{"entity":{"id":"hpv-independent-vulvar-cancer","kind":"cancer","name":"HPV-independent vulvar squamous cell carcinoma (p53-mutant)","aka":["HPV-negative vulvar cancer","p53-abnormal vulvar squamous cell carcinoma","Keratinising vulvar carcinoma","Vulvar cancer arising from differentiated VIN and lichen sclerosus"],"tldr":"HPV-independent vulvar cancer is the commoner type of vulvar squamous cell cancer, arising in older women from the chronic skin condition lichen sclerosus rather than from HPV, and marked by faults in the p53 gene. It recurs locally far more often than the HPV type, so treatment centres on complete surgical removal, control of the surrounding skin disease and long follow-up.","summary":"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.\n\nSurgery 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.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Vulvar_cancer","links":[{"label":"NCCN Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Vulvar_cancer"}],"tags":["subtype-page","gynaecologic"],"related":["hpv-associated-vulvar-cancer","vulvar","cutaneous-scc"],"cancers":[],"sections":[],"technologies":["sentinel-node","imrt-igrt","checkpoint-inhibitor","precancer-ablation"],"targets":["tp53","pd1"],"drugs":["cisplatin","carboplatin","paclitaxel","bevacizumab","pembrolizumab","cemiplimab"],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-p16","cps","lymphadenectomy","chemoradiation"],"trials":["nct05903833","nct05932212"],"people":[],"bottlenecks":[],"keyPapers":["paper-groinss-v-ii-radiotherapy-vulvar-micrometastases-jco-2021","paper-groinss-v-sentinel-node-vulvar-cancer-jco-2008"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"The majority of vulvar squamous cell carcinomas, typically in women over 70 with long-standing lichen sclerosus; the subtype with the highest local recurrence rate.","subtypes":["Differentiated vulvar intraepithelial neoplasia (dVIN, HPV-independent precursor)","HPV-independent p53-mutant vulvar squamous cell carcinoma (keratinising)","HPV-independent p53 wild-type vulvar squamous cell carcinoma (NOTCH1 or HRAS mutant, intermediate prognosis)","Verrucous carcinoma of the vulva (locally destructive, rarely metastatic)","Vulvar cancer with lichen sclerosus (field at risk of further tumours)"],"biomarkers":["p53 immunohistochemistry (mutant patterns: overexpression, null, cytoplasmic)","p16 immunohistochemistry (negative)","TP53 sequencing where immunohistochemistry is equivocal","NOTCH1 and HRAS mutations (p53 wild-type HPV-independent group)","Margin status and presence of differentiated VIN or lichen sclerosus at the margin","PD-L1 combined positive score"],"standardOfCare":[{"setting":"Precursor (differentiated VIN) and lichen sclerosus","approach":"Excision of differentiated VIN; long-term potent topical corticosteroids for lichen sclerosus; low threshold for biopsy of new lesions.","refs":["precancer-ablation"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Early stage","approach":"Wide local excision with attention to margins, sentinel node biopsy or inguinofemoral lymphadenectomy by the GROINSS-V criteria; adjuvant radiotherapy for close margins or positive nodes.","refs":["sentinel-node","lymphadenectomy","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Locally advanced disease","approach":"Cisplatin chemoradiotherapy with surgery for residual disease; responses are less complete than in p16-positive tumours.","refs":["cisplatin","imrt-igrt","chemoradiation"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Recurrent or metastatic disease","approach":"Carboplatin and paclitaxel with or without bevacizumab; pembrolizumab for PD-L1-positive tumours; trials of pembrolizumab with lenvatinib and of cadonilimab.","refs":["carboplatin","paclitaxel","bevacizumab","pembrolizumab","nct05903833","nct05932212"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Follow-up","approach":"Lifelong surveillance of the vulvar skin because new tumours arise in the lichen sclerosus field years