BRAF inhibitor therapy-associated melanocytic lesions lack the BRAF V600E mutation and show increased levels of cyclin D1 expression

Summary Newly appearing or changing melanocytic lesions (MLs) are a recently reported toxicity of BRAF inhibitor (BRAFi) therapy. Morphologically, MLs associated with BRAFi therapy (BRAFi-MLs) may demonstrate alarming features of melanoma with an epithelioid cell phenotype with notable cytologic atypia. We sought to characterize the clinicopathological and molecular features of BRAFi-MLs. A retrospective review over a 4-year period revealed 20 patients in which 44 MLs (including 11 control nevi) were characterized by histopathology, review of clinical medical records, and immunohistochemical (IHC) studies (with anti-BRAF V600E, anti-BAP1, anti-cyclin D1, and anti-p16); the percentage of IHC+ cells was scored. Of the 20 patients, 3 (15%) whose BRAFi-MLs were biopsied had a second primary cutaneous melanoma. Of the 44 BRAFi-MLs tested, 37 (100%) of 37 MLs available for BRAF V600E testing lacked expression in contrast to 1 (9%) of 11 control nevi (lesions not associated with targeted therapy). A significantly higher level of cyclin D1 expression (>50% IHC+ cells) was more commonly seen in BRAFi-MLs (44%) than in control nevi (9%). No difference in p16 expression in melanocytes was seen between the 2 groups. BRAF mutation status distinctly differs between BRAFi-MLs from melanomas and nevi biopsied in patients who do not receive BRAFi therapy. Morphologically, BRAFi-MLs demonstrate a greater degree of atypia than do control nevi. Furthermore, BRAFi-MLs with coexisting cutaneous keratinocyte toxicity developed during fewer days of targeted therapy. Paradoxical activation of the MAPK pathway in BRAF^WT melanocytes may account for ∼15% to 21% of patients developing a second new primary melanoma within a year of starting BRAFi therapy; thus, close clinical surveillance is warranted.