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Endometrial Cancer

MBBS Essay - Obstetrics & Gynaecology

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Definition

• Berek & Novak's Gynecology, p. 2141
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 932

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Epidemiology

• Predominantly a disease of postmenopausal women; peak incidence in the 6th-7th decade, average age at diagnosis ~60 years
• 75% of cases occur in women over 50 years of age
• Overall lifetime risk: approximately 2.8% of women
• Overall 5-year survival rate: approximately 75%
• Deaths from endometrial carcinoma rose ~2% per year from 2010 to 2014, reflecting an increasing burden
• Berek & Novak's Gynecology, p. 2141

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Pathogenesis: Two Major Types

• Berek & Novak's Gynecology, p. 2141

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Risk Factors

• Obesity - adipose tissue converts androgens to estrone (peripheral aromatization); major risk in Western populations
• Nulliparity
• Late menopause (after age 52)
• Unopposed exogenous estrogen therapy - risk increased 4 to 8 times; risk increases with duration and dose
• Tamoxifen use (weak estrogen agonist on endometrium)
• Polycystic ovarian syndrome (PCOS)
• Estrogen-secreting tumours (granulosa cell tumours)
• Type 2 diabetes mellitus, hypertension - commonly co-occur with obesity

• Lynch syndrome (Hereditary Non-Polyposis Colorectal Cancer - HNPCC) - mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2); lifetime endometrial cancer risk up to 40-60%
• Cowden syndrome (PTEN hamartoma tumour syndrome)

• Combined oral contraceptive pill use (reduces risk by ~50%)
• Progestogen therapy (opposes estrogenic stimulation)
• Multiparity
• Smoking (paradoxically reduces risk via anti-estrogenic effects - not recommended)
• Physical activity
• Berek & Novak's Gynecology, p. 2141; Robbins, p. 932

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Molecular Pathogenesis

1. Ultramutated / POLE tumours - Mutations in DNA polymerase epsilon (POLE); exceptionally high somatic mutation burden; paradoxically good prognosis
2. Hypermutated / MSI (Microsatellite Instability) - Mutations or epigenetic silencing of DNA mismatch repair genes (MLH1 promoter hypermethylation most common); ~20% of sporadic tumours; associated with Lynch syndrome
3. Copy number low / Non-specific molecular phenotype - Common subtype; associated with endometrioid morphology; multiple mutations upregulating PI3K/AKT pathway (PTEN, PIK3CA, KRAS, ARID1A)
4. Copy number high / TP53 mutated - Aggressive tumours with serous or high-grade endometrioid morphology; TP53 mutations >90% of serous carcinomas; worst prognosis

• PTEN - most frequently mutated gene (30-80%)
• PIK3CA - activating mutations (~40%)
• KRAS - (~25%)
• ARID1A - loss of function (~33%)
• TP53 - late event; found in ~50% of poorly differentiated tumours
• Robbins, p. 932-933

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Precursor Lesion: Endometrial Hyperplasia

• Hyperplasia without atypia - Low risk of malignant progression (<5%)
• Atypical hyperplasia (Endometrial Intraepithelial Neoplasia - EIN) - High risk; ~30% progress to carcinoma if untreated; some cases of "atypical hyperplasia" are already carcinoma on hysterectomy specimen

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Pathology / Histological Types

1. Endometrioid Adenocarcinoma (Most Common - 80-85%)

• Arises from endometrial hyperplasia
• Mimics proliferative endometrial glands (hence "endometrioid")
• Histologic grading (FIGO):
  • Grade 1 (well-differentiated): <5% non-squamous solid growth
  • Grade 2 (moderately differentiated): 6-50% solid areas
  • Grade 3 (poorly differentiated): >50% solid growth pattern
• May contain foci of squamous differentiation (up to 20% of cases); graded on glandular component alone

2. Serous Carcinoma (Uterine Papillary Serous Carcinoma - UPSC) (~15%)

• Type II tumour; arises on a background of endometrial atrophy in older women
• Highly aggressive; fibrovascular papillary stalks lined by highly atypical cells with tufting
• Psammoma bodies frequently present
• TP53 mutations >90%
• Despite being <10% of endometrial cancers, accounts for >50% of all endometrial cancer deaths
• Has propensity for intraperitoneal spread even without myometrial invasion (simulates ovarian carcinoma)
• Berek & Novak's Gynecology, p. 2158

3. Clear Cell Carcinoma

• Type II; aggressive tumour; poor prognosis
• Clear cells (glycogen-rich cytoplasm) and hobnail cells
• Also arises in older, postmenopausal women without hyperestrogenism

4. Mucinous Carcinoma

• Rare; most are low-grade and well-differentiated
• Must be distinguished from endocervical carcinoma

5. Mixed Carcinomas

• Combinations of histologic types (especially endometrioid + serous); behave as aggressively as the higher-grade component

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Clinical Features

Symptoms

• Postmenopausal bleeding - cardinal symptom; present in ~90% of patients
  • Any postmenopausal bleeding must be investigated until cancer is excluded
• Abnormal perimenopausal bleeding - irregular, heavy
• Pelvic pressure or pain - indicates uterine enlargement or extrauterine spread
• Purulent vaginal discharge - if cervical stenosis causes hematometra/pyometra (poor prognostic sign)
• <5% are asymptomatic (detected incidentally on imaging or Pap smear)

Signs

• Uterine enlargement on bimanual palpation
• In advanced disease: adnexal mass, ascites, inguinal lymphadenopathy
• Pap smear may show malignant cells in ~50% (not a screening test)

