OncologyTier 2Disease (DEADMAN)

Malignancies - gynaecological malignancies

Description

Ovarian

High-grade serous carcinoma (HGSC) is the commonest epithelial subtype
- Arises from fallopian tube fimbrial epithelium (STIC lesion), not the ovary - hence salpingectomy in risk reduction
- TP53 mutated in ~96%; homologous recombination deficient in ~50%
Other epithelial: low-grade serous (KRAS/BRAF, indolent, chemo-resistant), endometrioid and clear cell (endometriosis-associated, ARID1A), mucinous (exclude a GI primary)
Non-epithelial: germ cell (young, AFP/hCG/LDH), sex cord-stromal (granulosa - inhibin, oestrogen -> endometrial hyperplasia; Sertoli-Leydig - virilisation)

Endometrial

	Type I	Type II
Histology	Low-grade endometrioid	Serous, clear cell, carcinosarcoma
Driver	Oestrogen-dependent	Oestrogen-independent
Genetics	PTEN, PI3K, KRAS, MMR	TP53, aneuploid
Precursor	Atypical hyperplasia	Serous intraepithelial Ca
Prognosis	Good	Poor, early metastasis

Molecular classification now drives adjuvant therapy (incorporated into FIGO 2023 staging)

Group	%	Prognosis
POLE ultramutated	~10%	Excellent - de-escalate/omit adjuvant therapy
MMR-deficient (MSI-H)	~30%	Intermediate; immunotherapy-responsive
p53-abnormal	~15%	Worst - escalate; chemotherapy +/- HER2 targeting
No specific molecular profile	~45%	Intermediate; ER/PR-driven

Cervical

Squamous ~70%, adenocarcinoma ~25% (rising, less well detected by cytology - the reason for HPV-based screening)
~95% HPV-driven; precursor CIN/HSIL

Epidemiology

Ovarian

~1,800/yr AU; lifetime risk ~1 in 85; peak 60s
Leading cause of gynaecological cancer death - 70% present at stage III/IV
BRCA1/2 carriers: 40-60% lifetime risk (BRCA1 ~40%, BRCA2 ~15-20%)

Endometrial

Commonest gynaecological cancer in Australia (~3,500/yr) and rising with obesity
Postmenopausal, median age ~63; 75% present stage I (postmenopausal bleeding presents early)

Cervical

~900/yr AU, falling steeply with HPV vaccination and screening
Bimodal peaks 30s and 60s; Australia on track to be the first country to eliminate cervical cancer

Aetiopathogenesis

Ovarian

Risk inc: nulliparity, early menarche/late menopause, endometriosis (clear cell/endometrioid), age, HRT
Risk dec (all reduce ovulation or retrograde flow): combined OCP (~50% with prolonged use), pregnancy, breastfeeding, tubal ligation, salpingectomy
- Incessant ovulation and retrograde reflux of menstrual products onto the ovary are the unifying mechanisms
Hereditary ~20%
- BRCA1/2 - homologous recombination repair -> HRD -> PARP inhibitor synthetic lethality
- Lynch syndrome (MMR) - endometrioid and clear cell
- RAD51C/D, BRIP1, PALB2
Offer germline + somatic testing to every woman with non-mucinous epithelial ovarian cancer

Endometrial

Unopposed oestrogen is the theme
- Obesity (peripheral aromatisation - the dominant driver), nulliparity, PCOS/anovulation, early menarche/late menopause
- Tamoxifen (partial agonist at endometrium), oestrogen-only HRT, oestrogen-secreting tumours (granulosa cell)
- T2DM, hypertension
Protective: combined OCP, progestogen IUD, parity, smoking (epidemiological only)
Lynch syndrome - endometrial cancer is the commonest extracolonic cancer and often the sentinel malignancy (esp. MSH6)
- -> test MMR/MSI on every endometrial cancer

