van der Avoort I A M, Shirango H, Hoevenaars B M, Grefte J M M, de Hullu J A, de Wilde P C M, Bulten J, Melchers W J G, Massuger L F A G
Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Int J Gynecol Pathol. 2006 Jan;25(1):22-9. doi: 10.1097/01.pgp.0000177646.38266.6a.
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.
已提出两条导致外阴癌的独立途径。首先，是一条依赖人乳头瘤病毒（HPV）的途径，在外阴癌的癌前阶段为典型的外阴上皮内瘤变（VIN）病变。其次，是一条不依赖HPV的途径，与分化型VIN III病变和/或硬化性苔藓相关。为深入了解这些途径背后的机制，我们确定了HPV DNA与非恶性和（前）恶性外阴病变中p14（ARF）和p16（INK4A）表达之间的关系。选择了73份非肿瘤性和（前）肿瘤性外阴病变的存档样本，使用广谱HPV检测/基因分型检测法（SPF(10)-LiPA）检测hr-HPV DNA，并检测p14（ARF）和p16（INK4A）的表达。HPV的患病率随典型VIN病变的严重程度增加而升高；在VIN I中未检测到hr-HPV，在VIN II中为43%，在VIN III中71%的样本为hr-HPV阳性。p14（ARF）和p16（INK4A）的表达情况大致相同。p14（ARF）和p16（INK4A）的同时表达与hr-HPV DNA的存在高度相关。在分化型VIN III病变中仅1例检测到hr-HPV，而未发现p14（ARF）的表达，仅2例存在p16（INK4A）。所有16份外阴癌样本的hr-HPV DNA均为阴性，尽管分别有63%和25%的样本表达p14（ARF）和p16（INK4A）。在20份非肿瘤性外阴病变中未发现hr-HPV与p14（ARF）和p16（INK4A）的表达之间存在关联。我们的结果进一步证明，外阴鳞状细胞癌是一种由两种不同途径发展而来的多因素疾病。首先，是一条依赖HPV的途径，与CIN病变和宫颈癌有显著相似性；其次，是一条不依赖HPV的途径，其中hr-HPV阴性的分化型VIN III病变可能是前驱病变。
