Endometrial and ovarian cancer

Endometrial Carcinoma

Endometrial cancer is the most common gynaecological malignancy in Australia, with over 3,300 new diagnoses annually. It predominantly affects postmenopausal women, with a median age at diagnosis of 63 years.

Histological Subtypes & Pathogenesis

• Type I (Endometrioid Adenocarcinoma, ~80%): Oestrogen-dependent, arising against a background of atypical endometrial hyperplasia. Characterized by PTEN mutations, microsatellite instability, and PIK3CA mutations. Typically low-grade, confined to the uterus, and carries a favourable overall prognosis.
• Type II (Non-Endometrioid: Serous and Clear Cell, ~20%): Oestrogen-independent, arising in an atrophic endometrium in older postmenopausal women. Characterized by TP53 mutations and HER2 amplification. Highly aggressive, poorly differentiated, prone to early intraperitoneal and lymphovascular dissemination, with poor 5-year survival.

Risk Factors for Endometrial Cancer

All risk factors for Type I disease reflect prolonged, unopposed oestrogenic stimulation of the endometrium without luteal progesterone:

• Obesity ($BMI \ge 30\text{ kg/m}^2$): The single greatest modifiable risk factor. Adipocytes contain aromatase enzymes that convert adrenal androstenedione into estrone.
• Endogenous Oestrogen Exposure: Early menarche ($< 12\text{ years}$), late menopause ($> 55\text{ years}$), nulliparity, and chronic anovulation (polycystic ovary syndrome).
• Exogenous Oestrogens: Oestrogen-only menopausal hormone therapy in a woman with an intact uterus, or tamoxifen therapy (which acts as a partial oestrogen agonist on endometrial tissue while antagonizing breast tissue).
• Genetic Syndromes: Lynch syndrome (hereditary non-polyposis colorectal cancer / HNPCC, caused by germline mutations in DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS2) conveys a 40% to 60% lifetime risk of endometrial carcinoma. Universal screening for Lynch syndrome via reflex mismatch repair immunohistochemistry (MMR IHC) is performed on all endometrial cancers diagnosed in Australia.

Clinical Presentation and Postmenopausal Bleeding (PMB) Workup

• Cardinal Symptom: Any vaginal bleeding occurring $\ge 12\text{ months}$ following the menopause is postmenopausal bleeding (PMB). Endometrial cancer is the underlying cause in approximately 10% of women presenting with PMB (the remaining 90% have benign causes: atrophic vaginitis, endometrial atrophy, or endometrial polyps). In any postmenopausal woman, endometrial cancer is the primary diagnosis to exclude.
• First-Line Diagnostic Investigation: Transvaginal Ultrasound (TVUS):
  • In postmenopausal women with PMB, an endometrial thickness $\le 4\text{ mm}$ with a thin, homogeneous, distinct stripe carries a $> 99\%$ negative predictive value for endometrial cancer. If bleeding does not recur, conservative observation is appropriate.
  • An endometrial thickness $> 4\text{ mm}$, an irregular or heterogeneous stripe, or persistent/recurrent bleeding mandates urgent histological tissue sampling.
• Histological Sampling Modalities:
  • Outpatient Pipelle endometrial aspiration biopsy: High diagnostic accuracy for global endometrioid cancer, but may miss focal polyps or fundal lesions.
  • Hysteroscopy with Dilatation and Curettage (D&C): Indicated if Pipelle biopsy is inadequate, cannot traverse the internal os due to cervical stenosis, demonstrates hyperplasia, or if abnormal bleeding recurs despite a benign Pipelle result.

Surgical Management and Adjuvant Therapy

• Definitive treatment consists of total laparoscopic hysterectomy with bilateral salpingo-oophorectomy (TLH/BSO) with sentinel lymph node mapping or selective pelvic and para-aortic lymphadenectomy.
• Adjuvant treatment (vaginal vault brachytherapy, pelvic external beam radiotherapy, or carboplatin/paclitaxel systemic chemotherapy) is tailored to FIGO stage and molecular risk groups (POLE ultramutated, MMR-deficient, p53 abnormal, or no specific molecular profile).

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Ovarian Carcinoma

Ovarian cancer has the highest mortality of all gynaecological malignancies in Australia due to its insidious onset, absence of effective population screening, and presentation at an advanced stage (Stage III or IV in $> 70\%$ of cases).

Histopathology

• Epithelial Ovarian Carcinoma (EOC, > 90%): The predominant histological subtype is high-grade serous ovarian carcinoma (HGSOC, 70%). Contemporary pathogenetic evidence proves that most HGSOCs arise from the fimbriated end of the fallopian tubes as serous tubal intraepithelial carcinomas (STICs), subsequently shedding onto the ovarian surface and peritoneum.
• Other epithelial subtypes include endometrioid and clear cell carcinomas (frequently arising from pre-existing pelvic endometriosis), and mucinous carcinomas.
• Non-epithelial tumours include germ cell tumours (dysgerminomas, yolk sac tumours; typically in young women aged 15–30, secreting $\beta$-hCG, AFP, or LDH) and sex cord-stromal tumours (granulosa cell tumours secreting oestrogen and inhibin, producing abnormal bleeding).