Cervical

High-risk HPV persistence - 16 and 18 cause ~70%
- E6 -> degrades p53; E7 -> inactivates Rb
Cofactors: smoking, immunosuppression (HIV, transplant), long-term OCP, high parity, other STIs, early coitarche, multiple partners
Most HPV infection clears within 2 years - persistence is what matters

Diagnosis

Ovarian

Vague, late symptoms: bloating, early satiety, pelvic/abdominal pain, urinary urgency
CA-125 + transvaginal ultrasound (+ abdominal US); RMI/ROMA to triage
- CA-125 raised in endometriosis, fibroids, PID, cirrhosis, heart failure, pregnancy, any peritoneal irritation - poor specificity premenopausally
CT C/A/P; no benefit from population screening (UKCTOCS - no mortality reduction)
Diagnosis usually at laparotomy/laparoscopy; image-guided biopsy or ascitic cytology if neoadjuvant planned
Germ cell markers (AFP, hCG, LDH) if young; inhibin if granulosa suspected

Endometrial

*Postmenopausal bleeding = endometrial cancer until excluded* (~10% have cancer)
Transvaginal ultrasound - endometrial thickness >4 mm postmenopausal warrants sampling
Pipelle biopsy in rooms; hysteroscopy + D&C if inadequate, non-diagnostic, or bleeding persists
MRI for local staging; CT for distant. CT/PET not used for initial diagnosis
MMR IHC + p53 + POLE on all specimens

Cervical

National Cervical Screening Program: 5-yearly HPV test, age 25-74, including self-collection
- HPV 16/18 detected -> direct colposcopy
- Other high-risk HPV -> reflex LBC, then colposcopy or 12-month repeat
Diagnosis: colposcopy + biopsy; LLETZ/cone for microinvasive assessment
FIGO staging now incorporates imaging and pathology (MRI for local extent, PET-CT for nodes)

Management

A. Ovarian cancer

Surgery

Complete cytoreduction (no visible residual) is the strongest modifiable prognostic factor
Primary debulking if achievable; otherwise neoadjuvant chemotherapy x3 -> interval debulking
Fertility-sparing unilateral salpingo-oophorectomy for stage IA germ cell/low-grade disease

Chemotherapy

Carboplatin + paclitaxel x6 is the backbone in all stages beyond IA grade 1
Add bevacizumab for suboptimally debulked or stage IV, continued as maintenance
HIPEC at interval debulking is an option in selected patients

Maintenance - the axis is HRD status

Status	Maintenance
BRCA1/2 mutant	Olaparib 2 yr (SOLO-1 - huge PFS gain, OS benefit)
HRD-positive, BRCA wild-type	Olaparib + bevacizumab (PAOLA-1)
HRD-negative	Bevacizumab +/- niraparib

PARP inhibitor toxicity: myelosuppression (check FBE monthly), fatigue, nausea; MDS/AML in ~1%

Relapse - defined by platinum-free interval

Platinum-sensitive = relapse >6 months after last platinum -> re-challenge with a platinum doublet +/- bevacizumab; consider secondary cytoreduction
Partially platinum-sensitive = 6-12 months
Platinum-resistant = <6 months -> single-agent non-platinum (pegylated liposomal doxorubicin, weekly paclitaxel, topotecan, gemcitabine) +/- bevacizumab; mirvetuximab soravtansine if folate receptor-alpha high
Platinum-refractory = progression on treatment

Risk reduction in BRCA carriers

Risk-reducing bilateral salpingo-oophorectomy before 40 (BRCA1) / 45 (BRCA2) - dec ovarian cancer risk ~80%
- Remove the tubes - HGSC originates there
- Discuss HRT until the average age of menopause if no prior breast cancer

