Maternal Floor Infarction (MFI)

• Poorly understood — thought to be maternal immune rejection/trophoblast dysfunction
• Gross: thickened, firm, yellow-white plaque covering maternal surface (basal plate) — "maternal floor"
• Microscopy: extensive deposition of fibrinoid material (massive perivillous fibrin deposition — MPFD) in the basal plate and throughout the intervillous space
• Clinical association: IUGR, oligohydramnios, stillbirth, recurrence in subsequent pregnancies (~50%)
• Pathophysiology: impaired maternal-fetal exchange due to fibrin deposition surrounding villi → chronic hypoxia

Decidual Vasculopathy / Atherosis

• Hallmark pathology of preeclampsia (and also seen in SLE, antiphospholipid syndrome)
• Site: maternal spiral arteries in the decidua
• Normal pregnancy: trophoblast invades spiral arteries → transforms them into high-flow, low-resistance vessels (wide, flaccid, no smooth muscle, no elastic lamina)
• Preeclampsia: failure of trophoblast invasion → spiral arteries retain their musculo-elastic wall → acute atherosis:
• Fibrinoid necrosis of arterial wall
• Foam cells (lipid-laden macrophages) in intima
• Perivascular lymphocytic infiltrate
• Thrombosis → luminal occlusion
• Consequences: placental ischaemia → oxidative stress → release of anti-angiogenic factors (sFlt-1, sEndoglin) → maternal endothelial dysfunction → hypertension, proteinuria, HELLP, eclampsia
• Microscopy findings in preeclamptic placenta:
• Decidual vasculopathy / atherosis
• Placental infarcts (peripheral, often multiple)
• Increased syncytial knots
• Villous hypovascularity / accelerated maturation
• Villous infarction (>10% of placenta = significant)

Chorioamnionitis

• Inflammation of the fetal membranes — usually due to ascending bacterial infection
• Risk factors: prolonged rupture of membranes (PROM), preterm labour, nulliparity, multiple vaginal exams, smoking, bacterial vaginosis, GBS colonisation
• Pathogens: Ureaplasma urealyticum, Mycoplasma hominis, E. coli, GBS, anaerobes, Candida
• Gross: opaque, cloudy, green/yellow membranes, foul odour (if severe)
• Microscopy: Neutrophil infiltration of:
• Stage 1 (maternal): neutrophilic exudate in subchorionic space (membranous chorioamnionitis)
• Stage 2 (maternal): neutrophils infiltrate chorion and amnion
• Stage 3 (fetal): Funisitis — neutrophils in umbilical cord (Wharton's jelly, vessel walls)
• Stage 3 also: Fetal inflammatory response syndrome (FIRS) — fetal vasculitis in chorionic plate vessels
• Grading:
• Grade 1 (mild): scattered neutrophils in subchorion
• Grade 2 (moderate): neutrophils in chorion/amnion
• Grade 3 (severe): dense sheets of neutrophils with tissue necrosis
• Histology: neutrophils seen lining the subchorionic space, chorion, amnion. Chorioamnionitis = acute inflammation of membranes (not just subchorionic)
• Clinical significance: associated with preterm labour, preterm PROM, neonatal sepsis (early-onset), cerebral palsy (via fetal inflammatory response), prolonged labour, postpartum endometritis
• Chronic chorioamnionitis: lymphocytic/plasma cell infiltration — associated with chronic villitis and VUE

Funisitis

• Acute inflammation of the umbilical cord — part of fetal inflammatory response
• Microscopy: neutrophils in Wharton's jelly and/or umbilical vessel walls
• Three stages:
• Phlebitis (vein first — most common)
• Arteritis (arteries later)
• Necrotising funisitis (severe — ring of necrotic debris + neutrophils encircling vessels)
• Clinical: marker of severe chorioamnionitis → increased risk of neonatal sepsis, pneumonia, cerebral palsy, neurodevelopmental impairment

Villitis of Unknown Etiology (VUE)

• Chronic villitis with no identifiable infectious cause (infection workup negative)
• Cause: hypothesised to be maternal anti-fetal rejection (allograft rejection-like)
• Prevalence: ~5-15% of term placentas
• Recurrence risk: high (~50-60%)
• Microscopy:
• Lymphohistiocytic infiltrate in chorionic villi (fetal tissue)
• Macrophages + CD8+ T cells (maternal origin? Fetal? Mixed)
• Villous destruction → stromal obliteration
• Avascular villi (end-stage — loss of fetal capillaries)
• Grading:
• Low-grade: <10 villi involved per focus, few foci per slide
• High-grade: >10 villi per focus, multiple foci, confluent
• Associated with: IUGR, stillbirth, recurrent pregnancy loss, preterm birth
• Differential: infectious villitis (CMV, toxoplasma, rubella, syphilis, HSV, parvovirus B19, listeria, TB) — special stains and PCR needed

Fetal Thrombotic Vasculopathy (FTV)

