title: High levels of p53 expression correlate with DNA aneuploidy in (pre)malignancies of the vulva.
abstract: The molecular pathogenesis of human papilloma virus-unrelated vulvar squamous cell carcinoma is not well known. Whether malignant progression of lichen sclerosus and differentiated vulvar intraepithelial neoplasia to vulvar squamous cell carcinoma could be accompanied by altered DNA content has not been studied extensively. DNA content in isolated nuclei of microdissected normal vulvar epithelium (n = 2), lichen sclerosus (n = 9), differentiated vulvar intraepithelial neoplasia (n = 13), and squamous cell carcinoma (n = 17) from 22 patients was measured via DNA image cytometry. For additional analysis, 6 differentiated vulvar intraepithelial neoplasia lesions were selected, bringing the number of patients to 28. p53 expression was determined by immunohistochemistry on consecutive tissue sections. Thirty-eight percent (5/13) of differentiated vulvar intraepithelial neoplasia lesions and 65% (11/17) of squamous cell carcinomas were DNA aneuploid or tetraploid. In lesions that contained differentiated vulvar intraepithelial neoplasia and adjacent squamous cell carcinoma, the ploidy status of differentiated vulvar intraepithelial neoplasia did not exceed that of squamous cell carcinoma. We observed a strong correlation between high p53 expression and DNA aneuploidy. This relation was also present at the level of a single nucleus, measured by sequential image cytometry of p53 immunohistochemistry followed by DNA image cytometry on formalin-fixed tissue sections. Similarly, we found p53-positive nonproliferating cells with increased DNA content in the superficial compartment of 6 additional solitary differentiated vulvar intraepithelial neoplasia lesions that were not associated with squamous cell carcinoma, indicating ascending aneuploid cells from the basal compartment. DNA ploidy measurements suggest that differentiated vulvar intraepithelial neoplasia has a higher malignant potential than lichen sclerosus and thus is a more likely precursor of squamous cell carcinoma. Furthermore, high p53 expression correlates with increased DNA content and aneuploidy; but it requires further research to unveil a possible causal relation.
authors.affiliation: Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. hidetaka@surgpath.med.kyushu-u.ac.jp
authors.forename: Irene A M
authors.initials: IA
authors.lastname: van der Avoort
authors.forename: Hedwig P
authors.initials: HP
authors.lastname: van de Nieuwenhof
authors.forename: Irene
authors.initials: I
authors.lastname: Otte-Höller
authors.forename: Ella
authors.initials: E
authors.lastname: Nirmala
authors.forename: Johan
authors.initials: J
authors.lastname: Bulten
authors.forename: Leon F A G
authors.initials: LF
authors.lastname: Massuger
authors.forename: Jeroen A W M
authors.initials: JA
authors.lastname: van der Laak
authors.forename: Piet J
authors.initials: PJ
authors.lastname: Slootweg
authors.forename: Joanne A
authors.initials: JA
authors.lastname: de Hullu
authors.forename: Léon C L T
authors.initials: LC
authors.lastname: van Kempen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D014844:Vulva / Q000378:metabolism / Q000473:pathology; D007724:Vulvar Lichen Sclerosus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014846:Vulvar Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D004247:DNA