Squamous cell carcinoma (SCC) is a keratinocyte-derived carcinoma that occurs most frequently on sun-exposed areas such as the face and hands. However, SCC may also occur on the female genitalia of older individuals. It is the most common vulvar neoplasm and accounts for 85%-95% of vulvar cancers, which have an annual incidence and mortality of 6000 and 1200 cases in the United States, respectively. Anal cancer, of which SCC comprises a majority, newly afflicts 5600 women and is fatal in another 700 each year in the United States.

Almost one-third of patients with vulvar tumors present with locally advanced disease, usually resulting from late presentation due to older age, lack of access to medical care, or perceived embarrassment regarding tumor location. Late-stage tumors are more difficult to treat and may require radical surgical intervention.

The clinical presentation is variable. SCC often presents as a hyperkeratotic papule or nodule that may ulcerate, but it may also be smooth, plaque-like, exophytic, or papillomatous. Lesions are often red to skin colored. Secondary changes such as scale, crust, erosion, and ulceration may be present. The progression of lesions over time varies. Some enlarge slowly, while others progress rapidly to grow, infiltrate deeper tissue, and metastasize. Pain and tenderness can be present. Anal carcinomas may also present with rectal bleeding and a sensation of an object in the rectum.

The pathogenesis of SCC is multifactorial. It may evolve from intraepithelial neoplasia (including vulvar intraepithelial neoplasia or anal intraepithelial neoplasia) or arise de novo. TP53, CDKN2A, PIK3CA, HRAS, NOTCH1, TERT promoter, and FBXW7 gene mutations have been implicated. Any repetitive trauma or insult increases the risk of SCC. Additional risk factors for anogenital SCC include smoking, sexually transmitted infections, HIV infection, human papillomavirus (HPV) infection, poor genital hygiene, anogenital injury, lichen sclerosus, and erosive lichen planus.

Recent genomic studies highlight distinct mutational landscapes of HPV-associated and HPV-independent anogenital SCCs. In vulvar and vaginal SCC, TP53 mutations are the most common genetic alteration in HPV-independent tumors. These often co-occur with CDKN2A and NOTCH1 mutations and correlate with aggressive histology and poorer survival. TERT promoter mutations are also frequent in HPV-independent disease and may represent early initiating events.

Conversely, PIK3CA mutations predominate in HPV-associated SCCs. HRAS mutations, present in a subset of HPV-negative vulvar SCC, have been linked to worse clinical outcomes.

Related topics: bowenoid papulosis, squamous cell carcinoma in situ