• Thrombosis of fetal blood vessels (chorionic plate vessels, stem villi vessels)
• Gross: pale, white areas on fetal surface (avascular villi)
• Microscopy:
• Organised thrombus in chorionic plate vessel or stem villus vessel
• Avascular villi (downstream from occlusion) — fibrotic, hyalinised, no capillaries, syncytial cells may persist
• ± Hemosiderin deposition (chronic)
• Associated with: IUGR, stillbirth, cerebral palsy, neonatal encephalopathy, neurodevelopmental impairment
• Risk factors: cord abnormalities (hypercoiling, velamentous insertion, knots, cord prolapse), maternal diabetes, thrombophilia, fetal thrombophilia, meconium exposure (vasospasm → thrombosis)
• Extensive FTV (>15% of placenta affected) → significant fetal morbidity

Meconium Macrophages

• Meconium-stained amniotic fluid (MSAF) → fetal distress/vagal stimulation → meconium passage
• Meconium: swallowed by fetus → macrophages phagocytose meconium in fetal membranes
• Microscopy: Meconium-laden macrophages in amnion/chorion — golden-brown, granular, refractile pigment
• Time course:
• <1 hour: no macrophages (meconium on surface only)
• 1-3 hours: meconium-laden macrophages in amnion
• >3-6 hours: macrophages in chorion
• >12-24 hours: macrophages in deeper layers, vascular necrosis
• Chronic meconium exposure → meconium-induced vascular necrosis → can cause FTV
• Significance: marker of fetal distress, associated with meconium aspiration syndrome (MAS), cerebral palsy (but MSAF alone is common — need clinical context)

Placental Haemorrhage (Abruption)

• Abruptio placentae: premature separation of normally implanted placenta from the decidua
• Gross: retroplacental haematoma (clot adherent to maternal surface of placenta) with compression/indentation of overlying cotyledon
• Microscopy:
• Acute abruption: recent clot, compressed villi, ± decidual necrosis
• Chronic abruption: haemosiderin-laden macrophages (chronic bleeding), old clot, raised placental indentation, fibrosis of basal plate
• Clinical: vaginal bleeding, abdominal pain, uterine hypertonus, fetal distress, DIC (consumptive coagulopathy)
• Associations: preeclampsia, trauma, cocaine, smoking, thrombophilia, advanced maternal age, previous abruption
• NB: Marginal sinus separation = bleeding from the edge of placenta, not retroplacental — less severe

Placenta Accreta Spectrum (PAS)

• Abnormal adhesion of placenta to myometrium due to decidua basalis defect (failed Nitabuch layer)
• Risk factors: previous caesarean section (most important), placenta praevia, Asherman's syndrome, previous uterine surgery, advanced maternal age, multiparity, IVF
• Types (depth of invasion):
• Accreta vera: attachment to myometrium (no decidua). 77%
• Increta: invasion into myometrium. 15%
• Percreta: invasion through myometrium to serosa / adjacent organs (bladder). 8%
• Gross: Placenta fails to separate at delivery. Surgical specimen: ragged, irregular basal plate, myometrial fibres attached
• Microscopy:
• Absence of decidua between villi and myometrium
• Villi directly abut / invade myometrial smooth muscle
• No Nitabuch's layer (fibrinoid layer normally present at decidua-myometrium interface)
• Percreta: villi reach serosa or beyond
• Diagnosis: Antenatal ultrasound (colour Doppler → turbulent flow in placental-myometrial interface). MRI for depth assessment
• Management: Caesarean hysterectomy (standard). Conservative management (placenta left in situ → delayed hysteroscopic resection) in carefully selected cases (high morbidity: haemorrhage, infection, sepsis, delayed hysterectomy)
• Complications: massive obstetric haemorrhage, DIC, bladder/ureteric injury, ICU admission, maternal death

Vasa Praevia

• Fetal vessels (umbilical or velamentous) run across the internal os, unprotected by placenta or membranes
• Types:
• Type 1: Velamentous insertion of cord → vessels traverse membranes over os
• Type 2: Vessels connecting a bilobed/succenturiate lobe run over the os
• Diagnosis: Antenatal (ultrasound colour Doppler), or at delivery (palpation of pulsating vessels; Apt test — test for fetal Hb in vaginal blood: alkali denaturation — fetal Hb resists denaturation)
• Catastrophic complication: Rupture of vasa praevia at membrane rupture → fetal exsanguination (fetal blood volume only ~300 mL at term — loss of 60-100 mL → severe anaemia, loss of 150-200 mL → death)
• Management: elective caesarean section at 34-36 weeks

Placenta Praevia

• Placenta partially or completely covers the internal os
• Types: complete (total) vs partial vs marginal (low-lying) placenta
• Risk factors: previous CS, previous placenta praevia, multiparity, advanced maternal age, smoking, multiple gestation, previous curettage
• Complications: Antepartum haemorrhage (painless, bright red), PPH (lower segment poorly contractile), PAS (associated scar), preterm delivery
• Management: elective C-section (at 36-37 weeks for complete praevia; 38 weeks for marginal)

