Vulvar Squamous Cell Carcinoma is a Multifactorial Disease Following Two Separate and Independent Pathways

Abstract

Two separate pathways leading to vulvar carcinoma have been suggested. First, a human papillomavirus (HPV)-dependent pathway, in which premalignant stages of vulvar cancer are the classic vulvar intraepithelial neoplasia (VIN) lesions. Second, an HPV-independent pathway, associated with differentiated VIN III lesions and/or lichen sclerosus. To obtain insight into the mechanisms underlying these pathways, we determined the relationship between HPV DNA and the expression of p14(ARF) and p16(INK4A) in non- and (pre)malignant vulvar lesions. Seventy-three archival samples of non- and (pre)neoplastic vulvar lesions were selected and tested for hr-HPV DNA using a broad-spectrum HPV detection/genotyping assay (SPF(10)-LiPA) and the expression of p14(ARF) and p16(INK4A). The prevalence of HPV increased with the severity of the classic VIN lesions; in VIN I no hr-HPV was detected, in VIN II 43%, and in VIN III 71% of the samples were hr-HPV-positive. Roughly the same was true for the expression of p14(ARF) and p16(INK4A). The simultaneous expression of p14(ARF) and p16(INK4A) was highly associated with the presence of hr-HPV DNA. Hr-HPV was detected in only a single case of the differentiated VIN III lesions, whereas no expression of p14(ARF) was found and 16(INK4A) was present in only two cases. All 16 samples of vulvar cancer were hr-HPV DNA- negative, although in respectively 63% and 25%, p14(ARF) and p16(INK4A) was expressed. No relation was found between hr-HPV and the expression of p14(ARF) and p16(INK4A) in the 20 nonneoplastic vulvar lesions. Our results provide further evidence that vulvar squamous cell carcinoma is a multifactorial disease that develops from two different pathways. First, an HPV-dependent pathway with a remarkable resemblance to CIN lesions and cervical carcinoma and second, an HPV-independent pathway in which differentiated VIN III lesions that are hr-HPV-negative may be precursors.

HPV Detection and Genotyping in Vulvar Squamous Cell Carcinoma in Northern Thailand

“…However, the incidence rate of vulvar cancer does not always correlate with that of cervical cancer in the other regions such as Uganda and Zimbabwe, where there is a very high incidence of cervical cancer 3) but a rather low incidence of vulvar cancer (ASR 0.3-0.7) (Curado et al, 2007). The explanation for geographic variation of the incidence of vulvar cancer remains unclear, although this could be partly due to heterogenous etiologies of vulvar cancer (van der Avoort et al, 2006). The incidence of vulvar cancer in our region was only slightly lower than the overall ASR of 1.4 in the United States (SEER, 14 registries) and in Canada (Curado et al, 2007).…”

“…Recent information in the literature indicates that there are 2 different pathogenic pathways of vulvar SCC, one is associated with HPV infection whereas the other is not (Del Pino et al, 2013). In the HPV-associated pathway, vulvar SCC evolves from ususal-type VIN (van der Avoort et al, 2006). In the other pathway unassociated with HPV infection, vulvar SCC is mostly of keratinizing type and is associated with p53 mutations (Pinto et al, 2010;Del Pino et al, 2013).…”

MIB1 expression in basal cell layer: a diagnostic tool to identify premalignancies of the vulva

“…This type of tumour is probably not associated with human papillomavirus (HPV) infection. [1][2][3][4] The less common type, accounting for about one-third of all vulvar squamous-cell carcinomas, is associated with HPV, predominantly HPV types 16 and 18. This type of tumour often occurs as a multifocal lesion in relatively young women and is usually preceded by high-grade usual VIN lesions (also referred to as classic VIN lesions).…”

Urothelial carcinoma with prominent squamous differentiation in the setting of neurogenic bladder: role of human papillomavirus infection

“…Basaloid and warty morphologies are characteristic of HPV-associated squamous cell carcinomas and have been shown to correlate with viral status in oropharyngeal, 8 vulvar, 5 penile, 38 and anal carcinomas. 53 Bladder squamous cell carcinoma very rarely shows basaloid/warty features, which is consistent with the infrequent finding of HPV in bladder squamous cell carcinoma.…”

“…The prototypical model for carcinogenesis is squamous cell carcinoma of the uterine cervix, in which nearly all such carcinomas are associated with HPV infection. 3,4 The oncogenic role of HPV is also well established for a subset of squamous cell carcinomas in the vulva, 5 penis, 6 anus, 7 and oropharynx. 8 The possible role of HPV infection in bladder tumors has not been completely elucidated as HPV detection rates vary widely from 0 to 100%, depending on the study.…”