PAPILLOMAVIRUS, P53 ALTERATION, AND PRIMARY-CARCINOMA OF THE VULVA

Twenty-nine samples from 28 cases of vulvar squamous cell carcinoma, o f which 13 fulfilled the criteria of the bowenoid subtype (mean age 45 years, range 31-68) and 16 of the usual subtype of invasive squamous cell carcinoma (ISCC) (mean age 67.5 years, range 34-83) were investig ated for human papillomavirus (HPV) DNA, TP53 alterations, and mdm2 an d bcl-2 gene product deregulation, Microscopically all the bowenoid su btype cases (group I) showed a high-grade intraepithelial (VIN 3, carc inoma in situ) lesion associated with early invasive carcinoma in six cases and overt invasive carcinoma in one, By contrast, no evidence of early carcinoma was present in the ISCCs (group II). By in situ hybri dization and/or Southern blot hybridization or polymerase chain reacti on (PCR), HPV-DNA was detected in all cases of group I and in four of 16 cases (25%) of group II, two only by Southern blot after PCR. By si ngle-strand conformation polymorphism and immunocytochemistry only wil d-type TP53 and absence of detectable p53 product, respectively, were found in all cases of group I, i.e., in high-risk HPV-positive carcino mas, whereas mutations and/or p53 overexpression accounted for 75% in group II, i.e., in mainly HPV-negative carcinomas. The TP53 gene mutat ions observed in invasive carcinomas were significantly related to nod e-positive cases (p = 0.04). Taken together and in agreement with in v itro data, these results support the view that an alteration of TP53, gained either by interaction with viral oncoproteins or by somatic mut ations, is a crucial event in the pathogenesis of vulvar carcinomas, b ut that TP53 mutations are mainly associated with disease progression. Finally, a preliminary immuno-cytochemical analysis seems to speak ag ainst the possible involvement of both MDM2 and BCL-2 gene products in the development of vulvar carcinoma.