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6. Gestational Trophoblastic Disease (GTD)

6.1 Overview

• Spectrum of disorders characterised by abnormal proliferation of trophoblast (placental-derived tissue)
• Ranges from benign hydatidiform mole (complete/partial) → invasive mole → choriocarcinoma → PSTT → ETT
• Trophoblast types:
• Cytotrophoblast: mononuclear, stem cells
• Syncytiotrophoblast: multinucleated, produces hCG, invasive
• Intermediate trophoblast: implantation site type (invades decidua/myometrium/arteries) vs chorionic type (anchoring villus)
• All GTD produces ↑ β-hCG (except PSTT which has only moderate β-hCG elevation — hCG free β-subunit may be better)

6.2 Hydatidiform Mole

Complete Mole (CM)

• Incidence: ~1/1000 pregnancies (higher in Asia/Middle East, lower in North America/Europe)
• Karyotype: 46,XX (85%) or 46,XY (15%) — all paternal in origin (androgenetic conception)
• 46,XX: empty egg (no maternal DNA) fertilised by single sperm (23X) → duplicates (46XX) → homozygous
• 46,XY: empty egg fertilised by 2 sperm (dispermy) → heterozygous
• Genetics: all chromosomes are paternal → paternal genome is imprinted — excess expression of paternally imprinted genes (IGF2, PEG10) → trophoblast hyperplasia
• Gross: Diffuse swelling of all chorionic villi → "bunch of grapes" appearance. No identifiable fetal tissue
• Microscopy:
• Hydropic swelling of all villi (central cistern formation)
• Circumferential trophoblast hyperplasia (both cytotrophoblast and syncytiotrophoblast) — key diagnostic feature
• Absence of fetal vessels
• Atypia in trophoblast
• IHC: p57KIP2 (paternally imprinted, maternally expressed gene) — NEGATIVE in villous cytotrophoblast and stroma (due to absence of maternal genome). Positive in decidua (internal control)

Partial Mole (PM)

• Karyotype: Triploid — 69,XXY (most common), 69,XYY, or 69,XXX — two paternal + one maternal set (diandry: usually dispermy)
• Gross: Focal villous swelling (some normal villi, some hydropic). Fetal tissue may be present (often with IUGR, congenital anomalies)
• Microscopy:
• Focal hydropic swelling (two populations of villi — normal and hydropic)
• Focal trophoblast hyperplasia (less pronounced than complete mole)
• Irregular villous outlines (scalloped, cremated, "cauliflower-like")
• Trophoblast inclusions (invaginations of trophoblast into villous stroma)
• Fetal vessels often present with nucleated fetal RBCs
• IHC: p57KIP2 — POSITIVE (maternal genome present) → distinguishes from complete mole
• Ultrasound: "Swiss cheese" pattern (cystic spaces)

Comparison: Complete vs Partial Mole

Feature	Complete Mole	Partial Mole
Karyotype	46,XX or 46,XY (all paternal)	69,XXY/XYY/XXX (diandric triploid)
Fetal tissue	Absent	May be present
Villi	Diffuse swelling	Focal swelling (two populations)
Trophoblast hyperplasia	Diffuse, circumferential, marked	Focal, mild
p57KIP2	Negative in villous stroma	Positive
hCG	Very high (>100,000 IU/L)	Moderately elevated
Malignant progression	15-20% (to choriocarcinoma/invasive mole)	<5%

Diagnosis and Management of Hydatidiform Mole

• Presentation: vaginal bleeding (most common), hyperemesis, early preeclampsia (<24 weeks), hyperthyroidism (hCG cross-reacts with TSH receptor), theca-lutein cysts (bilateral, due to high hCG — regress after evacuation), absent fetal heart tones
• Diagnosis: Ultrasound (classic "snowstorm" appearance for complete mole; "Swiss cheese" for partial). β-hCG (very high)
• Treatment: Suction evacuation under US guidance (regardless of uterine size). Avoid medical induction (increased risk of haemorrhage, incomplete evacuation, malignant transformation). Rhogam if Rh-negative
• Follow-up: Serial β-hCG weekly until undetectable X3, then monthly for 6 months (complete mole) or variable protocols
• Why surveillance? Risk of GTN (gestational trophoblastic neoplasia)
• Contraception needed during follow-up (to avoid confusing pregnancy with recurrence)
• Subsequent pregnancy: normal pregnancy outcomes. No increased risk of recurrence unless history of prior mole (recurrence risk ~1-2% after one mole, ~15-20% after two)

6.3 Gestational Trophoblastic Neoplasia (GTN)

Definition

• Persistent/invasive GTD after evacuation — diagnosed by rising/plateauing β-hCG
• WHO scoring system determines risk category → guides treatment

WHO Prognostic Scoring for GTN (Modified)

