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🔴 CARCINOMA OF THE CERVIX

(MUHS Favourite - Frequently Asked)

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1. DEFINITION & INCIDENCE

• Most common gynecological malignancy in India (2nd worldwide after breast cancer)
• Peak age: 45-55 years (squamous); adenocarcinoma slightly older
• Precedes by 10-15 years of precancerous SIL (squamous intraepithelial lesion)

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2. ETIOLOGY & RISK FACTORS

MUHS Key Point: HPV 16 = SCC; HPV 18 = Adenocarcinoma (remember "18 = 8 letters = Adeno")

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3. PATHOGENESIS

• HPV is a DNA virus that infects immature squamous cells at the transformation zone (junction of squamous and columnar epithelium at ectocervix/endocervix)

┌─────────────────────────────────────────────┐
│         HPV Oncoproteins                    │
├──────────────┬──────────────────────────────┤
│   E6 protein │ Binds & destroys p53         │
│              │ → blocks apoptosis           │
│              │ → activates telomerase       │
├──────────────┼──────────────────────────────┤
│   E7 protein │ Binds RB protein             │
│              │ → releases E2F               │
│              │ → uncontrolled cell cycle    │
└──────────────┴──────────────────────────────┘

• Low-risk HPV (6, 11): remain episomal - cause condylomas only
• High-risk HPV (16, 18): integrate into host genome - disrupts E2 gene (which normally suppresses E6/E7) → overexpression of E6/E7 → malignant transformation

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4. PRECANCEROUS LESIONS - SIL / CIN

• LSIL = Low-grade SIL = CIN I
• HSIL = High-grade SIL = CIN II + CIN III

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5. HISTOPATHOLOGY OF SIL - (Easy to Draw Diagram)

NORMAL     |  CIN I (LSIL)  | CIN II (HSIL) | CIN III (HSIL)
           |                |               |
SURFACE    |  Koilocytes    | Koilocytes +  | No maturation
           |  (perinuclear  | atypia lower  | Atypia full
MIDDLE     |   halos)       | 2/3           | thickness
           |  Atypia lower  |               |
BASAL      |  1/3 only      | Atypia lower  | Atypia all
           |                | 2/3           | layers
BASEMENT   |~~~~~~~~~~~~~~~~|~~~~~~~~~~~~~~~|~~~~~~~~~~~~~~~
MEMBRANE   |   INTACT       |    INTACT     |   INTACT
(No invasion in SIL - draw BM intact!)

• Koilocytes = Hallmark of HPV infection = squamous cells with perinuclear halo + wrinkled/raisin-like nucleus
• As grade increases: ↑ nuclear:cytoplasmic ratio, ↑ mitoses (including atypical), ↓ maturation
• CIN III = carcinoma in situ = full thickness atypia, intact basement membrane

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6. INVASIVE CARCINOMA OF CERVIX

Types:

• Squamous cell carcinoma (SCC) - 80% (most common)
• Adenocarcinoma + adenosquamous carcinoma - 15%
• Small cell neuroendocrine carcinoma - <5% (worst prognosis)

Gross Pathology (Easy to Draw):

┌──────────────────────────────────┐
│   GROSS TYPES OF CA CERVIX       │
│                                  │
│  1. EXOPHYTIC (most common)      │
│     Cauliflower/fungating mass   │
│     Protrudes out of cervical os │
│                                  │
│  2. ENDOPHYTIC/ULCERATIVE        │
│     Crater-like ulcer            │
│     Necrotic base                │
│                                  │
│  3. BARREL CERVIX                │
│     Circumferential growth       │
│     Encircles entire cervix      │
│     Hard, barrel-shaped cervix   │
└──────────────────────────────────┘

Microscopy - SCC:

• Tongues and nests of squamous cells invading stroma
• Desmoplastic stromal response (fibrous stroma)
• Keratin pearls (well-differentiated tumors) = concentric layers of squamous cells with central keratin
• Atypical mitoses
• Stromal and vascular invasion

