p53/CK17 Dual Stain Improves Accuracy of Distinction Between Differentiated Vulvar Intraepithelial Neoplasia and Its Mimics

Abstract

Accurate diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN) is challenging, in part due to the sometimes subtle nature of its atypia. Many dVIN lesions demonstrate aberrant p53 staining; however, staining patterns overlap between dVIN and benign/reactive entities. We evaluate a p53/CK17 dual stain in an initial cohort of dVIN (n=30), benign vulvar skin (n=5), lichen sclerosus (LS, n=10), lichen simplex chronicus (LSC, n=10), and pseudoepitheliomatous hyperplasia (PEH, n=10). In the initial cohort, aberrant p53 staining was seen only in dVIN (50%, 15/30). Equivocal p53 staining patterns were seen in dVIN (37%, 11/30), LS (50%, 5/10), LSC (40%, 4/10), and PEH (40%, 4/10). All 30 dVIN cases were positive for CK17 (strong partial-thickness or full-thickness staining), but positive CK17 staining was also seen in LS (70%, 7/10), LSC (50%, 5/10), and PEH (100%, 10/10). In the initial cohort, the combination of aberrant p53 and positive CK17 was seen only for dVIN (50%, 15/30). Forty cases of LS with known follow-up (20 with progression to dVIN, 20 without) were stained to assess prognostic value. Three LS cases showed aberrant p53 staining with CK17 positivity; all progressed to dVIN. Equivocal p53 staining and CK17 positivity were seen in cases with and without progression. The p53/CK17 dual stain is more diagnostically useful than either stain alone. Negative/focal staining for CK17 argues against a diagnosis of dVIN, while aberrant p53 staining with CK17 positivity strongly supports the diagnosis.

Diagnosis of verruciform acanthotic vulvar intra‐epithelial neoplasia (vaVIN) using CK17, SOX2 and GATA3 immunohistochemistry

“…First, cytokeratin 17 (CK17) has been shown by several authors to be frequently positive in dVIN and vaVIN (under the term DEVIL) compared to nondysplastic vulvar mucosa, which is often negative or only weakly positive. [8][9][10] Similar results have been documented for SRY-box transcription factor 2 (SOX2), a transcription factor involved in squamous cell carcinoma carcinogenesis. 11 Lastly, loss of GATAbinding protein 3 (GATA3) expression in the basal squamous epithelium has recently been shown in dVIN 12 and VAM and is, in turn, retained in most HPV-associated lesions and vulvar dermatoses.…”

“…Recent literature has documented a role for several markers in the diagnosis of HPV‐independent VIN. First, cytokeratin 17 (CK17) has been shown by several authors to be frequently positive in dVIN and vaVIN (under the term DEVIL) compared to non‐dysplastic vulvar mucosa, which is often negative or only weakly positive 8–10 . Similar results have been documented for SRY‐box transcription factor 2 (SOX2), a transcription factor involved in squamous cell carcinoma carcinogenesis 11 .…”

“…Among these criteria, determining absence of significant epithelial atypia (basal or otherwise) and the routine use of p53 and p16 are emphasised, as these steps will be the most helpful in excluding other forms of vulvar intra‐epithelial neoplasia. In such a diagnostic work‐up, CK17, SOX2 and GATA3 are not useful as they frequently show positivity/abnormal results in other precursors, particularly dVIN 10,12 …”

ORF1p Is a Potential Novel Diagnostic Marker for Differentiated Vulvar Intraepithelial Neoplasia

“…Similarly, CK17 expression is not specific for dVIN and has been found in a significant proportion of mimics. In small series, CK17 was present in 63% to 70% LS, 29% to 50% lichen simplex chronicus, and 100% of pseudoepitheliomatous hyperplasias 16,17. These studies might indicate that ORF1p could potentially possess an improved specificity compared with CK17, but this needs to be evaluated in larger follow-up studies.…”

“…Previously, CK17 and SOX2 have been explored for their diagnostic value in dVIN (5,9). In the published literature, diffuse moderate-to-strong CK17 expression was detected in a high percentage of cases comprising 88% (48/54), 80% (45/56), 93% (27/29), and 100% (30/30), respectively (5,9,16,17). SOX2 was found in 48/56 (86%) specimens ( 9).…”