Prognostic Factor	Score 0	Score 1	Score 2	Score 4
Age	<40	≥40	—	—
Antecedent pregnancy	Mole	Abortion	Term pregnancy	—
Interval (months from index pregnancy)	<4	4-6	7-12	>12
Pre-treatment hCG (IU/L)	<10³	10³-10⁴	10⁴-10⁵	>10⁵
Largest tumour size (cm)	<3	3-4	≥5	—
Site of metastases	None	Spleen, kidney	GI tract	Brain, liver
Number of metastases	0	1-4	5-8	>8
Prior failed chemotherapy	None	—	Single drug	2+ drugs

Risk Categories: - Low-risk: score 0-6 → single-agent chemotherapy (methotrexate or actinomycin D) - High-risk: score ≥7 → multi-agent chemotherapy (EMA-CO)

Invasive Mole

• Local myometrial invasion of hydatidiform mole (usually complete mole)
• Microscopy: hydropic villi + trophoblast hyperplasia invading myometrium
• Villi present (distinguishes from choriocarcinoma)
• Behaviour: can cause uterine perforation, haemorrhage; may metastasise (rarely, to lung/vagina — but these are usually cured with chemo)
• Treatment: chemotherapy. Hysterectomy if uncontrollable bleeding
• β-hCG: elevated; responds well to chemotherapy

Choriocarcinoma

• Highly malignant — AFP,AFP, but very chemosensitive
• No villi (pure trophoblast — invasive)
• Aetiology: can follow any pregnancy:
• Complete mole (50%)
• Spontaneous abortion (20-25%)
• Normal term pregnancy (20-25%)
• Ectopic pregnancy (rare)
• Partial mole (rare)
• Gross: haemorrhagic, necrotic, soft, dark red mass
• Microscopy:
• Biphasic pattern: cytotrophoblast (mononuclear, clear/pale, well-defined borders) + syncytiotrophoblast (multinucleated, dark eosinophilic, lacelike) + intermediate trophoblast
• No villi (essential diagnostic criterion)
• Extensive haemorrhage and necrosis
• Marked nuclear atypia, high mitotic rate
• Vascular invasion prominent
• IHC: β-hCG+ (syncytiotrophoblast), CK7+, Ki-67 very high
• Metastasis: Haematogenous → lungs (most common — 80%, may present with haemoptysis, dyspnoea), vagina (blue/red nodules), brain (cerebral haemorrhage — catastrophic), liver, kidney, GI tract
• Diagnosis: ↑ β-hCG + clinical presentation (vaginal bleeding, metastatic symptoms, persistent hCG after any pregnancy)
• Treatment:
• Low-risk (WHO 0-6): single-agent methotrexate (or actinomycin D). Cure rate ~100%
• High-risk (WHO ≥7): EMA-CO (etoposide, methotrexate, actinomycin D / cyclophosphamide, vincristine). Cure rate ~85-90%
• Brain metastases: add intrathecal methotrexate or whole-brain RT
• Prognosis: Excellent even with advanced disease — one of the most curable solid tumours. Choriocarcinoma after term pregnancy has higher risk (longer interval, higher initial hCG)

Placental Site Trophoblastic Tumour (PSTT)

• Rare (<2% of GTN)
• Derived from implantation site intermediate trophoblast
• Biologic behaviour: indolent, less chemosensitive than choriocarcinoma. Often resistant to chemotherapy
• Presentation: amenorrhea, irregular bleeding, modestly elevated β-hCG (serum hCG lower than expected for tumour burden — <5000 IU/L usually)
• Microscopy:
• Sheets of mononuclear intermediate trophoblast (polyhedral/round, abundant eosinophilic/amphophilic cytoplasm)
• Infiltrates myometrium — separates individual muscle fibres ("dissecting" pattern)
• Vascular invasion (replaces vessel walls)
• No villi, no biphasic pattern (no two-cell population)
• IHC: hPL (human placental lactogen)+ (strong), Mel-CAM (CD146)+, β-hCG (weak, focal), CK18+, S100A1+. Ki-67: intermediate (10-30%) — lower than choriocarcinoma but higher than placental site nodule
• Diagnosis: histology + moderate hCG + doppler ultrasound (vascular mass) + MRI (myometrial invasion)
• Treatment: Hysterectomy is primary treatment (less chemo-sensitive). LND if positive nodes (nodal involvement in ~10-15%). Chemotherapy (EMA-EP — etoposide, methotrexate, actinomycin D/etoposide, cisplatin) for metastatic/recurrent
• Prognosis: Stage I → excellent (>90% survival). Advanced → poor (30-50% survival). Adverse factors: interval >2 years from index pregnancy, deep myometrial invasion, high mitotic count, necrosis, FIGO stage >II
• Differential: placental site nodule (benign, well-circumscribed, hyalinised, Ki-67 <5%), epithelioid trophoblastic tumour

