25.2 Gynecologic Oncology: Cervical Cancer Screening, Staging & Treatment, Endometrial Cancer and Lynch Syndrome, Ovarian Tumors and BRCA, Vulvar and Vaginal Cancer, Survival and Quality of Life

Why this area matters

TOS area R asks you to:

• classify malignant tumors of the reproductive tract and their risk factors;
• describe their symptoms, grading, staging and histology;
• carry out early diagnosis, screening and treatment;
• explain their clinical course, cure rates, survival and quality of life.

In the Philippines, cervical cancer is one of the most common cancers in women, second to breast cancer. Many women present at advanced stages because screening coverage is low. The National Integrated Cancer Control Act (RA 11215, 2019) aims to improve prevention, early detection, treatment, survivorship and palliative care, and HPV vaccination of girls is part of school-based immunization.

Gynecologic Oncology

Cervical Carcinoma

• Etiology: Persistent infection with high-risk Human Papillomavirus (HPV) genotypes, overwhelmingly HPV 16 (causes ~50-60% of cases, predominantly squamous cell carcinoma) and HPV 18 (causes ~10-15%, predominantly adenocarcinoma). High-risk viral oncoproteins drive carcinogenesis:
  • E6 oncoprotein: Binds and targets the p53 tumor suppressor protein for ubiquitin-mediated proteasomal degradation.
  • E7 oncoprotein: Binds and inactivates the Retinoblastoma tumor suppressor protein (pRb), displacing E2F transcription factor and driving unrestricted cell cycle entry.
• Screening and Cytology (The Bethesda System): Routine cervical cytology (Pap smear) with high-risk HPV DNA co-testing. Cytologic classifications include ASC-US (atypical squamous cells of undetermined significance), LSIL (low-grade squamous intraepithelial lesion / CIN 1), and HSIL (high-grade squamous intraepithelial lesion / CIN 2, CIN 3, carcinoma in situ).
• Diagnostic Workup: Abnormal cytology warrants Colposcopy with application of 3% to 5% acetic acid (reveals acetowhite changes, punctation, mosaicism, and atypical branching vessels) and endocervical curettage (ECC) with directed cervical biopsies.
• Staging and Principles of Management (FIGO Staging):
  • Stage IA1 (Microinvasive, depth $\le 3\text{ mm}$): Diagnostic cervical conization or simple hysterectomy.
  • Stage IA2 to IIA (Early invasive, confined to cervix or upper 2/3 of vagina without parametrial invasion): Radical Hysterectomy with bilateral pelvic lymphadenectomy (Wertheim procedure) or definitive chemoradiation.
  • Stage IIB to IVA (Locally advanced: parametrial invasion, lower 1/3 of vagina, pelvic sidewall extension, hydronephrosis, or bladder/rectal mucosa invasion): Radical surgery is not the standard treatment. The definitive standard of care is Concurrent Chemoradiation (external beam radiation therapy + intracavitary brachytherapy + weekly radiosensitizing Cisplatin).

Endometrial Carcinoma

• Epidemiology and Clinical Presentation: Most common gynecologic malignancy in developed settings. The cardinal presenting symptom in over 90% of cases is postmenopausal vaginal bleeding.
• Dual Pathogenetic Classification:
  • Type I (Endometrioid Adenocarcinoma, 80-85%): Estrogen-dependent, arising in the background of endometrial hyperplasia (EIN) in perimenopausal or postmenopausal women with prolonged unopposed estrogen exposure (obesity, nulliparity, late menopause, PCOS, tamoxifen therapy). Associated with PTEN inactivation, microsatellite instability (Lynch syndrome). Favorable prognosis.
  • Type II (Serous and Clear Cell Carcinomas, 10-15%): Estrogen-independent, arising in an atrophic endometrium in older postmenopausal women. Associated with p53 mutations. Poorly differentiated, aggressive, high risk of early extrauterine peritoneal dissemination.
• Workup of Postmenopausal Bleeding: Initial diagnostic investigation is Transvaginal Ultrasonography (TVUS) to measure double-layer endometrial stripe thickness:
  • Endometrial stripe $\le 4\text{ mm}$: Exceedingly low risk of malignancy ($> 99\%$ negative predictive value). Biopsy can be safely deferred unless bleeding recurs.
  • Endometrial stripe $> 4\text{ mm}$ (or persistent/recurrent bleeding): Mandates in-office endometrial tissue biopsy (Pipelle biopsy) or fractional D&C.
• Staging and Treatment: Surgically staged via Total Abdominal Hysterectomy with Bilateral Salpingo-Oophorectomy (TAHBSO), pelvic and para-aortic lymphadenectomy, and peritoneal washings.

Ovarian Neoplasms

Ovarian carcinoma is the leading cause of gynecologic cancer mortality due to late presentation at advanced stage (Stage III or IV) with insidious vague symptoms (abdominal bloating, early satiety, pelvic pressure, ascites, and omental caking).

