Diagnostic Utility of p16 and MTAP Immunohistochemistry for Cellular Neurothekeomas

Aims Cellular neurothekeoma (cNTK) is a benign cutaneous tumor of uncertain histogenesis. Recent genomic characterization identified recurrent deletions on chromosome 9p21.3, encompassing CDKN2A (p16), as a primary driver event in cNTK. We assessed the potential utility of p16 and MTAP immunohistochemistry for discriminating cNTKs from morphologic mimics. Methods and Results Immunohistochemistry for p16 and MTAP was performed on 21 and 19 cNTKs, respectively, and a broad comparison group of fibrohistiocytic neoplasms. Staining distribution was scored semi‐quantitatively. Low/absent p16 expression (Score 1) was observed in 17 of 21 (81%) cNTK cases. Low/absent p16 was significantly more likely in cNTK relative to atypical fibrous histiocytoma, dermatofibroma, Langerhans cell histiocytosis, and pleomorphic dermal sarcoma. However, there was no statistical difference relative to some other tumor types, including plexiform fibrohistiocytic tumor or atypical fibroxanthoma. Only 26% of assessed cNTK cases (5/19) showed loss of MTAP; this did not reach statistical significance relative to other tumor types. Conclusions Low/absent p16 expression is common in cNTKs, corroborating recent genetic evidence for 9p21.3 deletion. Diagnostic utility of low/absent p16 varied, with high specificity in comparison to atypical fibrous histiocytoma and low utility for plexiform fibrohistiocytic tumor. Despite its proximity to CDKN2A on 9p21.3, MTAP immunohistochemistry shows low sensitivity for cNTKs, with diminished staining in only a small subset of tumors. Our findings suggest that low/absent p16 can be diagnostically informative for cNTK in certain contexts; however, low specificity against some tumor types is an important limitation.