  SURFACE EPITHELIUM
  ___________________
  ↓ Invasion
 [Nest] [Keratin Pearl] [Nest]
   ↓           ↓           ↓
  ||||  Stroma (fibrous/desmoplastic)  ||||
 [Nest]                           [Nest]
         Blood vessel with tumor

Microscopy - Adenocarcinoma:

• Mucin-secreting glandular cells
• Endocervical gland-like structures
• More common with HPV 18

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7. STAGING OF CA CERVIX (FIGO)

MUHS tip: Stage I → Surgery; Stage II/III → Radiation + Chemotherapy

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8. SPREAD & METASTASIS

DIRECT EXTENSION:
Cervix → Vagina → Parametrium → Pelvic wall
       → Bladder (anterior) → Rectum (posterior)

LYMPHATIC (most important):
→ Internal iliac → External iliac → Para-aortic nodes

BLOOD-BORNE (late):
→ Lungs, Liver, Bones

• Risk of lymph node metastasis: <1% if invasion <3mm; >10% if invasion >3mm

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9. CLINICAL FEATURES

• Most common symptom: Post-coital bleeding (contact bleeding)
• Irregular vaginal bleeding / metrorrhagia
• Foul-smelling vaginal discharge (leukorrhea)
• Dyspareunia (painful intercourse)
• Dysuria (bladder involvement)
• Back pain (pelvic wall involvement)

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10. DIAGNOSIS

• Pap smear (Papanicolaou test) = gold standard screening
• Colposcopy (acetic acid → white lesions = acetowhite)
• Biopsy + Cone biopsy
• Schiller's test (iodine staining - normal = brown, abnormal = unstained)

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11. TREATMENT & PROGNOSIS

• Stage I: Radical hysterectomy + pelvic lymph node dissection
• Stage II-III: Radiotherapy + Cisplatin chemotherapy
• Small cell: Very poor prognosis
• 5-year survival: Stage I ~90%; Stage IV ~15%

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🟠 CARCINOMA OF ENDOMETRIUM

(Very Frequently Asked in MUHS - Type I vs Type II is a must!)

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1. EPIDEMIOLOGY

• Most common gynecological cancer in developed countries
• Peak age: 55-65 years (postmenopausal)
• Usually presents early with postmenopausal bleeding

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2. CLASSIFICATION - TYPE I vs TYPE II

Mnemonic: "Type I = POKE me gently (PTEN, OKE = obesity/K-RAS/estrogen) = good prognosis" "Type II = TP53 = Terrible Prognosis = bad"

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3. RISK FACTORS FOR TYPE I

┌──────────────────────────────────────────────┐
│     RISK FACTORS - CA ENDOMETRIUM           │
│                                              │
│  ↑ ESTROGEN (unopposed = no progesterone)   │
│                                              │
│  • Obesity - adipose tissue converts        │
│    androgens to estrogens (aromatase)        │
│  • Nulliparity                               │
│  • Late menopause                            │
│  • Estrogen-secreting ovarian tumors         │
│    (granulosa cell tumor)                   │
│  • Exogenous estrogens                       │
│  • Tamoxifen use (weak estrogen effect)      │
│  • Polycystic ovarian syndrome (PCOS)        │
│  • Lynch syndrome (hereditary)               │
│    - MLH1, MSH2 mutations                   │
│  • Cowden syndrome - PTEN germline mutation  │
└──────────────────────────────────────────────┘

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4. PATHOGENESIS

Type I (Endometrioid):

Unopposed Estrogen
       ↓
Endometrial Hyperplasia (without atypia)
       ↓
Atypical Hyperplasia (PTEN mutation = earliest event)
       ↓
Well-differentiated Endometrioid Carcinoma
       ↓
Mutations: PTEN (30-80%) → PIK3CA (40%) → KRAS (25%) → ARID1A (30%)
       ↓
Poorly differentiated with TP53 mutation (late event)

Type II (Serous):

Endometrial Atrophy (thin, atrophic endometrium)
       ↓
Serous Endometrial Intraepithelial Carcinoma (SEIC)
       ↓
TP53 mutation (EARLY event, >90%)
       ↓
High-grade Serous Carcinoma

