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.
The clinical corollary worth committing to memory: HPV-associated/p16-positive vulval SCC has a better prognosis; HPV-independent/p53-aberrant SCC behaves worse. This is now reflected in the ESGO vulvar cancer guideline (2023 update), which endorses HPV/p16 and p53 characterisation as prognostically and biologically meaningful, paralleling the cervical and endometrial moves toward molecularly informed pathology.
| Feature | HPV-associated SCC | HPV-independent SCC |
|---|---|---|
| Driver | High-risk HPV (esp. 16) | TP53 mutation; chronic dermatosis |
| Precursor | HSIL (usual VIN 2–3) | dVIN (± DEVIL/VAAD) |
| p16 IHC | Block-positive | Negative |
| p53 IHC | Wild-type pattern | Aberrant (overexpression or null) |
| Morphology | Warty / basaloid | Keratinising |
| Age | Younger | Older |
| Focality | Often multifocal | Usually unifocal |
| Background skin | Often normal | Lichen sclerosus |
| Prognosis | Better | Worse |
Less common squamous and squamous-related types
Within squamous carcinoma several morphological variants matter. Verrucous carcinoma is a highly differentiated, slow-growing, locally destructive exophytic squamous tumour with a characteristic broad, pushing (rather than infiltrative) advancing front; it rarely metastasises to nodes, is generally HPV-independent, and is treated by wide local excision — radiotherapy is classically avoided because of historical concern over anaplastic transformation, and the diagnosis requires a generous deep biopsy because superficial sampling cannot distinguish it from a benign verrucous lesion or condyloma. Basaloid and warty are the morphological subtypes of HPV-associated SCC noted above.
Non-squamous carcinomas and tumours of the vulva
Figure D13.2 — Histopathological types of vulval cancer: keratinising vs warty/basaloid SCC (~90%), plus melanoma, basal cell carcinoma, Bartholin adenocarcinoma and Paget disease.
The remaining ~10% comprise a diverse group the registrar must be able to list and differentiate.
Vulval (extramammary) Paget disease. An intraepithelial adenocarcinoma of the apocrine-gland–bearing skin, presenting as a chronic, eczematous, well-demarcated, "cake-icing" erythematous plaque that is frequently misdiagnosed and treated as dermatitis for months. Histology shows large pale Paget cells (mucin-positive, CK7-positive) scattered through the epidermis. Most cases are primary intraepithelial disease, but a minority harbour an underlying invasive adnexal adenocarcinoma, and a further subset is secondary to an associated regional adenocarcinoma (anorectal or urothelial) — so a new diagnosis mandates a search for an occult GI/urological primary. It is notorious for histological extension well beyond the clinically visible margin, which is why surgical margins are so often positive.
Melanoma. The second most common vulval malignancy after SCC, accounting for a meaningful minority of vulval cancers and arising from melanocytes of the mucocutaneous junction; see melanoma. It often presents as a pigmented (sometimes amelanotic) lesion and is staged and prognosticated principally by Breslow depth/tumour thickness rather than the FIGO system used for SCC — a key examiner discriminator. Prognosis is generally poor and it is managed in concert with a melanoma/oncology service.
Bartholin gland carcinoma. A rare adenocarcinoma (or squamous, or adenoid cystic) carcinoma arising in the Bartholin gland; suspect it in any solid Bartholin mass in a postmenopausal woman, in whom a "Bartholin cyst" should not simply be marsupialised without histology. Adenoid cystic variants show characteristic perineural spread and late recurrence.
Basal cell carcinoma. The same indolent, locally invasive, essentially non-metastasising skin cancer seen elsewhere; managed by local excision.
Adenocarcinoma otherwise may arise from sweat glands, ectopic breast tissue, or be of mammary-type.
Mesenchymal (sarcomatous) tumours — leiomyosarcoma, epithelioid sarcoma, dermatofibrosarcoma protuberans, rhabdomyosarcoma (the embryonal "sarcoma botryoides" in children) — are rare and are addressed alongside the wider group in gynaecological-sarcomas; they are not "carcinomas" strictly (sarcoma = mesenchymal, carcinoma = epithelial), and the examiner will reward that distinction.
Patterns of spread (shared across types)
Figure D13.3 — Local growth and orderly inguinofemoral lymphatic spread: nodal status as the key prognostic factor, and the sentinel-node concept (ESGO 2023 / GROINSS-V II).
