Combined utility of p16 and BRAF V600E in the evaluation of spitzoid tumors: Superiority to PRAME and correlation with FISH

BACKGROUND: Spitzoid melanocytic neoplasms are diagnostically challenging; criteria for malignancy continue to evolve. The ability to predict chromosomal abnormalities with immunohistochemistry (IHC) could help select cases requiring chromosomal evaluation. METHODS: Fluorescence in situ hybridization (FISH)‐tested spitzoid neoplasms at our institution (2013–2021) were reviewed. p16, BRAF V600E, and preferentially expressed antigen in melanoma (PRAME) IHC results were correlated with FISH. RESULTS: A total of 174 cases (1.9F:1M, median age 28 years; range, 5 months–74 years) were included; final diagnoses: Spitz nevus (11%), atypical Spitz tumor (47%), spitzoid dysplastic nevus (9%), and spitzoid melanoma (32%). Sixty (34%) were FISH positive, most commonly with absolute 6p25 gain (RREB1 > 2). Dermal mitotic count was the only clinicopathologic predictor of FISH. Among IHC‐stained cases, p16 was lost in 55 of 134 cases (41%); loss correlated with FISH positive (p < 0.001, Fisher exact test). BRAF V600E (14/88, 16%) and PRAME (15/56, 27%) expression did not correlate with FISH alone (p = 0.242 and p = 0.359, respectively, Fisher exact test). When examined together, however, p16‐retained/BRAF V600E‐negative lesions had low FISH‐positive rates (5/37, 14%; 4/37, 11% not counting isolated MYB loss); all other marker combinations had high rates (56%–75% of cases; p < 0.001). CONCLUSIONS: p16/BRAF V600E IHC predicts FISH results. “Low‐risk” lesions (p16(+)/BRAF V600E(−)) uncommonly have meaningful FISH abnormalities (11%). PRAME may have limited utility in this setting.