B. Endometrial cancer

Total hysterectomy + BSO + sentinel node mapping - laparoscopic/robotic is safe with shorter stay and equal oncological outcome
Adjuvant therapy by risk group, now refined by molecular class
- Low risk (stage IA, G1-2, endometrioid, no LVSI) -> observation
- POLE-mutated -> de-escalate, often omit adjuvant therapy entirely
- Intermediate/high-intermediate -> vaginal brachytherapy +/- external beam
- High risk / p53-abnormal -> chemotherapy (carboplatin-paclitaxel) + radiotherapy
Advanced or recurrent: chemotherapy + immunotherapy
- dMMR -> carboplatin/paclitaxel + dostarlimab or pembrolizumab (RUBY, NRG-GY018) - dramatic benefit
- pMMR -> chemotherapy + pembrolizumab; later lenvatinib + pembrolizumab
Fertility-sparing for grade 1 stage IA in young women: progestogen (Mirena or high-dose oral) with 3-6 monthly sampling
Endocrine therapy (progestogens, tamoxifen, aromatase inhibitors) for low-grade ER-positive advanced disease
Weight loss and metabolic management are part of treatment, not adjunct advice

C. Cervical cancer

Prevention: HPV vaccination (9-valent, school program at 12-13 in Australia, single dose since 2023) - the definitive intervention
Microinvasive (IA1) - cone biopsy/LLETZ if fertility desired; simple hysterectomy otherwise
Early (IB1-IB2) - radical hysterectomy + pelvic lymphadenectomy
- *Open, not minimally invasive* - LACC trial showed worse survival with laparoscopic/robotic radical hysterectomy
- Fertility-sparing radical trachelectomy in selected cases
Locally advanced (IB3-IVA) - concurrent chemoradiation: weekly cisplatin + external beam pelvic RT + brachytherapy
- Brachytherapy is essential - omitting it markedly worsens survival
- Add pembrolizumab to chemoradiation (KEYNOTE-A18) - improves OS; induction chemotherapy before chemoradiation (INTERLACE) also improves survival
Metastatic/recurrent - carboplatin/paclitaxel + bevacizumab + pembrolizumab; tisotumab vedotin at progression

Associations

Lynch syndrome - endometrial (commonest extracolonic), ovarian, colorectal, urothelial
BRCA1/2 - ovarian, fallopian tube, primary peritoneal, breast, pancreatic, prostate
Endometriosis - clear cell and endometrioid ovarian cancer
Meigs syndrome - ovarian fibroma + ascites + pleural effusion
Granulosa cell tumour -> oestrogen -> endometrial hyperplasia/carcinoma; inhibin marker
Sertoli-Leydig tumour -> virilisation
Struma ovarii -> thyrotoxicosis; ovarian teratoma -> anti-NMDA receptor encephalitis
Krukenberg tumour - bilateral ovarian metastases from gastric/colorectal signet-ring cancer
PCOS, obesity, T2DM, Cowden syndrome (endometrial)
HIV and other immunosuppression (cervical)
Peutz-Jeghers - sex cord tumour with annular tubules, adenoma malignum of cervix

Natural history & complications

Ovarian

5-yr survival overall ~48%; stage I ~90%, stage III-IV ~30%
Spreads transcoelomically - peritoneal surfaces, omental cake, ascites, diaphragm; late haematogenous
Relapse is the rule in advanced disease - the platinum-free interval shortens with each line
Complications: malignant bowel obstruction (often multi-level, frequently not surgical), ascites, VTE, malnutrition
Rising CA-125 alone should not trigger earlier chemotherapy (MRC OV05 - no survival benefit, worse QoL)

Endometrial

5-yr survival ~83% overall; stage I ~95%, stage IV ~20%
Most recurrences within 3 years; vaginal vault recurrence is often salvageable with radiotherapy
Serous/carcinosarcoma and p53-abnormal disease behave like ovarian cancer - peritoneal spread

Cervical

5-yr survival ~74% overall; stage I >90%, stage IV ~20%
Local extension -> parametria, bladder, rectum, ureters
Death is often from uraemia due to bilateral ureteric obstruction
Complications: fistula (vesicovaginal, rectovaginal), lymphoedema, radiation proctitis/cystitis, vaginal stenosis, premature menopause
Survivorship: sexual function, fertility loss, and lymphoedema are underestimated and rarely raised by the patient

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