HPV-independent vulvar squamous cell carcinoma (p53-mutant)

Most vulvar squamous cell carcinomas have nothing to do with HPV. They arise in a background of lichen sclerosus or chronic inflammation through the precursor differentiated VIN, a subtle lesion that is easily missed on biopsy, and they carry TP53 mutations in most cases, shown by abnormal p53 immunohistochemistry (overexpression or complete loss); a smaller HPV-independent, p53 wild-type group with NOTCH1 or HRAS mutations sits between the two main types and has an intermediate prognosis. HPV-independent tumours are usually keratinising, occur in women a generation older than those with HPV-associated disease, and in the AGO-CaRE-1 cohort and other series had a markedly higher rate of local recurrence and worse disease-specific survival stage for stage, with recurrences arising years later in the diseased skin around the original tumour.

Surgery is the same stage-based approach as for HPV-associated disease, wide local excision with sentinel node biopsy or lymphadenectomy, but with more attention to margins and to the surrounding field: lichen sclerosus is treated with potent topical steroids, which appears to reduce the risk of cancer, and any new lesion is biopsied. Adjuvant radiotherapy is given for close margins and node-positive disease, and locally advanced tumours receive cisplatin chemoradiotherapy, although p53-mutant tumours respond less completely than p16-positive ones. Recurrent and metastatic disease is treated with carboplatin and paclitaxel, and pembrolizumab is an option for PD-L1-positive tumours; response rates to checkpoint inhibitors are modest and trials combining PD-1 antibodies with lenvatinib or testing cadonilimab enrol both subtypes. Because these tumours share biology with cutaneous squamous cell carcinoma, cemiplimab and epidermal growth factor receptor inhibitors are also being explored.