Clinical overview
Vulval cancer is uncommon — roughly 4% of all gynaecological malignancies — but it carries disproportionate clinical weight for the South African registrar for two reasons. First, it is overwhelmingly a disease of the squamous epithelium, and its commonest aetiology in our population is the same high-risk human papillomavirus (HPV) that drives cervical disease, layered onto an HIV prevalence among the highest in the world. Younger HIV-positive women with multifocal HPV-associated high-grade squamous intraepithelial lesions (HSIL) of the lower genital tract now form a recognisable clinic population, and a proportion progress to invasive squamous carcinoma at an age far below the classical sixth-to-eighth-decade peak. Second, the histopathological type is not a piece of trivia — it dictates aetiology, the precursor lesion you should have caught, the expected behaviour, the role of HPV and p53, and increasingly the systemic options. A p16-positive HPV-associated squamous carcinoma in a 38-year-old woman with CD4 of 150 is a fundamentally different disease from an HPV-independent, p53-mutant squamous carcinoma arising in longstanding lichen sclerosus in a 76-year-old — even though both are "squamous cell carcinoma of the vulva".
This chapter addresses the objective directly: the histopathological types of vulval carcinoma, their precursors, their molecular drivers, and how typing changes diagnosis and management. The unifying framework is the WHO Classification of Tumours of the Female Genital Tract, 5th edition (2020), which reorganised vulval squamous lesions and carcinomas explicitly around HPV status — HPV-associated versus HPV-independent — mirroring the same dualism now embedded in cervical and head-and-neck pathology.
Core knowledge
The dominant type: squamous cell carcinoma and its two pathways
Figure D13.1 — The two pathways to vulval squamous carcinoma: HPV-associated (usual-type VIN, p16, younger) vs HPV-independent (dVIN on lichen sclerosus, p53, older).
Around 90% of vulval carcinomas are squamous cell carcinomas (SCC). The single most important conceptual shift in the WHO 2020 classification is that vulval SCC is not one disease but two biologically distinct entities defined by HPV status, each with its own precursor, demographic, morphology and prognosis.
HPV-associated (HPV-dependent) squamous carcinoma. This arises through transforming infection with high-risk HPV, predominantly HPV-16 (and to a lesser extent 18, 33 and others), exactly as for the cervix. The viral oncoproteins E6 and E7 inactivate p53 and Rb respectively; E7-driven Rb loss causes reactive over-expression of p16^INK4a^, so these tumours are diffusely (block-positive) p16 immunoreactive — p16 is the workhorse surrogate marker for HPV transcriptional activity. The precursor is vulval HSIL (the WHO 2020/LAST term; equivalent to the older VIN 2–3, "usual-type VIN" or warty/basaloid VIN). Note the deliberate use of LSIL/HSIL terminology: low-grade squamous intraepithelial lesion (LSIL ≈ flat condyloma / VIN 1, not a true neoplastic precursor) and high-grade squamous intraepithelial lesion (HSIL ≈ VIN 2–3, the genuine precursor). Morphologically these cancers are warty or basaloid, occur in younger women, are frequently multifocal and associated with multicentric lower-genital-tract neoplasia (cervix, vagina, anus — hence the field-cancerisation concept), and link strongly to smoking, immunosuppression and HIV. In the South African context this is the pathway amplified by the HIV epidemic, and it is the type most relevant to the WHO 90-70-90 cervical-cancer-elimination logic and to nonavalent HPV vaccination, both of which cover the same oncogenic genotypes that cause this vulval type.
HPV-independent squamous carcinoma. This arises through HPV-negative pathways, most often on a background of chronic dermatosis — lichen sclerosus (see Lichen sclerosus) and, less commonly, lichen planus or longstanding squamous hyperplasia. The defining molecular event is TP53 mutation in the majority, giving an aberrant p53 immunostain (either strong/diffuse overexpression or complete "null" loss), and these tumours are p16-negative. The precursor is differentiated VIN (dVIN) — a deceptively bland, well-differentiated intraepithelial lesion that is easily missed histologically yet carries a higher and faster malignant potential than HSIL. WHO 2020 also recognises a third, more recently characterised HPV-independent precursor, differentiated exophytic vulvar intraepithelial lesion / vulvar acanthosis with altered differentiation (DEVIL/VAAD), which may be p53-wild-type. HPV-independent SCC is typically keratinising, occurs in older women (seventh-to-eighth decades), is usually unifocal, and — importantly — has a worse prognosis with higher local recurrence than its HPV-associated counterpart at equivalent stage. The p53-aberrant subgroup is the most aggressive.