Epithelioid Trophoblastic Tumour (ETT)

• Rarest GTN — derived from chorionic-type intermediate trophoblast
• Behaviour: similar to PSTT (indolent but can be aggressive)
• Histology: nests/cords of epithelioid cells (resembling carcinoma), eosinophilic hyaline material (resembles keratin), geographic necrosis
• IHC: p63+ (nuclear) — distinguishes from PSTT (p63−). CK7+, β-hCG (weak), hPL (weak)
• Treatment: hysterectomy (primary)

β-hCG Surveillance in GTD

• Essential for monitoring response to treatment and detecting recurrence
• After mole evacuation: weekly until undetectable ×3, then monthly ×6 (complete mole) or monthly until undetectable (partial mole)
• After chemotherapy for GTN: weekly until normal, then monthly ×6, then annual for life (for high-risk)
• Interpretation:
• Plateau (hCG stable over 3 weeks) → GTN
• Rise (increase >10% over 2 weeks) → GTN
• Persistence >6 months after evacuation → GTN
• Pregnancy after GTD: hCG monitoring in first trimester + ultrasound to confirm normal pregnancy. HCG may be confusing — must document rising levels and US
• False-positive hCG: heterophile antibodies (phantom hCG) — treat with serial dilutions, urine hCG, different assay

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7. Endometriosis & Adenomyosis

7.1 Endometriosis

Definition

• Presence of endometrial glands and stroma OUTSIDE the uterine cavity
• Oestrogen-dependent — regresses after menopause
• Affects 6-10% of reproductive-age women; 20-50% of infertile women; 40-70% of women with chronic pelvic pain

Theories of Origin

1. Sampson's Theory of Retrograde Menstruation (Most Widely Accepted): - Menstrual tissue (viable endometrial cells) refluxes through fallopian tubes → implants on peritoneal surfaces - Supporting evidence: (a) Menstrual reflux occurs in 90% of women with patent tubes, (b) Endometriosis is more common on dependent peritoneal surfaces (pouch of Douglas, ovarian surfaces), (c) Endometriosis-like lesions can be produced in primates by surgically diverting menstrual flow into the peritoneum, (d) Obstructive anomalies (cervical atresia, imperforate hymen) → increased risk - Limitations: does not explain (1) endometriosis in women with absent uterus (e.g., Turner syndrome — coelomic metaplasia), (2) thoracic endometriosis (lung pleura, diaphragm — lymphatic embolisation), (3) endometriosis in men (rare — usually post-oestrogen therapy for prostate cancer — coelomic metaplasia)

2. Coelomic Metaplasia (Meyer / Iwanoff): - Metaplasia of peritoneal mesothelium → endometriosis in situ - Explains endometriosis in: women without menstrual reflux, men on oestrogen therapy, pleural endometriosis, perihepatic (Fitz-Hugh-Curtis-like), and endometriosis in PMB-removed rats - Limitations: less direct evidence

3. Other Theories: - Lymphatic/Haematogenous dissemination — explains distant sites (lung, brain, skin, lymph nodes) - Direct implantation (iatrogenic) — after C-section, episiotomy, myomectomy, hysterotomy, tubal surgery - Müllerian remnant theory — persistence of embryologic müllerian rests - Immunologic / Stem cell theory — altered immune surveillance fails to clear retrograde menstrual cells; bone marrow stem cells may differentiate into endometrial cells

Sites of Endometriosis (Frequency)

1. Ovary — most common site (→ endometrioma / "chocolate cyst")
2. Pouch of Douglas / Rectovaginal septum (deeply infiltrating endometriosis — DIE)
3. Uterosacral ligaments
4. Fallopian tubes (serosal implants — can cause adhesions, tubal blockage)
5. Peritoneum (parietal/visceral)
6. Bladder / Ureter (→ hydronephrosis)
7. Bowel (sigmoid colon, rectum, appendix) — may cause dyschezia, rectal bleeding
8. Cervix / Vagina (visible blue/red nodules on speculum)
9. Abdominal wall (C-section scar)
10. Diaphragm / Pleura / Lung (thoracic endometriosis → catamenial pneumothorax)
11. Inguinal canal / Round ligament
12. Perineal / Episiotomy scar

Macroscopic Pathology

Ovarian Endometrioma ("Chocolate Cyst"): - Gross: cyst filled with dark brown, thick, "chocolate syrup" fluid (degraded blood products) - Wall: fibrous, may have adhesions, ruptures spontaneously or at surgery - Pathophysiology: endometriosis on ovarian surface → invaginates → forms pseudocyst lined by endometrial tissue + fibrosis → cyclical bleeding → accumulation of altered blood → cyst expansion - Bilateral in ~30-40% - Differential: haemorrhagic corpus luteal cyst (looks similar — histology confirms)

Peritoneal Implants: - Red lesions (active, early) — vascularised, glandular tissue with stroma - Black/blue powder-burn lesions (classic, later) — fibrotic, hemosiderin deposition - White lesions (inactive, fibrotic) - Fibrotic adhesions — often dense, obliterating pouch of Douglas

