Emily M. Hartsough

CK17 Immunohistochemistry Is a Useful Adjunct in the Diagnosis of HPV-independent, TP53-wild-type Verruciform/Acanthotic Vulvar Intraepithelial Neoplasia (vaVIN)

Verruciform/acanthotic vulvar intraepithelial neoplasia (vaVIN) is a rare, recently defined HPV-independent, TP53-wild type lesion of the vulva that predisposes to vulvar squamous cell carcinoma (VSCC). VaVIN encompasses a variety of histomorphologic subtypes, including verruciform lichen simplex chronicus (vLSC), differentiated exophytic vulvar intraepithelial lesion (DEVIL), and vulvar acanthosis with altered differentiation (VAAD). Given the rarity of the lesion, subtle histopathologic features, and overlap with other preneoplastic entities and benign dermatoses, vaVIN is a diagnostic challenge. Therefore, immunohistochemistry (IHC) may be a helpful diagnostic adjunct in differentiating vaVIN from mimickers. Cytokeratin 17 (CK17) immunohistochemistry has been previously described as a useful diagnostic tool in diagnosing differentiated vulvar intraepithelial neoplasia (dVIN) and VSCC and has only recently been applied to vaVIN. In this study, we identified a total of ten cases of vaVIN, including four classified as vLSC, five classified as DEVIL, and one classified as VAAD. CK17 was expressed by all vaVIN lesions, with superficial to suprabasal expression in the vLSC subtype and uniform suprabasal expression in the DEVIL and VAAD subtypes. The pattern of CK17 expression may be helpful in differentiating vaVIN subtypes, notably demonstrating only superficial expression in some cases of the least aggressive phenotype, vLSC. Suprabasal expression corresponds to the more aggressive phenotypes of DEVIL and VAAD. However, additional confirmatory studies in a larger cohort are needed to validate these findings.

D2-40 and CK17 Immunohistochemistry as a Diagnostic Adjunct for HPV-Independent Squamous Lesions in the Vulva and Their Role in Defining Atypical Lichen Sclerosus

Vulvar lichen sclerosus (LS) is a common, chronic inflammatory disorder with a subset of cases progressing to differentiated vulvar intraepithelial neoplasia (dVIN) and/or squamous cell carcinoma (SCC). Histopathologic diagnosis of LS and dVIN can be challenging, and it is difficult to predict the subset of LS cases that progress. Immunohistochemistry (IHC) may be a useful diagnostic aid in this setting. CK17 has been shown to be overexpressed in invasive SCC and dVIN, and less commonly in LS. Similar to CK17, D2-40 has been correlated with cutaneous SCC prognosis but has not been evaluated in vulvar lesions. We identified a total of 13 patients with HPV-independent vulvar SCC that had precursor LS or dVIN. CK17 and D2-40 IHC stain intensity and pattern was scored in foci of LS, dVIN, and SCC. An increase in basal layer D2-40 expression was observed with progression from LS to dVIN with strong and diffuse staining in SCC. CK17 maintained similar stain intensity among squamous lesions, but displayed different patterns of staining, with superficial staining in LS, suprabasal staining in dVIN, and diffuse staining in SCC. A subset of LS cases displayed an intermediate (suprabasal) CK17 IHC profile, wild-type p53 expression, and cytomorphologic and architectural features intermediate between LS and dVIN; we defined such cases as “atypical LS.” We found that a panel of D2-40/CK17 can serve as a diagnostic adjunct to differentiate LS, dVIN, and invasive SCC. Additional studies with larger patient cohorts are needed to validate these findings and determine their prognostic significance.