Important note: DC Dutta's Textbook of Gynecology is not in the medical library. The comprehensive answer above is compiled from Berek & Novak's Gynecology (the most comparable standard gynecology textbook) and Robbins & Cotran Pathologic Basis of Disease - both at the same depth and scope that Dutta covers this topic.

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Carcinoma of the Endometrium - Complete Notes

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1. Introduction & Epidemiology

• Most common invasive cancer of the female genital tract (Western countries)
• Accounts for 7% of all invasive cancers in females (excluding skin)
• Has overtaken cervical cancer due to better cervical screening programs
• Peak incidence: 55-65 years (postmenopausal); uncommon before age 40
• Incidence in younger women is rising
• About 80% of cases are stage I at diagnosis

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2. Risk Factors

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3. Type I vs Type II Classification

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4. Pathogenesis & Molecular Biology

Type I - Key mutations (all drive PI3K/AKT pathway):

• PTEN: Most common (30-80%); tumor suppressor; loss of function
• PIK3CA: ~40%; activating mutation (encodes PI3K catalytic subunit)
• KRAS: ~25%; activating mutation
• ARID1A: ~1/3; chromatin remodeling; also mutated in endometriosis-associated ovarian cancers
• MMR defects: ~20% sporadic; MLH1 epigenetically silenced; Lynch syndrome has germline MMR mutations
• POLE mutations: <10%; ultramutated; paradoxically excellent prognosis

Type II - Key mutation:

• TP53: >90% of serous carcinomas

TCGA Four Molecular Subtypes (in order of prognosis, best to worst):

1. POLE ultramutated - best prognosis
2. MSI hypermutated - intermediate
3. Copy number low/nonspecific - intermediate
4. Copy number high/TP53 mutated - worst (serous-like)

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5. Precursor: Endometrial Hyperplasia

• Established precursor to Type I (endometrioid) carcinoma
• WHO classification: Hyperplasia without atypia vs. Atypical Hyperplasia/EIN (endometrial intraepithelial neoplasia)
• Atypical hyperplasia: 25-29% harbor concurrent carcinoma; high progression risk

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6. Pathology

Classification of Endometrial Carcinomas:

• Endometrioid adenocarcinoma (+ variants: villoglandular/papillary, secretory, with squamous differentiation)
• Mucinous carcinoma
• Papillary serous carcinoma
• Clear cell carcinoma
• Squamous carcinoma
• Undifferentiated carcinoma
• Mixed carcinoma

Gross Morphology:

• Localized polypoid mass or diffuse involvement of endometrial lining
• Typically arises in fundus
• Spreads: myometrial invasion → adjacent structures → lymph nodes → distant (lungs, liver, bones)

Endometrioid Adenocarcinoma (80-85%):

• Glands resembling normal proliferative endometrium
• Columnar cells, basally oriented nuclei, little intracytoplasmic mucin
• Invasion criteria: desmoplastic stroma, back-to-back glands (no intervening stroma), extensive papillary pattern, squamous differentiation (area >4.2 mm)
• Up to 20% have squamous differentiation (graded by glandular component only)

FIGO Grading:

• Significant nuclear atypia upgrades tumor by 1 grade
• Serous and clear cell = always high-grade (grading not needed)

Serous Carcinoma (~10-15%):

• Arises in atrophic endometrium; occurs ~10 years later than endometrioid
• Precursor: Endometrial Intraepithelial Carcinoma (EIC) - malignant cells on surface epithelium only
• Papillary architecture; marked cytologic atypia; TP53 mutated (>90%)
• Spreads via transtubal route to peritoneum despite superficial uterine involvement
• 5-year survival 18-27%; recurrence rate up to 80% even when confined to uterus
• More common in women of African descent (2-fold higher mortality)

Clear Cell Carcinoma (~5%):

• High-grade; postmenopausal
• Clear (glycogen-rich) cytoplasm; distinct cell membranes; prominent nucleoli
• Back-to-back glandular pattern; binucleated and multinucleated forms

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7. Clinical Features

Symptoms:

• Postmenopausal uterine bleeding (PMB) - cardinal symptom; present in >90%
  • BUT remember: only ~10% of PMB is due to endometrial cancer; most is atrophy (60-80%)
• Perimenopausal: menometrorrhagia, oligomenorrhea, or cycles persisting past usual menopause age
• Watery/blood-stained vaginal discharge (early feature)
• Pyometra in elderly (malodorous discharge)
• Pelvic/lower abdominal pain - late feature
• Bladder/bowel symptoms in advanced disease

Signs:

