title: 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.
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: I A M
authors.initials: IA
authors.lastname: van der Avoort
authors.forename: H
authors.initials: H
authors.lastname: Shirango
authors.forename: B M
authors.initials: BM
authors.lastname: Hoevenaars
authors.forename: J M M
authors.initials: JM
authors.lastname: Grefte
authors.forename: J A
authors.initials: JA
authors.lastname: de Hullu
authors.forename: P C M
authors.initials: PC
authors.lastname: de Wilde
authors.forename: J
authors.initials: J
authors.lastname: Bulten
authors.forename: W J G
authors.initials: WJ
authors.lastname: Melchers
authors.forename: L F A G
authors.initials: LF
authors.lastname: Massuger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002278:Carcinoma in Situ / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002648:Child; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004279:DNA, Viral / Q000302:isolation & purification; D005260:Female; D006801:Humans; D008875:Middle Aged; D027383:Papillomaviridae / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000150:complications* / Q000473:pathology; D011230:Precancerous Conditions / Q000150:complications / Q000473:pathology; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D007724:Vulvar Lichen Sclerosus / Q000150:complications* / Q000473:pathology; D014846:Vulvar Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D025803:Tumor Suppressor Protein p14ARF