Differential Diagnosis of Postmenopausal Bleeding

• Endometrial atrophy (most common, 60-80%)
• Endometrial polyps (2-12%)
• Exogenous estrogen therapy
• Endometrial hyperplasia
• Endometrial carcinoma
• Cervical/vaginal/vulval pathology
• Atrophic vaginitis (up to 15%)

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Investigations

Step 1 - Endometrial Biopsy (Gold Standard)

• Office endometrial aspiration biopsy (Pipelle biopsy) - first-line, accepted standard
• Sensitivity for endometrial cancer: ~90-95%
• If inadequate sample or high clinical suspicion: proceed to D&C ± hysteroscopy

Step 2 - Transvaginal Ultrasound (TVS)

• Endometrial thickness:
  • >4-5 mm in postmenopausal women is threshold for further investigation
  • Atrophic endometrium (<4 mm) makes cancer very unlikely
• A thin endometrial stripe essentially excludes malignancy

Step 3 - Hysteroscopy + Directed Biopsy

• Direct visualization of endometrial cavity
• Best for detecting polyps and focal lesions missed by blind biopsy
• Considered gold standard for diagnosis

Further Workup (Pre-treatment):

• Complete Blood Count, LFT, RFT, blood glucose
• CA-125 (elevated in advanced disease, serous type)
• Chest X-ray, CT chest/abdomen/pelvis - for staging, lymph node assessment, metastases
• MRI pelvis - best modality for assessing depth of myometrial invasion and cervical involvement
• Cystoscopy / Proctoscopy - if bladder/bowel involvement suspected (Stage IVA)

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Staging

• Berek & Novak's Gynecology, p. 2141

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Prognostic Factors

1. Advanced age
2. Non-endometrioid histology (serous, clear cell) or Grade 3 histology
3. Deep myometrial invasion (≥50%) - Stage IB and beyond
4. Lymph-vascular space invasion (LVSI)
5. Large tumour size (>2 cm)
6. Cervical extension (Stage II)
7. Lymph node metastasis (Stage IIIC)
8. Intraperitoneal spread
9. Positive peritoneal cytology
10. Hormone receptor negativity (ER/PR negative tumours behave more aggressively)
11. Abnormal DNA ploidy (aneuploidy)

• Berek & Novak's Gynecology, p. 2142

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Treatment

Surgical Treatment (Primary)

• Total Hysterectomy + Bilateral Salpingo-Oophorectomy (TAH+BSO)
• Peritoneal washings/cytology
• Lymph node assessment - pelvic and para-aortic lymph node dissection in most patients
  • May be omitted in low-risk patients (Grade 1-2, Stage IA, no LVSI)
• Omentectomy and peritoneal biopsies for serous/clear cell histology

• Laparoscopic/robotic-assisted preferred over open laparotomy (comparable oncologic outcomes, faster recovery, lower morbidity)
• Open laparotomy for bulky disease or advanced stages

• High-dose progestin therapy (medroxyprogesterone acetate / megestrol acetate)
• Close surveillance with serial biopsies
• Hysterectomy recommended after childbearing is complete

Radiotherapy

• Vaginal brachytherapy - for Stage I intermediate/high-intermediate risk; reduces vaginal vault recurrence (up to 80% salvage for isolated vaginal recurrence)
• External Beam Pelvic Radiotherapy (EBRT) - Stage IB high grade, Stage II; decreases pelvic recurrence
• Extended-field radiation (para-aortic) - when para-aortic nodes involved
• Whole-abdomen radiation - occasionally for peritoneal spread (largely replaced by chemotherapy)
• Radiotherapy as primary treatment is reserved for medically unfit patients who cannot undergo surgery

Chemotherapy

• Indicated for high-risk disease (serous, clear cell, Grade 3, advanced stage)
• Standard regimen: Carboplatin + Paclitaxel (preferred over older cisplatin-doxorubicin-paclitaxel due to similar efficacy with less toxicity)
• For Stage III/IV: combined modality approach (chemotherapy + radiation)
• "Sandwich" chemotherapy-radiation-chemotherapy protocol shows improved survival in some studies

Hormonal Therapy

• Progestins (medroxyprogesterone acetate, megestrol acetate) - for recurrent/metastatic disease with ER/PR-positive tumours
• Response rates ~15-25% in recurrent disease
• Also used for fertility preservation

Treatment by Stage:

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Pattern of Spread

1. Direct extension - myometrium → cervix → vagina → parametria → bladder, rectum
2. Lymphatic - to pelvic (obturator, external iliac) and para-aortic lymph nodes
3. Transtubal / Peritoneal - through fallopian tubes to peritoneal cavity (especially serous type)
4. Haematogenous - lungs, liver, bone (late stage)

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Recurrent Disease

• Vaginal recurrence most common (vault)
• Managed by: radiotherapy (if not previously irradiated), surgery, chemotherapy, hormonal therapy
• Isolated vaginal recurrences: salvage in up to 80% of patients with radiotherapy
• Berek & Novak's Gynecology, p. 2142

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Uterine Sarcomas (Brief Mention)

• Berek & Novak's Gynecology, p. 2142

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Summary of Key Points

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• Berek & Novak's Gynecology, pp. 2141-2165
• Robbins, Cotran & Kumar: Pathologic Basis of Disease, pp. 932-934
• Goldman-Cecil Medicine (International Edition)