Vulval SCC spreads by direct extension to adjacent structures (urethra, vagina, anus) and, critically, by lymphatic spread to the inguinofemoral nodes first, then to pelvic nodes — this orderly, predictable, stepwise nodal drainage is the anatomical basis of sentinel-node assessment (below). Haematogenous spread is late. Nodal status is the single most powerful prognostic factor in vulval SCC.
Assessment
History and examination
A vulval lump, ulcer, persistent pruritus, bleeding, pain or a non-healing lesion in an older woman should always prompt examination and a biopsy — never empirical creams alone. In younger women the presentation is increasingly HPV-driven HSIL/early invasion, often in the setting of known HIV, prior abnormal cervical screening, or multicentric lower-genital-tract disease. Document lesion site, size, distance from and involvement of the midline/clitoris/urethra/anus, and palpate both groins for nodes. Examine the cervix and vagina because of field cancerisation; offer/confirm HIV testing.
Biopsy — the decisive step
Diagnosis is histological and the typing depends on it. The mandatory investigation is an adequate incisional/keyhole punch biopsy that includes the dermis and the lesion–normal-skin interface so the pathologist can judge depth of invasion and read the background dermatosis. Excisional biopsy of the whole lesion before staging is discouraged because it can obliterate the anatomy needed to plan definitive surgery and sentinel-node mapping. The pathology request should ask explicitly for the WHO 2020 type, depth of invasion (mm), and HPV/p16 plus p53 status, because — as above — these define the two squamous pathways and carry prognostic weight under the ESGO 2023 guideline. In South Africa this tissue work is delivered through NHLS laboratories; p16 immunohistochemistry is widely available, HPV genotyping less uniformly so, and p53 IHC is the practical surrogate for the HPV-independent pathway.
Staging work-up
Vulval SCC is staged by the FIGO/TNM system (a clinicopathological system distinct from the depth-based staging used for melanoma). Stage hinges on tumour size, extension to adjacent perineal structures, and — dominantly — nodal involvement, including the number, size and presence of extracapsular spread of inguinofemoral node metastases, with distant/pelvic-node disease defining the highest stage. Imaging (groin ultrasound ± fine-needle aspiration of suspicious nodes, MRI of the pelvis for local extent, and CT/PET for advanced disease) supports clinical staging. Because the exact FIGO numerical cut-offs and stage groupings are not reproduced in the verified-source material available to me, the prudent exam answer states the principles (size, local extension, nodal burden) and the dominant prognostic role of nodal status rather than quoting specific stage numbers — and confirms the current FIGO/TNM cut-offs against the primary document before asserting them.
Management
Management is governed by the ESGO Guidelines for vulvar cancer (2023 update), and is type- and stage-dependent — which is precisely why correct histopathological typing precedes treatment.
Precursor lesions
HSIL (HPV-associated) may be treated with wide local excision, laser ablation, or topical imiquimod, with surveillance, because of the multifocal field risk. dVIN, by contrast, should be excised — its rapid progression to HPV-independent SCC and its association with occult invasion make ablation/medical therapy inappropriate. Treating the underlying lichen sclerosus with potent topical steroids and maintaining long-term surveillance is part of cancer prevention in the HPV-independent pathway.
Early invasive squamous carcinoma
The principle is wide local excision to clear margins with appropriate groin assessment. The pivotal modern refinement is sentinel lymph node biopsy (SLNB), endorsed by ESGO 2023 for unifocal tumours <4 cm with clinically (and radiologically) negative groins — sparing the substantial morbidity (lymphoedema, wound breakdown) of full inguinofemoral lymphadenectomy in node-negative women. Groin treatment is indicated for tumours beyond the most superficially invasive category (i.e. more than minimally invasive "T1a"–type disease). The GROINSS-V II study refined sentinel-node-positive management: where the sentinel node shows micrometastasis ≤2 mm, groin radiotherapy can replace completion inguinofemoral lymphadenectomy; macrometastasis >2 mm still mandates lymphadenectomy ± radiotherapy. When adjuvant radiotherapy is indicated, it should start promptly — ESGO highlights that the interval from surgery to completion of radiotherapy should ideally be under ~104 days, as delay worsens outcome.
Locally advanced and advanced disease
Larger or anatomically unfavourable tumours (involving urethra, anus or requiring exenterative surgery for clearance) are managed with (chemo)radiation, often to downstage before more conservative surgery and to preserve sphincter/urethral function, in a multidisciplinary setting with clinical and radiation oncology — conceptually analogous to the chemoradiation paradigm established for locally advanced cervical disease, though the vulval evidence base is far smaller. Recurrent and metastatic disease has limited systemic options; given the HPV-driven biology of the HPV-associated subtype, immune-checkpoint approaches are of investigative interest but are not established standard-of-care for vulval cancer in the verified guidance here, and should not be quoted as routine.
