HPV-associated vulvar squamous cell carcinoma

The 2020 WHO classification splits vulvar squamous cell carcinoma into HPV-associated and HPV-independent disease because the two arise by different routes and behave differently. HPV-associated tumours follow persistent high-risk HPV infection, above all type 16, through the precursor high-grade squamous intraepithelial lesion (usual-type VIN), often in women who smoke or are immunosuppressed and often alongside cervical or anal HPV disease. They are basaloid or warty under the microscope, express p16 diffusely and keep wild-type p53. Large series and the AGO-CaRE-1 cohort have shown that p16-positive tumours have fewer local recurrences and better survival than p53-mutant tumours, and that they respond more completely to radiotherapy, which is why molecular subtype is now part of the pathology report even though it does not yet change first treatment.

Treatment follows stage rather than subtype. Usual-type VIN is excised or treated with imiquimod, with trials of topical agents such as artesunate under way; early cancers are removed by wide local excision with sentinel node biopsy for tumours under four centimetres with more than a millimetre of invasion (GROINSS-V I), and GROINSS-V II showed that groin radiotherapy can replace lymphadenectomy when the sentinel node metastasis is two millimetres or smaller. Locally advanced disease is treated with cisplatin chemoradiotherapy (GOG 205) to avoid exenterative surgery, and recurrent or metastatic disease with carboplatin and paclitaxel, with pembrolizumab available for PD-L1-positive tumours after chemotherapy on the strength of the KEYNOTE-158 vulvar cohort. Trials now test PD-1 antibodies with lenvatinib or with the PD-1 and CTLA-4 bispecific cadonilimab in recurrent disease, and the nonavalent HPV vaccine prevents the infections that start the disease.