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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.
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.
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.
Most high-grade ovarian cancers begin at the tip of the fallopian tube; endometrial cancer lines the uterus, cervical cancer starts at the transformation zone; each drains to a different node group.
Same organ: Adenosquamous carcinoma of the cervix, Small cell neuroendocrine carcinoma of the cervix, Bartholin gland carcinoma, Vulvar melanoma, Vaginal melanoma, High-grade serous ovarian cancer, Low-grade serous ovarian cancer, Clear cell ovarian cancer, Mucinous ovarian cancer, Adult granulosa cell tumour of the ovary, Ovarian cancer, Endometrial cancer, Cervical cancer, Vulvar cancer, Gestational trophoblastic neoplasia, Uterine sarcoma, Vaginal cancer, POLE-ultramutated endometrial cancer, Mismatch-repair-deficient endometrial cancer, p53-abnormal endometrial cancer, including uterine serous carcinoma, Endometrial cancer with no specific molecular profile, Advanced or recurrent endometrial cancer, Uterine carcinosarcoma, Early cervical cancer and fertility-sparing surgery, Locally advanced cervical cancer, Recurrent or metastatic cervical cancer, Platinum-sensitive ovarian cancer, Platinum-resistant ovarian cancer, HPV-associated vulvar squamous cell carcinoma, Vaginal squamous cell carcinoma (HPV-associated), Vaginal adenocarcinoma (including DES-associated clear cell adenocarcinoma), Low-risk gestational trophoblastic neoplasia (FIGO score 0 to 6), High-risk gestational trophoblastic neoplasia (FIGO score 7 or more, including ultra-high-risk), Placental-site trophoblastic tumour and epithelioid trophoblastic tumour
Excision of differentiated VIN; long-term potent topical corticosteroids for lichen sclerosus; low threshold for biopsy of new lesions.
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.
Cisplatin chemoradiotherapy with surgery for residual disease; responses are less complete than in p16-positive tumours.
Carboplatin and paclitaxel with or without bevacizumab; pembrolizumab for PD-L1-positive tumours; trials of pembrolizumab with lenvatinib and of cadonilimab.
Lifelong surveillance of the vulvar skin because new tumours arise in the lichen sclerosus field years later.
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The size of the deposit in the sentinel node now decides treatment: radiotherapy for micrometastases, full groin dissection (with or without chemoradiotherapy) for macrometastases.
Women with small, unifocal vulvar cancers and clinically negative groins can be staged with a sentinel node procedure and spared full groin dissection when the node is clear.
Query for this cancer: (TITLE:"HPV-independent vulvar squamous cell carcinoma" OR ABSTRACT:"HPV-independent vulvar squamous cell carcinoma" OR TITLE:"p53-mutant" OR ABSTRACT:"p53-mutant" OR TITLE:"HPV-negative vulvar cancer" OR ABSTRACT:"HPV-negative vulvar cancer" OR TITLE:"p53-abnormal vulvar squamous cell carcinoma" OR ABSTRACT:"p53-abnormal vulvar squamous cell carcinoma" OR TITLE:"Keratinising vulvar carcinoma" OR ABSTRACT:"Keratinising vulvar carcinoma" OR TITLE:"Vulvar cancer arising from differentiated VIN and lichen sclerosus" OR ABSTRACT:"Vulvar cancer arising from differentiated VIN and lichen sclerosus") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about HPV-independent vulvar squamous cell carcinoma (p53-mutant), not a curated reading list.
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Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
Dose by Calvert formula using GFR (see the calculators).
Dose reduce or avoid for CrCl below 60 (carboplatin is the alternative).
See all on the product pages:BevacizumabCarboplatinCisplatinPaclitaxel / nab-paclitaxelPembrolizumab·Printable cards in the navigator
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