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5. ENDOMETRIAL HYPERPLASIA - Precursor

NORMAL ENDOMETRIUM:
 [G][  S  ][G][  S  ][G]   G=gland, S=stroma
 Equal gland:stroma ratio

HYPERPLASIA WITHOUT ATYPIA:
 [G][G][S][G][G][S][G]
 ↑ Glands, some crowding, NO atypia

ATYPICAL HYPERPLASIA (back-to-back glands):
 [G][G][G][G][G][G][G]
 Back-to-back glands, minimal stroma
 Cells: rounded vesicular nuclei, prominent nucleoli

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6. GROSS PATHOLOGY

┌──────────────────────────────────────┐
│    GROSS - CA ENDOMETRIUM           │
│                                      │
│  Uterus enlarged                     │
│                                      │
│  Two patterns:                       │
│  1. POLYPOID/EXOPHYTIC mass         │
│     → Soft, tan-gray mass            │
│     → Projects into uterine cavity  │
│     → Like cauliflower               │
│                                      │
│  2. DIFFUSE - entire endometrium    │
│     involved                         │
│                                      │
│  Cut section:                        │
│  → Gray-white tumor                  │
│  → May invade myometrium             │
│  → Necrosis and hemorrhage          │
└──────────────────────────────────────┘

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7. HISTOPATHOLOGY

• Tubular glands resembling proliferative endometrium
• Back-to-back glands with minimal intervening stroma
• Cells: columnar, stratified nuclei, moderate atypia
• Grading (FIGO 1-3):

Grade 1: >95% glandular pattern (well differentiated)
Grade 2: 6-50% solid areas
Grade 3: >50% solid areas (poorly differentiated)

• Papillary tufts and small clusters of highly atypical cells
• Marked cytologic atypia: high N:C ratio, atypical mitoses, hyperchromasia, prominent nucleoli
• IHC: Diffuse strong p53 positivity (mutant p53 accumulates)

          ╔══╗ ╔══╗ ╔══╗
          ║  ║ ║  ║ ║  ║   ← Back-to-back tubular glands
          ╚══╝ ╚══╝ ╚══╝     resembling endometrium
           ↑     ↑     ↑
        Minimal stroma between
        
  ↓ Myometrial invasion
  ████████████████████████  ← myometrium (smooth muscle)

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8. SPREAD & STAGING

1. Direct: Myometrial invasion → cervix → vagina
2. Lymphatic: Pelvic → para-aortic nodes
3. Blood-borne: Lungs, liver (late)
4. Note: Serous carcinoma spreads transtubal → peritoneal implants (like ovarian Ca)

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9. CLINICAL FEATURES

• Postmenopausal vaginal bleeding (cardinal symptom - early sign)
• Uterine enlargement
• Watery vaginal discharge
• Pelvic/back pain (advanced)

MUHS tip: "Any postmenopausal bleeding = carcinoma endometrium until proven otherwise"

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10. DIAGNOSIS & TREATMENT

• Endometrial biopsy / D&C = definitive diagnosis
• TVUS: endometrial thickness >4mm (postmenopausal) = suspicious
• Treatment: Total abdominal hysterectomy + bilateral salpingo-oophorectomy (TAH + BSO)
• Radiotherapy if myometrial invasion >50%
• Prognosis: Overall 5-year survival ~75%; Stage I serous has worse prognosis than Stage I endometrioid

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🟡 OVARIAN TUMORS

(Most Complex Topic - Asked Every Year in MUHS)

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1. CLASSIFICATION (WHO / MUHS Standard)

