Teaching pack: Vulvar cancer

Vulvar squamous cell carcinoma has two pathways: HPV-associated (usual-type VIN, p16-positive, younger patients, better prognosis) and HPV-independent (differentiated VIN arising in lichen sclerosus, p53-mutant, older patients, higher recurrence). Rarer histologies include melanoma, Bartholin gland adenocarcinoma, Paget disease and basal cell carcinoma. Nodal status is the dominant prognostic factor.

Early disease is treated with radical local excision and sentinel lymph node biopsy (GROINSS-V I established safety for tumours <4 cm with unifocal disease, replacing inguinofemoral lymphadenectomy and its lymphoedema in most); GROINSS-V II showed radiotherapy can replace lymphadenectomy for micrometastases ≤2 mm. Locally advanced disease receives chemoradiation (cisplatin-based, GOG 205/279) to avoid exenteration. Metastatic or recurrent disease has limited options: platinum-based chemotherapy, pembrolizumab for PD-L1-positive or TMB-high disease (KEYNOTE-158), cemiplimab in trials, and, for HPV-independent p53-mutant disease, no targeted therapy.

• Sentinel-node biopsy and radiotherapy for micrometastases (GROINSS-V I/II) have removed lymphadenectomy morbidity for most early patients.
• Molecular classification (HPV/p16 vs p53) is entering staging and predicts recurrence better than stage alone.
• Chemoradiation avoids exenteration in most locally advanced disease.
• Systemic therapy remains borrowed from cervical cancer; dedicated trials are few.

1. 1912Basset describes radical vulvectomy with en bloc lymphadenectomy
2. 1990Separate groin incisions replace en bloc dissection
3. 2008GROINSS-V I: sentinel node biopsy safe in early vulvar cancer
4. 2016HPV-independent vs HPV-associated pathways defined (WHO 2020 adopts)
5. 2021GROINSS-V II: radiotherapy for sentinel micrometastases
6. 2021GOG 279: cisplatin-gemcitabine chemoradiation for locally advanced disease

• Pembrolizumab (treatment)
• Cemiplimab (treatment)
• Lorigerlimab (treatment)

• Evaluate the Efficacy, Immunogenicity and Safety of 9-valent HPV Recombinant Vaccine in Chinese Healthy Females (phase 3, n=8,000): result not yet recorded
• KEYNOTE-158 (phase 2, n=1,609): Objective response rate, biliary adenocarcinoma cohort (independent central review): 5.8%
• Electrochemotherapy With Carboplatinum Plus Bleomycin Versus Bleomycin Alone in Vulvar Cancer (phase 2, n=92): result not yet recorded
• Pembrolizumab Combination With Lenvatinib in Pts With Recurrent,Persistent,Metastatic or Locally Advanced Vulvar Cancer Not Amenable to Curative Surge (phase 2, n=42): result not yet recorded
• AK104 for Recurrent or Metastatic Vulvar Cancer (phase 2, n=20): result not yet recorded
• Phase II Study of Artesunate Ointment for the Treatment of Vulvar High Grade Squamous Intraepithelial Lesions (Vulvar HSIL, VIN2/3) (phase 2, n=27): result not yet recorded

• HPV-independent p53-mutant disease recurs often and has no targeted therapy.
• Lichen sclerosus surveillance and prevention of malignant transformation.
• Few dedicated trials; therapy extrapolated from cervical cancer.
• Psychosexual morbidity after treatment.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.

• NCCN Guidelines: Vulvar Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476
• GROINSS-V II (JCO 2021): https://doi.org/10.1200/JCO.21.00006
• NCI PDQ: vulvar cancer: https://www.cancer.gov/types/vulvar/patient/vulvar-treatment-pdq
• Wikipedia: https://en.wikipedia.org/wiki/Vulvar_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476