Deeply Infiltrating Endometriosis (DIE): - >5-10 mm depth of infiltration into peritoneum/retroperitoneal tissues - Femoral triangle, pouch of Douglas, uterosacral ligaments, rectovaginal septum - Histology: dense fibrosis, smooth muscle metaplasia, glandular/stromal elements

Microscopic Pathology

Classic Triad: 1. Endometrial-type glands (columnar epithelium, may show secretory/proliferative changes — hormone-responsive) 2. Endometrial stroma (spindle/ovoid cells, fine chromatin, may be cellular) 3. Hemosiderin-laden macrophages (chronic hemorrhage → golden-brown pigment)

Other features: - Acute/chronic inflammation - Fibrosis - Secondary changes: stromal decidualisation (pregnancy/progesterone), glandular atrophy, metaplastic changes (tubal, mucinous, eosinophilic) - Atypia: rarely — atypical endometriosis — nuclear enlargement, hyperchromasia, increased N:C ratio — may be precursor for clear cell and endometrioid ovarian cancers - Malignant transformation: endometriosis-associated ovarian cancer (EAOC) — usually clear cell (50%) or endometrioid (40%) carcinoma arising from endometriosis. Risk: ~1% lifetime. Clues: large size, solid areas in endometrioma, rapid growth, loss of hormone responsiveness

Clinical Features

• Chronic pelvic pain (cyclical or acyclical)
• Dysmenorrhoea (worsening, classically starts after years of pain-free periods)
• Dyspareunia (deep)
• Infertility (mechanical: adhesions, tubal distortion; immunologic: altered peritoneal environment; decreased oocyte quality)
• Dyschezia, dysuria (DIE)
• Menorrhagia, irregular bleeding
• Asymptomatic (incidental finding at laparoscopy)

Diagnosis

• Gold Standard: Laparoscopy + Histology (visual inspection + biopsy confirmation)
• Imaging: Transvaginal ultrasound (TVUS) for endometriomas, DIE, adhesions; MRI for deep pelvic disease, DIE
• CA-125: often elevated (mild-moderate) — non-specific (also elevated in PID, ovarian cancer)
• ?? biomarkers: no reliable serum test (CA-125, HE4, cytokines under investigation)

Staging of Endometriosis (Revised ASRM Classification)

• Stage I (Minimal): few isolated implants, no adhesions
• Stage II (Mild): superficial implants <5 cm total, minimal adhesions
• Stage III (Moderate): multiple deep implants, endometrioma <3 cm, tubal/ovarian adhesions
• Stage IV (Severe): large endometrioma (>3 cm), dense adhesions, obliterated pouch of Douglas

7.2 Adenomyosis

Definition

• Presence of endometrial glands and stroma WITHIN the myometrium (ectopic endometrium inside the uterine wall)
• Distinction from endometriosis: adenomyosis is diffuse or focal involvement of myometrium; endometriosis is outside the uterus

Epidemiology

• Affects 20-35% of hysterectomy specimens
• Peak age: 40-50 years (multiparous women)
• Risk factors: multiparity, previous uterine surgery (C-section, myomectomy, D&C), endometriosis, smoking, tamoxifen use

Clinical Features

• Menorrhagia (most common — 60-80%)
• Dysmenorrhoea (severe, cramping)
• Dyspareunia
• Chronic pelvic pain
• Enlarged, tender, "boggy" uterus (especially on exam)
• May be asymptomatic (incidental finding on imaging/hysterectomy)

Gross Pathology

• Diffuse: symmetrical, globular enlargement of uterus (no well-defined nodule). Cut surface: thickened, trabeculated myometrium with small hemorrhagic foci/cysts (chocolate-like fluid). Myometrium may have a "Swiss cheese" appearance
• Focal (adenomyoma): nodular mass resembling leiomyoma but less circumscribed, with cystic spaces

Microscopic Pathology

• Diagnostic criteria: Endometrial glands + stroma located >2.5 mm (one low-power field) below the basal layer of endometrium AND surrounded by hypertrophic/hyperplastic smooth muscle (myometrial hypertrophy)
• Myometrium adjacent to glands: shows smooth muscle hypertrophy and hyperplasia (causes bulkiness)
• Glands may show: proliferative, secretory, or atrophic changes (less hormone-responsive than endometriosis — often unresponsive)
• Basal endometrium is not shed during menstruation → adenomyosis often has "basalis-type" glands (less cyclic change)
• Stromal decidualisation can occur in pregnancy → gestational adenomyosis
• Adenomyosis vs well-differentiated endometrioid adenocarcinoma invading myometrium: look for absence of desmoplastic response (adenomyosis has normal smooth muscle around glands, no atypia, no inflammation)

