Vulva, vagina & female urethra

Squamous carcinoma and precursor lesions

HPV independent squamous cell carcinoma

Last author update: 1 September 2014
Last staff update: 1 March 2023

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PubMed Search: Verrucous carcinoma [title] vulva

Priya Nagarajan, M.D., Ph.D.
Sara B. Peters, M.D., Ph.D.
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Cite this page: Nagarajan P, Peters SB. HPV independent squamous cell carcinoma. website. Accessed September 26th, 2023.
Definition / general
  • Not a common tumor
  • Verrucous carcinoma was first described in 1948 in the oral cavity (Surgery 1948;23:670)
  • Though verrucous carcinoma has traditionally been considered to be in the spectrum of giant condylomas histologically, recent studies have suggested that verrucous carcinomas are distinct entities with a non human papillomavirus (HPV) etiology (Am J Surg Pathol 2004;28:638, Int J Gynecol Cancer 2003;13:317)
  • Most common in elderly, postmenopausal women
  • Almost all lesions in younger women with similar features are giant condyloma or warty carcinoma / basaloid carcinoma
  • Most commonly affected sites are labium majora > labia minora > posterior commissure
Clinical features
  • Slow growing firm mass, usually accompanied by pruritus and occasionally pain and discharge (especially if large, ulcerated or infected)
  • Histologic examination alone can be misleading due to superficial sampling or lack of an obvious invasive component
  • Therefore, clinical history indicating exophytic tumor in an elderly woman is often helpful
Radiology description
Radiology images

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Abdominal pelvic CT

Prognostic factors
  • Most important prognostic factors are depth of invasion and surgical margin status
  • Local recurrence is common (30 - 50%), especially after resection with inadequate margins (Br J Dermatol 2000;142:1195)
Case reports
  • Usually excision by partial, simple or radical vulvectomy, with or without inguinal or femoral lymphadenectomy
  • Local radiotherapy may be used as an adjuvant but has been associated with development of higher grade squamous cell carcinoma
  • Systemic acitretin treatment (dose: 25 mg/day, for 4 - 6 weeks) is effective, with tumor regression in most patients (Br J Dermatol 2000;142:1195)
  • Chemotherapy (cisplatin, bleomycin, methotrexate and leucovorin) (Eur J Gynaecol Oncol 2011;32:680)
Gross description
Gross images

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Microscopic (histologic) description
  • Exo-endophytic, well circumscribed tumor composed of closely packed papillary structures lined by well differentiated stratified squamous epithelium, with minimal cellular atypia
  • By definition, no invasion by clusters or single tumors cells should be present
  • Epithelium demonstrates prominent acanthosis with (bulbous) expansion of rete ridges that push into the dermis / submucosa with rounded borders or a broad front
  • In tangentially cut sections, the tumor is composed of large, back to back nests of well differentiated squamous epithelium
  • Massive hyperkeratosis and parakeratosis is present
  • Cells have abundant pale, eosinophilic cytoplasm with low nuclear to cytoplasmic ratio, no / mild nuclear pleomorphism, basally located mitotic figures
  • Mild to moderate chronic inflammation in stroma is common
  • If infection / ulceration, neutrophils may be prominent
  • Lymphovascular and perineural invasion are extremely rare
  • Coexisting non human papillomavirus (HPV) associated carcinomas of higher grade or precursors are not uncommon and should therefore be ruled out (Am J Surg Pathol 2004;28:638)
  • Background lichen simplex chronicus with diffuse verrucous features or lichen sclerosus may be seen; VIN is not usually present
Microscopic (histologic) images

Contributed by Priya Nagarajan, M.D., Ph.D.

Verrucous carcinoma of vulva

Verrucous carcinoma of vulva

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Globoid projections

Exophytic growth

Mild atypia

Cytology description
Positive stains
  • Ki67 proliferation index is variably increased but in 70 - 80% of cases, Ki67 expression is localized to basal layer of squamous epithelium
Negative stains
Molecular / cytogenetics description
Differential diagnosis
  • Giant condyloma acuminatum:
    • Predominantly exophytic
    • Human papillomavirus (HPV) associated cytopathic effects of koilocytes (wrinkled or raisinoid nuclei, perinuclear halo, multinucleation, suprabasal mitoses) are easily identified
    • HPV nucleic acids demonstrated by in situ hybridization (Arch Gynecol Obstet 2013;287:1047)
  • Other keratinizing squamous cell carcinomas:
    • Demonstrate at least focal stromal invasion by single cells or small clusters of tumors cells
    • Cellular atypia may be prominent
    • Variable differentiation
    • Rare metastases to regional lymph nodes
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