• Obesity (common)
• Usually normal pelvic examination in early disease
• Uterus may be slightly enlarged or bulky
• Bimanual: assess uterine size and mobility, adnexal masses, parametrial induration, cul-de-sac nodularity
• Check inguinal and supraclavicular lymph nodes
• Assess for hepatomegaly, ascites, omental masses (advanced disease)

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8. Diagnosis

1. Endometrial Aspiration Biopsy (First-line, office procedure)

• Sensitivity ~90%; adequate tissue in most cases
• Insufficient tissue or negative but high suspicion → D&C

2. Transvaginal Ultrasound (TVS)

• Endometrial thickness >4-5 mm in postmenopausal women requires biopsy
• Assesses myometrial invasion preoperatively

3. Fractional Curettage (D&C)

• Separate endocervical and endometrial curettings
• Endocervical involvement → Stage II
• Gold standard when office biopsy inconclusive

4. Hysteroscopy + Directed Biopsy

• Better visualization of focal lesions and polyps

5. MRI

• Best for preoperative assessment of myometrial invasion and cervical involvement

6. Papanicolaou Smear

• Inadequate for screening (positive in only ~50% of cases)

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9. Pretreatment Evaluation

• History and physical examination - most important; assess comorbidities (DM, HTN, obesity)
• Chest X-ray: Exclude pulmonary metastasis; assess cardiorespiratory status
• ECG, CBC, platelet count, blood group and screen
• Serum CA-125: Elevated in advanced disease; useful for monitoring
• CT abdomen/pelvis: Consider for Type II tumors; assess extrauterine spread
• MRI: Preoperative myometrial invasion assessment
• Cystoscopy, colonoscopy, IVP, barium enema: only if symptoms indicate
• Stage IV disease usually clinically evident from symptoms + examination

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10. FIGO Staging (Surgical)

• Stage I (grade 1/2): ~90%
• Stage I (grade 3): ~75%
• Stage II/III: ~50%
• Serous carcinoma overall: 18-27%

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11. Prognostic Variables

• No invasion: 1%
• Inner 1/3: 5%
• Middle 1/3: 6%
• Outer 1/3: 25%

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12. Routes of Spread

1. Direct extension - downward to cervix; outward through myometrium to serosa and adnexa
2. Lymphatic - to pelvic nodes (obturator, external/internal iliac), then para-aortic nodes
3. Hematogenous - lungs (most common), liver, bones, brain
4. Transperitoneal - especially serous carcinoma; via tubal regurgitation
5. Transcervical - to vagina

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13. Treatment

Surgery (Primary Treatment)

• TAH + BSO
• Peritoneal cytology
• Inspection of all peritoneal surfaces
• Lymph node assessment (sentinel node biopsy or formal dissection)
• Omental biopsy if indicated

• Equivalent oncologic outcomes to laparotomy
• Shorter hospital stay (52% vs 94% >2 days)
• Less blood loss and fewer postoperative complications (14% vs 21%)
• Longer operative time; 24% conversion rate (improved to 2.4% with modern technique)

Radiation Therapy

• Vaginal vault brachytherapy: Intermediate-risk; reduces vaginal recurrence
• External pelvic RT (EBRT): Higher-risk; deep invasion or LN metastasis
• Extended-field RT: Para-aortic involvement
• Primary RT: Medically unfit patients

Chemotherapy

• Carboplatin + paclitaxel: Most widely used for advanced/recurrent disease
• Indicated for: Stage III/IV, Type II tumors, recurrence

Hormonal Therapy

• Megestrol acetate 40-160 mg/day - most reliable for reversing hyperplasia and treating receptor-positive recurrent disease
• Progesterone receptor status predicts response
• Fertility-preserving protocol: Continuous progestins + serial biopsy q3-6 months
  • ~76% achieve complete response; ~24% never respond
  • ~20 patients achieved pregnancy in reviewed series
  • Must be counseled: temporary treatment; hysterectomy after childbearing

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14. Screening

• No effective population screening exists
• Pap smear: inadequate (insensitive)
• TVS + biopsy: too expensive for routine use
• Lynch II syndrome: Annual pelvic exam + TVS + endometrial biopsy from age 35-40
• Prophylactic hysterectomy + BSO after childbearing = 100% prevention in Lynch II carriers
• Universal MMR IHC testing (MLH1, MSH2, MSH6, PMS2) now recommended for all newly diagnosed endometrial cancers to identify Lynch syndrome

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15. Recurrent Disease

• Vaginal recurrence (if not previously irradiated): radiation therapy
• Pelvic exenteration: selected patients with central pelvic recurrence
• Chemotherapy: carboplatin + paclitaxel for systemic recurrence
• Hormonal therapy: progestins for receptor-positive, slow-growing recurrences

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