Adenomyosis vs Endometriosis — Comparison

Feature	Adenomyosis	Endometriosis
Location	Within myometrium	Outside uterus (peritoneum, ovary, etc.)
Histology	Endometrial glands + stroma in myometrium	Endometrial glands + stroma + hemosiderin
Symptom pattern	Menorrhagia, dysmenorrhoea	Dyspareunia, infertility, chronic pain
Uterus	Enlarged, boggy	Normal size (unless adenomyosis also present)
Association with CA	No direct malignant transformation	↑ Risk of clear cell/endometrioid carcinoma
Diagnosis	MRI / TVUS / Hysterectomy specimen	Laparoscopy + biopsy
Hormone responsiveness	Moderate (basalis-type)	High (functional layer type)
Treatment	Hysterectomy (definitive), Mirena IUS, UAE	Surgical excision, hormonal suppression, fertility preservation

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8. Pelvic Inflammatory Disease (PID)

8.1 Overview

• Infection and inflammation of upper female genital tract — endometrium, fallopian tubes, ovaries, pelvic peritoneum
• Ascending infection — from lower genital tract (vagina, cervix) → through uterine cavity → into tubes → peritoneum
• Sexually transmitted organisms are most common cause (but also postpartum, post-abortal, post-procedural)

8.2 Microbiology

• Neisseria gonorrhoeae — Gram-negative diplococcus (intracellular)
• Chlamydia trachomatis — intracellular bacterium — most common cause in young women (often asymptomatic, can cause significant tubal damage)
• Anaerobes — Bacteroides fragilis, Peptostreptococcus, Prevotella
• Mycoplasma genitalium — emerging, associated with cervicitis and PID
• Gardnerella vaginalis (bacterial vaginosis-associated organisms)
• E. coli, Group B Streptococcus — especially post-partum/post-abortal
• Polymicrobial — most PID is mixed (gonococcal, chlamydial, anaerobes, Gram-negatives)

8.3 Risk Factors

• Young age (<25) — cervical ectropion → larger transformation zone → easier infection
• Multiple sexual partners
• Previous PID / STI
• IUD insertion (highest risk in first 3 weeks after insertion)
• Cervical instrumentation (D&C, hysterosalpingography, abortion)
• Bacterial vaginosis
• Nulliparity, smoking, douching

8.4 Histopathology

Acute Salpingitis

Gross: - Tubes swollen, erythematous, oedematous - Fimbriae congested, may be stuck together - Purulent exudate from fimbrial end (pus)

Microscopy: - Extensive neutrophilic infiltration of tubal mucosa (lamina propria, epithelium) - Vascular congestion, oedema - Epithelial denudation / ulceration - Inflammation may extend into muscularis and serosa - Pus in tubal lumen (pyosalpinx)

Phases: 1. Endosalpingitis — inflammation confined to mucosal folds (early) 2. Salpingitis — full-thickness wall inflammation 3. Pyosalpinx — tube distended with pus, walls thinned (late) 4. Hydrosalpinx — end-stage: pus replaced by clear fluid, tube distended, thin-walled, fimbriae completely closed (club-shaped)

Chronic Salpingitis

• Sequelae of inadequately treated acute salpingitis
• Microscopy:
• Lymphocytes and plasma cells in lamina propria
• Fused, blunted, club-shaped mucosal folds (plical fusion → chronic salpingitis isthmica nodosa if proximal)
• Loss of normal architecture — pseudoglandular spaces (buried epithelium)
• ± Calcifications (chronic)
• ± Hydrosalpinx or pyosalpinx changes

Salpingitis Isthmica Nodosa (SIN)

• Localised diverticular outpouchings of tubal epithelium into myosalpinx — hyperplastic, not inflammatory (but associated with chronic inflammation)
• Gross: palpable nodularity at tubal isthmus (unilateral or bilateral)
• Microscopy: dilated, complex, branching gland-like structures within the thickened myosalpinx, lined by tubal epithelium, surrounded by smooth muscle hyperplasia
• Clinical: associated with infertility, ectopic pregnancy
• Aetiology: acquired (post-inflammatory) vs congenital (some argue it is a form of adenomyosis of tube)

Tubo-Ovarian Abscess (TOA)

• Complication of PID — severe inflammation → ovary involved → abscess cavity forms (adherent tube + ovary)
• Usually polymicrobial (mixed aerobes and anaerobes)
• Gross: complex, necrotic, friable mass of tube and ovary with purulent centres
• Histology:
• Abscess wall: dense neutrophilic infiltrate, granulation tissue, fibrous capsule
• Ovarian stroma: necrotic, inflamed
• Tubal involvement: severe acute/chronic salpingitis
• Complications: rupture → generalised peritonitis, bacteraemia, sepsis. Chronic → chronic pelvic pain, recurrent PID, infertility
• Management: IV antibiotics (broad spectrum covering gonococcus, chlamydia, anaerobes). Surgical drainage (if no response, large abscess, rupture, postmenopausal). Hysterectomy + BSO (definitive — if fertility not desired)