later.","refs":["hpv-p16"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}}],"stateOfArt":["p53 immunohistochemistry identifies the high-recurrence subtype at diagnosis.","Treating lichen sclerosus with topical steroids is the one preventive measure with supporting evidence.","Systemic options remain those borrowed from cervical and skin squamous cell carcinoma."],"history":[{"year":1961,"title":"Differentiated VIN described as a distinct precursor of keratinising vulvar carcinoma","refs":[]},{"year":2015,"title":"Treatment of lichen sclerosus with topical steroids associated with fewer vulvar cancers in a prospective cohort","refs":[]},{"year":2020,"title":"WHO classification defines HPV-independent vulvar squamous cell carcinoma; p53-mutant and wild-type groups recognised","refs":["hpv-p16"]},{"year":2021,"title":"GROINSS-V II node management applies to both subtypes","refs":["sentinel-node"]}],"pipeline":["pembrolizumab","cemiplimab","nct05903833","nct05932212"],"openProblems":["Differentiated VIN is hard to recognise and is often diagnosed only next to an invasive cancer.","Whether wider margins or adjuvant radiotherapy prevent the frequent local recurrences has not been tested prospectively.","p53-mutant tumours are relatively radioresistant and have no targeted therapy.","Older patients are under-represented in the few trials that exist."],"parent":"vulvar"},"route":"/cancers/hpv-independent-vulvar-cancer/","neighbours":{"cancer":[{"id":"cutaneous-scc","kind":"cancer","name":"Cutaneous squamous cell carcinoma","route":"/cancers/cutaneous-scc/"},{"id":"hpv-associated-vulvar-cancer","kind":"cancer","name":"HPV-associated vulvar squamous cell carcinoma","route":"/cancers/hpv-associated-vulvar-cancer/"},{"id":"vulvar","kind":"cancer","name":"Vulvar cancer","route":"/cancers/vulvar/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"imrt-igrt","kind":"technology","name":"IMRT / IGRT (modern external beam)","route":"/technologies/imrt-igrt/"},{"id":"sentinel-node","kind":"technology","name":"Sentinel lymph node biopsy","route":"/technologies/sentinel-node/"},{"id":"precancer-ablation","kind":"technology","name":"Thermal ablation and cryotherapy for cervical precancer","route":"/technologies/precancer-ablation/"}],"target":[{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"bevacizumab","kind":"drug","name":"Bevacizumab","route":"/drugs/bevacizumab/"},{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"cemiplimab","kind":"drug","name":"Cemiplimab","route":"/drugs/cemiplimab/"},{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"id":"paclitaxel","kind":"drug","name":"Paclitaxel / nab-paclitaxel","route":"/drugs/paclitaxel/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"term":[{"id":"chemoradiation","kind":"term","name":"Chemoradiation (chemoradiotherapy, CRT)","route":"/terms/chemoradiation/"},{"id":"cps","kind":"term","name":"Combined positive score (CPS)","route":"/terms/cps/"},{"id":"hpv-p16","kind":"term","name":"HPV-positive (p16) head and neck cancer","route":"/terms/hpv-p16/"},{"id":"lymphadenectomy","kind":"term","name":"Lymphadenectomy (lymph node dissection)","route":"/terms/lymphadenectomy/"}],"trial":[{"id":"nct05932212","kind":"trial","name":"AK104 for Recurrent or Metastatic Vulvar Cancer","route":"/trials/nct05932212/"},{"id":"nct05903833","kind":"trial","name":"Pembrolizumab Combination With Lenvatinib in Pts With Recurrent,Persistent,Metastatic or Locally Advanced Vulvar Cancer Not Amenable to Curative Surge","route":"/trials/nct05903833/"}],"paper":[{"id":"paper-groinss-v-ii-radiotherapy-vulvar-micrometastases-jco-2021","kind":"paper","name":"GROINSS-V II: radiotherapy versus inguinofemoral lymphadenectomy for vulvar cancer with sentinel node micrometastases","route":"/key-papers/paper-groinss-v-ii-radiotherapy-vulvar-micrometastases-jco-2021/"},{"id":"paper-groinss-v-sentinel-node-vulvar-cancer-jco-2008","kind":"paper","name":"GROINSS-V: sentinel node dissection is safe in early-stage vulvar cancer","route":"/key-papers/paper-groinss-v-sentinel-node-vulvar-cancer-jco-2008/"}]}}