Differentiated Vulvar Intraepithelial Neoplasia Contains p53 Mutations and Is Genetically Linked to Vulvar Squamous Cell Carcinoma
AP Pinto, A Miron, Y Yassin, N Monte, TYC Woo, F Medeiros, CP Crum. Federal University of Paran, Curitiba, PR, Brazil; Dana Farber Cancer Institute, Boston, MA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Mayo Clinic Foundation, Rochester, NM
Background: Differentiated vulvar intraepithelial neoplasia (dVIN) is a unique precursor to vulvar squamous cell carcinoma (VSCC) that unlike classic VIN (cVIN) is typically HPV-negative and associated with nuclear p53 staining. These features, in addition to allelic loss, imply a mode of pathogenesis involving somatic mutations. However, the genetic relationship of dVIN and VSCC and the role of p53 mutations in this process have not been resolved.
Design: We selected 10 dVINs, 2 cVINs, and 6 associated VSCCs from our pathology files. Sections were stained for p53 and multiple epithelial sites representing normal control tissues (n = 10), dVIN (n=17), cVIN (n=2), and VSCC (n=6), were subjected to laser capture microdissection, and scored for p53 mutations by sequence analysis of exons 2-11.
Results: In seven out of 10 cases at least one dVIN focus contained one or more p53 mutations. Four were strongly p53 immuno-positive, 3 were negative. All four dVIN associated carcinomas were p53 mutation positive in contrast to 1 of 2 cVIN associated malignancies. In two of three dVIN/VSCC cases, both entities shared an identical p53 mutation. However, disparate foci of dVIN often exhibited different mutations consistent with multiple neoplastic clones. One cVIN shared the same p53 mutation with its corresponding VSCC.
Conclusions: This study shows, for the first time, that HPV-negative vulvar cancers evolve in association with p53 mutations and that identical p53 mutations can be identified in the precursor lesion (dVIN). p53 immunostaining will identify some but not all of these lesions and will not invariably signal the presence of clones with p53 mutations. The multiplicity of p53 mutations in one or more epithelia from a single case is in keeping with the presence of multiple independent genetic events, some of which may lead to malignancy and which translate into the complex array of epithelial alterations associated with HPV-negative vulvar carcinomas.
Tuesday, March 10, 2009 2:30 PM
Platform Session: Section C, Tuesday Afternoon