Fitz-Hugh-Curtis Syndrome

• Perihepatitis — inflammation of the liver capsule (Glisson's capsule) without infection of liver parenchyma
• Associated with PID — usually Chlamydia trachomatis (more common than gonococcal)
• Pathophysiology: ascending infection → tubal exudate → spread via right paracolic gutter → into right subphrenic space → inflammation of liver capsule → fibrinous adhesions between liver capsule and diaphragm / anterior abdominal wall ("violin string adhesions")
• Histology: capsular fibrosis, chronic inflammation (lymphocytes, plasma cells), fibrinous exudate
• Clinical: acute right upper quadrant pain, pleuritic (exacerbated by inspiration), tenderness, ± fever. Often mimics biliary disease/cholecystitis in a young woman with PID
• Diagnosis: Laparoscopy — fibrinous adhesions on liver surface. CT/MRI may show capsular enhancement
• Treatment: antibiotics (for PID — doxycycline + ceftriaxone). Pain relief
• Prognosis: excellent with treatment; adhesions may persist but rarely cause long-term problems

Sequelae of PID

Complication	Mechanism	Clinical
Infertility	Tubal scarring, fimbrial phimosis, hydrosalpinx, TOA	~10-15% after one episode, ~50% after 3 episodes
Ectopic pregnancy	Tubal damage → impaired transport	Risk increased 6-10 fold
Chronic pelvic pain	Adhesions, chronic salpingitis, hydrosalpinx	~20% of PID patients develop chronic pain
Recurrent PID	Incomplete treatment, re-infection, damaged tubes	Damage accumulates with each episode
TOA	Severe PID	See above
Fitz-Hugh-Curtis	Perihepatitis	RUQ pain, adhesions
Post-PID adhesions	Peritoneal inflammation	Pelvic adhesions, bowel obstruction risk

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Appendix — Quick Reference Tables

Common IHC Markers in Gynaecological Pathology

Marker	Cell/Tissue Type	Key Uses
CK7	Epithelial (müllerian)	Ovarian, endometrial, cervical, breast carcinomas positive. Colorectal, renal negative
CK20	Intestinal, urothelial	Colorectal, Merkel cell, urothelial positive
EMA	Epithelial	Pan-epithelial marker
Vimentin	Mesenchymal	Endometrium, ovarian, sarcomas. Positive in endometrioid adenocarcinoma (helpful — CK7+/vimentin+ = müllerian)
p53	—	Mutant pattern (strong diffuse or null) in HGSOC, serous endometrial, many high-grade cancers
p16	—	HPV surrogate (block positive in cervical CIN/SCC). Also positive in serous endometrial ca (non-HPV)
WT1	Mesothelial, ovarian stroma	Positive in HGSOC, negative in endometrioid/clear cell. Also positive in tubal, peritoneal, mesothelial
PAX8	Müllerian epithelium	Excellent marker for ovarian, tubal, endometrial, cervical primary (very sensitive)
ER/PR	Hormone-responsive	Positive in endometrioid, ER+ breast, low-grade serous. Negative in HGSOC (often), clear cell, serous endometrial
Inhibin	Sex cord-stromal	Granulosa cell tumour, thecoma, Sertoli-Leydig (most specific)
Calretinin	Sex cord-stromal, mesothelial	GCT, thecoma, Leydig cells, mesothelioma
SALI4	Germ cell	Dysgerminoma, yolk sac, embryonal carcinoma, teratoma — very sensitive pan-germ cell marker
OCT3/4	Germ cell	Dysgerminoma, embryonal carcinoma, gonadoblastoma. Negative in yolk sac tumour
AFP	Yolk sac tumour	Yolk sac tumour (cytoplasmic + hyaline globules)
β-hCG	Syncytiotrophoblast	Choriocarcinoma, syncytiotrophoblast in germ cell tumours, GTD
CD30	Embryonal carcinoma	Embryonal carcinoma (membranous + Golgi). Negative in dysgerminoma
Desmin	Muscle	Leiomyoma, leiomyosarcoma, rhabdomyosarcoma
Smooth muscle actin (SMA)	Smooth muscle	Leiomyoma, leiomyosarcoma, myofibroblasts
h-caldesmon	Smooth muscle	Leiomyoma, leiomyosarcoma (more specific than desmin/SMA for smooth muscle)
CD10	Endometrial stroma	Endometrial stromal sarcoma (strong+), often negative in smooth muscle tumours
HEG1	Mesothelial	Mesothelioma, HGSOC (peritoneal origin)
Napsin A	Clear cell	Ovarian/endometrial/renal clear cell carcinoma (very specific)
HNF1B	Clear cell	Clear cell carcinoma of ovary/endometrium (nuclear positivity)
p57KIP2	—	Distinguish complete mole (negative) vs partial mole (positive)
Ki-67	Proliferation index	Higher in high-grade CIN, malignant tumours. Low in benign.

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