Cervical cancer: screening and FIGO 2018 staging

• Risk factors:
  • persistent high-risk HPV;
  • early sexual debut and multiple partners;
  • smoking;
  • HIV and other immunosuppression;
  • high parity;
  • long-term combined pill use;
  • lack of screening.
• Prevention and screening:
  • HPV vaccination of girls before sexual debut;
  • WHO 2021: primary HPV DNA testing from age 30, every 5 to 10 years, or VIA or cytology where HPV testing is not available;
  • women living with HIV start at 25 and are screened every 3 to 5 years;
  • positive screens are treated by ablation (cryotherapy, thermal ablation) or LEEP, often at the same visit.
• Symptoms: postcoital bleeding, intermenstrual or postmenopausal bleeding and foul discharge. In late disease: pelvic pain, leg edema, uremia from ureteral obstruction (a common cause of death), and vesicovaginal or rectovaginal fistula.
• FIGO 2018 staging:
  • IA: microscopic only. IA1 invades 3 mm deep or less; IA2 more than 3 to 5 mm.
  • IB: confined to the cervix. IB1 is 2 cm or less, IB2 more than 2 to 4 cm, IB3 more than 4 cm.
  • IIA: upper two-thirds of the vagina. IIB: parametrium.
  • IIIA: lower third of the vagina. IIIB: pelvic wall or hydronephrosis. IIIC: lymph nodes (C1 pelvic, C2 para-aortic), shown by imaging or pathology.
  • IVA: bladder or rectal mucosa. IVB: distant metastasis.
• Prognosis: stage is the most important factor. Early disease has high cure rates, while stage III and IV survival is low.
• Fertility-sparing options for very early disease are cone biopsy or radical trachelectomy.

Endometrial cancer: more detail

• Risk factors: the unopposed estrogen factors (obesity, nulliparity, early menarche and late menopause, PCOS, estrogen-only therapy, tamoxifen), plus diabetes, hypertension and Lynch syndrome.
• Protective factors: combined pills, the LNG-IUS, parity and smoking (which is not recommended for this purpose).
• Lynch syndrome (hereditary nonpolyposis colorectal cancer):
  • caused by mismatch-repair gene mutations;
  • lifetime endometrial cancer risk of about 40% to 60%, plus colorectal and ovarian cancer;
  • all endometrial cancers are now tested for mismatch-repair deficiency;
  • carriers are offered hysterectomy with bilateral salpingo-oophorectomy after childbearing.
• Molecular classification (FIGO 2023) refines prognosis: POLE-mutated (excellent), mismatch-repair deficient, p53-abnormal (poor) and no specific molecular profile.
• Treatment: surgery with hysterectomy, bilateral salpingo-oophorectomy and sentinel lymph node mapping, then adjuvant radiation or chemotherapy by risk. Most cases are found early because of postmenopausal bleeding, so overall survival is good.

Ovarian cancer: more detail

• Risk factors:
  • age;
  • BRCA1 or BRCA2 mutations (lifetime risk about 40% and 15% to 20% respectively);
  • Lynch syndrome;
  • nulliparity;
  • endometriosis (clear cell and endometrioid types).
• Protective factors: combined pills, pregnancy, breastfeeding and tubal ligation or salpingectomy.
• Origin: many high-grade serous cancers arise from the fallopian tube fimbriae (serous tubal intraepithelial carcinoma). For this reason opportunistic salpingectomy at other pelvic surgery is encouraged.
• Presentation: vague bloating, early satiety, urinary frequency and pelvic pain. Most present at stage III, with omental caking and ascites.
• Workup: ultrasound, CA-125 and CT. Paracentesis alone is avoided when surgery is planned.
• Treatment:
  • surgical staging and maximal cytoreduction (debulking), with carboplatin plus paclitaxel;
  • neoadjuvant chemotherapy when complete debulking is not feasible;
  • PARP inhibitor maintenance for BRCA-mutated or homologous recombination-deficient tumors.
• Prognosis: five-year survival is high for stage I but poor for stage III and IV. No screening test has been shown to reduce mortality in average-risk women.
• BRCA carriers are offered risk-reducing salpingo-oophorectomy at about 35 to 40 years (BRCA1) or 40 to 45 years (BRCA2), after childbearing.

Vulvar and vaginal cancer; quality of life

• Vulvar cancer:
  • squamous cell carcinoma in older women, often on a background of lichen sclerosus (differentiated VIN), or in younger women with HPV;
  • itch, a lump or an ulcer, often treated as an infection for too long, so biopsy any persistent vulvar lesion;
  • spreads to the inguinofemoral nodes;
  • treated by wide local excision or radical vulvectomy with node assessment (sentinel node).
• Vaginal cancer: usually squamous and HPV-related. Clear cell adenocarcinoma is linked to in utero diethylstilbestrol.
• Survivorship and quality of life:
  • treatment can cause surgical menopause, sexual dysfunction, lymphedema, bowel and bladder problems from radiation, and psychological distress;
  • fertility preservation, hormone management where safe, pelvic floor rehabilitation, sexual health counseling and palliative care, including pain control and management of fistula and bleeding, are part of comprehensive care.