┌─────────────────────────────────────────────────────┐
│              OVARIAN TUMORS                         │
├───────────────────────┬─────────────────────────────┤
│  I. SURFACE EPITHELIAL│ Most common (65-70%)        │
│     TUMORS            │                             │
│                       │ a. Serous (most common)     │
│                       │ b. Mucinous                 │
│                       │ c. Endometrioid             │
│                       │ d. Clear cell               │
│                       │ e. Brenner tumor            │
│                       │                             │
│                       │ Each can be:               │
│                       │  Benign/Borderline/Malignant │
├───────────────────────┼─────────────────────────────┤
│  II. GERM CELL TUMORS │ 15-20%                      │
│                       │ a. Teratoma (most common)   │
│                       │    - Mature (dermoid cyst)  │
│                       │    - Immature (malignant)   │
│                       │ b. Dysgerminoma             │
│                       │ c. Yolk sac tumor           │
│                       │ d. Choriocarcinoma          │
├───────────────────────┼─────────────────────────────┤
│  III. SEX CORD-STROMAL│ 5-10%                       │
│  TUMORS               │ a. Granulosa cell tumor     │
│                       │ b. Thecoma-fibroma          │
│                       │ c. Sertoli-Leydig cell      │
│                       │    (Arrhenoblastoma)        │
├───────────────────────┼─────────────────────────────┤
│  IV. METASTATIC       │ From GIT, breast, etc.      │
│  TUMORS               │ Krukenberg tumor (stomach)  │
└───────────────────────┴─────────────────────────────┘

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2. TYPE I vs TYPE II OVARIAN CARCINOMA

High-yield: BRCA1/BRCA2 mutations → almost ALL are high-grade serous (Type II) with TP53 mutations. Lifetime risk 20-60% with BRCA1/2 mutation.

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3. SURFACE EPITHELIAL TUMORS

A. SEROUS TUMORS (Most Common)

• Nulliparity, early menarche, late menopause
• Family history, BRCA1/2 mutations
• OCP use is protective (suppresses ovulation)

┌──────────────────────────────────────────────┐
│  SEROUS CYSTADENOMA (Benign)                │
│                                              │
│   ╭──────────────────────╮                  │
│   │  Thin-walled cyst    │                  │
│   │  Smooth inner lining │                  │
│   │  Clear serous fluid  │                  │
│   │  Few small papillae  │                  │
│   ╰──────────────────────╯                  │
│   Size: up to 30-40 cm                      │
│   25% bilateral                             │
│                                              │
│  SEROUS CYSTADENOCARCINOMA (Malignant)      │
│                                              │
│   ╭──────────────────────╮                  │
│   │  Complex papillary   │ ← Irregular,     │
│   │  projections         │   prominent      │
│   │  Solid areas         │   papillae       │
│   │  Necrosis present    │                  │
│   │  Nodular outer       │                  │
│   │  surface (invasion)  │                  │
│   ╰──────────────────────╯                  │
└──────────────────────────────────────────────┘

• Benign (Cystadenoma): Single layer of tall ciliated columnar epithelium lining cyst
• Borderline: Epithelial stratification (2-3 layers), mild atypia, NO stromal invasion
• Malignant (Carcinoma): Complex papillary formations, marked atypia, STROMAL INVASION
• Psammoma bodies = concentric calcifications = characteristic of serous tumors

BENIGN:           BORDERLINE:        MALIGNANT:
 ┌──────┐          ┌──────┐           ┌──────┐
 │  │   │          │ |||  │           │█████│
 │Cilia │          │Strat.│ No        │Papil│
 │Single│          │  2-3 │ invasion  │Atyp │
 │layer │          │layers│           │Invas│
 └──────┘          └──────┘           └──────┘

  [Concentric rings of calcification]
   like a target/bull's-eye
   ○○○ ← outer ring
    ○○ ← middle
     ○ ← central

• 5-year survival: borderline confined to ovary = 100%; malignant confined = 70%; malignant + peritoneal spread = 25%
• Often associated with ascites
• Spreads to peritoneal surfaces and omentum

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B. MUCINOUS TUMORS

• Rupture of mucinous tumor → mucin seeds peritoneum
• When caused by ovarian tumor: usually resolves
• Most cases of pseudomyxoma peritonei are actually from appendiceal mucinous tumors

• Metastatic mucin-secreting adenocarcinoma to both ovaries (bilateral)
• Most common primary site = stomach
• Histology: Signet ring cells (mucin pushes nucleus to periphery) in fibrous stroma

