title: Phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia.
abstract: As life expectancy lengthens, cases of non-viral-associated vulvar squamous cell carcinoma and its precursor lesion, so-called differentiated vulvar intraepithelial neoplasia (VIN), continue to increase in frequency. Differentiated VIN often is difficult to recognize and failure to detect it before invasion results in morbidity and mortality. Thus, identification of a reliable biomarker for this type of lesion would be of great clinical benefit. Our recent studies have identified activation (ser235/236 phosphorylation) of ribosomal protein S6 (p-S6) in basal epithelial cells as an event that precedes and accompanies laminin γ(2) overexpression in most preinvasive oral dysplasias. To test this as a potential biomarker of vulvar dysplasia, we immunostained seven differentiated VINs and nine papillomavirus-related 'classic' VINs, most of which were associated with carcinoma, for p-S6. All carcinomas, all differentiated VINs, and most classic VINs contained regions of p-S6 staining in the basal layer, whereas basal and parabasal cells of normal vulvar epithelium and hyperplastic and inflamed lesions lacking cellular atypia were p-S6 negative. Laminin γ(2) was expressed in a subset of VINs, always occurring within basal p-S6 positive regions, as we had found previously for oral dysplasias. Lichen sclerosus is considered a potential precursor of vulvar carcinoma. Two lichen sclerosus lesions of patients with a concurrent carcinoma and one of six lichen sclerosus lesions without atypia or known concurrent carcinoma were basal p-S6 positive. In summary, there is a distinct difference in p-S6 basal cell layer staining between benign and neoplastic vulvar squamous epithelium, with consistent staining of differentiated VIN and of some lichen sclerosus lesions. These results support further studies to assess the potential of p-S6 as a biomarker to identify vulvar lesions at risk of progressing to invasive cancer.
authors.affiliation: Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Alvaro P
authors.initials: AP
authors.lastname: Pinto
authors.forename: Martin
authors.initials: M
authors.lastname: Degen
authors.forename: Patricia
authors.initials: P
authors.lastname: Barron
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Crum
authors.forename: James G
authors.initials: JG
authors.lastname: Rheinwald
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000737:chemistry* / Q000473:pathology; D002278:Carcinoma in Situ / Q000737:chemistry* / Q000473:pathology; D018450:Disease Progression; D004847:Epithelial Cells / Q000737:chemistry* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin / Q000032:analysis; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000737:chemistry* / Q000473:pathology; D011237:Predictive Value of Tests; D038601:Ribosomal Protein S6 / Q000032:analysis*; D012307:Risk Factors; D007724:Vulvar Lichen Sclerosus / Q000378:metabolism / Q000473:pathology; D014846:Vulvar Neoplasms / Q000737:chemistry* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C400567:LAMC2 protein, human; D007797:Laminin; D038601:Ribosomal Protein S6