Vulvar intraepithelial neoplasia of the simplex (differentiated) type - A clinicopathologic study including analysis of HPV and p53 expression

The simplex (differentiated) variant of vulvar intraepithelial neoplasia (V IN) has not been well characterized. The authors studied the clinicopatholo gic features of 12 cases of simplex VIN and obtained follow-up data to asse ss its relationship to vulvar invasive squamous cell carcinoma (InvSCC). Ex pression of p53 protein was analyzed immunohistochemically and compared wit h adjacent non-neoplastic epidermal lesions. Assessment of human papilloma virus (HPV) deoxyribonucleic acid was done by polymerase chain reaction amp lification and in situ hybridization. All patients were of postmenopausal a ge (mean age, 66.8 years). Three patients had a history of prior vulvar Inv SCC and one had a separate synchronous vulvar InvSCC. Squamous hyperplasia was present in the adjacent epidermis in 10 patients and lichen sclerosus ( LS) was present in four patients. Histologically, simplex VIN differed from "classic" VIN by its highly differentiated features. The characteristic fe atures included parakeratosis, thickened epidermis with elongated and anast omosing rete ridges, enlarged abnormal keratinocytes with premature eosinop hilic cytoplasmic differentiation extending deeply within the epidermis, wh orling of enlarged keratinocytes or keratin pearl formation within rete rid ges, prominent intercellular bridges, and dysplastic basilar cells. One pat ient had minimal microinvasion (0.6 mm). Ten of 12 patients had positive p5 3 immunostaining staining with suprabasilar extension of p53 positive cells in each patient. The labeling index (LI) of basilar cells ranged from 0% t o 99% (median, 94.5%). Non-neoplastic lesions in the adjacent epidermis had p53-positive basal cells in nine of 11 evaluable cases. The LI was signifi cantly lower in these lesions, with a median of 4% in squamous hyperplasia and 7.5% in LS; none had suprabasilar extension of p53-positive cells. HPV (type 31/35/51) was identified in only one simplex VIN-a p53-negative lesio n. Staining for p53 often delineated sharply the junction between simplex V IN and squamous hyperplasia. Four patients subsequently developed vulvar In vSCC at 5, 6, 9, and 55 months. All four InvSCCs were of the conventional k eratinizing type and were HPV negative, as were the one synchronous and two prior InvSCCs. The authors conclude that (I) simplex VIN has a strong asso ciation with vulvar InvSCC and is a probable precursor lesion of HPV-negati ve vulvar InvSCCs, (2) HPV is very uncommon in simplex VIN and probably doe s not play an important role in its genesis, (3) alteration of the p53 gene appears to be involved in the development of simplex VIN, and (4) immunost aining for p53 protein may be helpful in the differential diagnosis of simp lex VIN.