Clinical Presentation: The "Silent" Symptoms

Symptoms are typically subacute and non-specific, frequently misattributed to irritable bowel syndrome or menopause. Hallmark symptoms occurring on $> 12\text{ days per month}$ for $< 12\text{ months}$ include:

• Persistent abdominal bloating or increased abdominal girth (ascites).
• Early satiety and difficulty completing normal meals.
• Persistent pelvic or lower abdominal pain.
• Increased urinary urgency or frequency.
• Unexplained fatigue, weight loss, or change in bowel habits.

Diagnostic Workup & Risk of Malignancy Index (RMI)

• Physical Examination: Bimanual pelvic examination may detect an irregular, firm, fixed adnexal mass; abdominal examination may reveal ascites (fluid wave) or an omental "cake".
• Biomarkers: Serum Cancer Antigen 125 (CA-125) is elevated in $> 80\%$ of advanced epithelial ovarian cancers. However, CA-125 is non-specific in premenopausal women, as it can be elevated by benign conditions (endometriosis, adenomyosis, fibroids, pelvic inflammatory disease, pregnancy, and menstruation). In postmenopausal women, elevated CA-125 is highly predictive of malignancy.
• Pelvic Transvaginal and Transabdominal Ultrasound: Evaluates mass size, architecture (unilocular vs multilocular), solid vascular components, thick septations, papillary projections, bilateral involvement, and the presence of ascites.
• Risk of Malignancy Index (RMI): Combines menopausal status ($M$), ultrasound score ($U$), and absolute serum CA-125 level ($U/\text{mL}$):

$$RMI = U \times M \times \text{CA-125}$$

• Ultrasound Score ($U$): 1 point each for multilocular cysts, solid areas, bilateral lesions, ascites, and intra-abdominal metastases ($U = 0$ for 0 features; $U = 1$ for 1 feature; $U = 3$ for 2 to 5 features).
  • Menopausal Status ($M$): Premenopausal = 1; Postmenopausal = 3.
  • Clinical Threshold: An $RMI > 200$ has a sensitivity of ~88% and specificity of ~97% for ovarian malignancy. Any patient with an $RMI > 200$ must be referred immediately to a certified gynaecological oncologist within a specialized tertiary cancer centre.
• Ovarian tissue assessment: Do not routinely aspirate an intact suspicious ovarian cyst. In advanced disease, a suitable peritoneal/omental biopsy may be appropriate before neoadjuvant treatment. The oncology MDT determines the strategy from extent, fitness and diagnostic need.

Genetic Susceptibility & Risk-Reducing Surgery

• Up to 15% to 20% of epithelial ovarian cancers are attributable to inherited germline mutations:
  • BRCA1: Lifetime ovarian cancer risk of 40% to 50%.
  • BRCA2: Lifetime ovarian cancer risk of 15% to 25%.
  • Lynch Syndrome: Lifetime ovarian cancer risk of 10% to 12%.
• All women diagnosed with non-mucinous epithelial ovarian cancer in Australia are offered germline and somatic genetic testing.
• Prophylactic Bilateral Salpingo-Oophorectomy (RRBSO): The standard risk-reducing intervention for mutation carriers, recommended at age 35 to 40 years for BRCA1, and age 40 to 45 years for BRCA2 (after completion of childbearing). Routine population screening with CA-125 and TVUS has not demonstrated mortality reduction and is strictly not recommended for average-risk asymptomatic women.

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Clinical comparison: NCSP Triage Pathways, Endometrial Cancer Workup, and Ovarian Cancer Risk Stratification

• NCSP: HPV 16 / 18: Primary Screening or Triage Tool: Primary HPV nucleic acid test; Diagnostic Threshold / Action Trigger: Oncogenic HPV 16 and/or 18 detected; Mandatory Clinical Action: Mandatory direct referral for colposcopy regardless of reflex cytology
• Negative follow-up HPV: In the standard intermediate-risk follow-up pathway, an HPV-negative 12-month test returns to routine five-year screening. Do not require an extra 12-month test without a separate indication.
• NCSP: High-Grade Cytology: Primary Screening or Triage Tool: Reflex Liquid-Based Cytology (LBC); Diagnostic Threshold / Action Trigger: LBC HSIL, ASC-H, atypical glandular cells; Mandatory Clinical Action: Immediate referral for colposcopy
• Postmenopausal Bleeding: Primary Screening or Triage Tool: Transvaginal ultrasound (TVUS); Diagnostic Threshold / Action Trigger: Endometrial thickness $\le 4\text{ mm}$ (thin/homogeneous); Mandatory Clinical Action: Reassure; observe clinically if bleeding ceases; repeat if bleeding recurs
• Postmenopausal Bleeding: Primary Screening or Triage Tool: Transvaginal ultrasound (TVUS); Diagnostic Threshold / Action Trigger: Endometrial thickness $> 4\text{ mm}$ or heterogeneous; Mandatory Clinical Action: Mandatory Pipelle endometrial biopsy or hysteroscopy with D&C
• Adnexal Mass Evaluation: Primary Screening or Triage Tool: Risk of Malignancy Index (RMI); Diagnostic Threshold / Action Trigger: $RMI = U \times M \times \text{CA-125} > 200$; Mandatory Clinical Action: Urgent referral to certified gynaecological oncologist in tertiary centre
• BRCA1 Mutation Carrier: Primary Screening or Triage Tool: Genetic counselling & testing; Diagnostic Threshold / Action Trigger: Completion of childbearing (age 35–40); Mandatory Clinical Action: Risk-reducing bilateral salpingo-oophorectomy (RRBSO)

Primary references (checked 7 October 2026): National cervical screening provider resources.