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C. ENDOMETRIOID TUMORS

• Resemble endometrial glands histologically (tubular glands)
• 20% bilateral
• 15-20% are associated with simultaneous endometrial carcinoma
• Associated with endometriosis
• Mutations: PTEN, PIK3CA (same as endometrial carcinoma)

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D. CLEAR CELL CARCINOMA

• Large cells with abundant clear cytoplasm (glycogen-rich)
• Resembles hypersecretory gestational endometrium
• Associated with endometriosis or endometrioid carcinoma
• Treated like other ovarian carcinomas

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4. GERM CELL TUMORS

TERATOMAS (15-20% of ovarian tumors; >90% are benign)

GROSS FEATURES (Easy Draw):
┌────────────────────────────────────────┐
│  DERMOID CYST / MATURE TERATOMA       │
│                                        │
│   ╭──────────────────────────╮         │
│   │  Outer: smooth capsule   │         │
│   │  Inner: skin-like lining │         │
│   │  Contents:               │         │
│   │    - Sebaceous material  │         │
│   │    - Hair / matted hair  │         │
│   │    - Teeth (25%)         │         │
│   │    - Bone/cartilage      │         │
│   │    - Thyroid tissue      │         │
│   │  "Rokitansky protuberance"│         │
│   │  = mural nodule with     │         │
│   │    teeth projecting      │         │
│   ╰──────────────────────────╯         │
│  Size: Usually <10 cm                 │
│  90% UNILATERAL                       │
│  Right side more common               │
└────────────────────────────────────────┘

• Tissues from ALL THREE germ cell layers:
  • Ectoderm: skin, hair, sebaceous glands, teeth, neural tissue
  • Endoderm: bronchial/intestinal epithelium, thyroid
  • Mesoderm: bone, cartilage, muscle

• Immature/embryonic neural tissue (neuroepithelium)
• Graded 1-3 by amount of immature neural tissue
• More common in young women
• AFP may be raised

• Struma ovarii = all thyroid tissue → can cause hyperthyroidism
• Carcinoid tumor of ovary

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5. SEX CORD-STROMAL TUMORS

GRANULOSA CELL TUMOR (Most Important)

KEY FACTS:
• Produces ESTROGEN (feminizing tumor)
• Causes: Precocious puberty (child), Postmenopausal bleeding, 
          Endometrial hyperplasia → endometrial carcinoma
• Histology: Call-Exner bodies (coffee bean nuclei)
• Marker: Inhibin positive
• Low malignant potential (late recurrence >20 years)

  Granulosa cells arranged around
  central accumulation of eosinophilic material
  
  [◦◦◦◦◦◦◦] ← granulosa cells
  [◦  ♦  ◦] ← Call-Exner body (eosinophilic center)
  [◦◦◦◦◦◦◦]
  
  "Coffee bean" nuclei = nuclear groove

THECOMA-FIBROMA

SERTOLI-LEYDIG CELL TUMOR (Arrhenoblastoma)

• Produces androgens (virilizing tumor)
• Causes: hirsutism, amenorrhea, clitoromegaly, deepening of voice
• Rare, young women

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6. MARKERS FOR OVARIAN TUMORS

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7. RISK FACTORS FOR EPITHELIAL OVARIAN CANCER

INCREASE RISK:         DECREASE RISK:
• Age >45              • OCP use (protective)
• Nulliparity          • Multiparity
• Early menarche       • Breastfeeding
• Late menopause       • Tubal ligation
• Family history       • Oophorectomy
• BRCA1/BRCA2         
• Lynch syndrome       
• Endometriosis

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8. CLINICAL FEATURES OF OVARIAN CANCER

• Silent killer - often presents late (Stage III/IV)
• Abdominal distension/pain
• Ascites (very common)
• Pelvic mass
• Weight loss
• Early satiety (omental involvement)
• Pleural effusion (advanced)

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9. FIGO STAGING - OVARIAN CANCER

70% cases are diagnosed at Stage III-IV (poor prognosis)

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COMPARATIVE SUMMARY TABLE (MUHS Exam Quick Review)

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FREQUENTLY ASKED MUHS EXAM QUESTIONS & SHORT ANSWERS

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