Non-squamous types
Paget disease requires wide excision (with the caveat of frequent positive margins from subclinical spread) and exclusion of an underlying invasive adnexal or visceral adenocarcinoma. Melanoma is managed with the melanoma service by wide excision guided by Breslow thickness ± sentinel-node assessment. Bartholin gland carcinoma needs radical excision ± groin management and is easily missed when a solid mass in an older woman is mistaken for a simple cyst.
South African service context
Care is concentrated in tertiary gynae-oncology units with NHLS pathology support; the prevention end of the spectrum is national — HPV vaccination (school-based girls' programme since 2014, moving toward single-dose, nonavalent cover) reduces the HPV-associated pathway, and the SASOG/BetterGyn (2024) cervical-screening framework with the NDoH cervical-cancer policy identifies the HIV-positive, HPV-exposed women who are simultaneously at highest risk of HPV-associated vulval disease — they should have a thorough vulval and lower-genital-tract examination, not a cervix-only review. Optimising HIV control (TLD-based ART under the SA HIV guidelines) is part of reducing HPV-associated neoplastic risk.
Red flags / pitfalls
- Treating a vulval lesion as dermatitis without biopsy. A persistent vulval ulcer, plaque or pruritic lesion — especially Paget's "eczema that won't settle" — must be biopsied. Months of topical steroid on an unbiopsied lesion is a recurring medico-legal pitfall.
- Missing dVIN. It is bland and easily under-called histologically, yet it is the precursor with the highest and fastest malignant potential. If lichen sclerosus shows any atypia, escalate review and excise — do not ablate.
- Forgetting the HPV/p16 + p53 work-up. Without typing you cannot prognosticate or contextualise the disease; p16-positive and p53-aberrant tumours behave differently. Always request both.
- Marsupialising a solid "Bartholin cyst" in a postmenopausal woman without histology — Bartholin gland carcinoma hides here.
- Confusing carcinoma with sarcoma. Mesenchymal vulval tumours are sarcomas, not carcinomas; keep the epithelial/mesenchymal distinction crisp (see gynaecological-sarcomas).
- Inadequate superficial biopsy of verrucous carcinoma, which then reads as benign condyloma — take a deep biopsy.
- Cervix-only thinking in HIV-positive women. Multifocal HPV field disease means the vulva, vagina and anus all need examination, not just the cervix.
- Doing a full groin dissection when SLNB would suffice (unifocal <4 cm, node-negative) — unnecessary lymphoedema and wound morbidity.
Evidence anchors
- WHO Classification of Tumours of the Female Genital Tract, 5th edition (2020) — the histological-typing framework for all vulval tumours; defines HPV-associated versus HPV-independent squamous carcinoma and the LSIL/HSIL terminology (HSIL ≈ usual VIN 2–3) replacing the older CIN/VIN grading in pathology.
- ESGO Guidelines for vulvar cancer — Update 2023 (Int J Gynecol Cancer) — sentinel lymph node biopsy for unifocal tumours <4 cm with clinically negative groins; groin treatment for disease beyond T1a; prompt adjuvant radiotherapy (surgery→RT completion ideally <104 days).
- GROINSS-V II — with sentinel-node micrometastasis ≤2 mm, groin radiotherapy may replace inguinofemoral lymphadenectomy; macrometastasis >2 mm still requires lymphadenectomy ± RT.
- South African cervical cancer screening — SASOG/BetterGyn Clinical Guideline (2024) + NDoH National Cervical Cancer Screening / Prevention & Control Policy — identifies the HIV-positive, HPV-exposed population at shared risk for HPV-associated vulval disease; HIV-positive women screened at diagnosis and more frequently regardless of age.
- WHO Cervical Cancer Elimination Strategy (2020) — 90-70-90 by 2030, single-dose and nonavalent HPV vaccination (SA school-based programme since 2014) — primary prevention of the HPV-associated squamous pathway shared with the cervix.
- South African National HIV/ART Consolidated Guidelines (2023) — TLD first-line; HIV control as part of reducing HPV-associated neoplastic risk.
Uncertainty flagged for the reader: exact FIGO/TNM stage cut-offs for vulval carcinoma and the routine role (if any) of checkpoint immunotherapy in advanced vulval cancer are not specified in the verified-source set used here and should be confirmed against the current primary documents before being quoted.