title: BRAF inhibitor therapy-associated melanocytic lesions lack the BRAF V600E mutation and show increased levels of cyclin D1 expression.
abstract: 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.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Kumaran
authors.initials: K
authors.lastname: Mudaliar
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tetzlaff
authors.affiliation: Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Duvic
authors.affiliation: Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Ana
authors.initials: A
authors.lastname: Ciurea
authors.affiliation: Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Sharon
authors.initials: S
authors.lastname: Hymes
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Denái R
authors.initials: DR
authors.lastname: Milton
authors.affiliation: Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Kenneth Y
authors.initials: KY
authors.lastname: Tsai
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. Electronic address: ctcabala@mdanderson.org.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Torres-Cabala
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. Electronic address: jlcurry@mdanderson.org.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Curry
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001706:Biopsy; D019938:Cyclin D1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008544:Melanocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008545:Melanoma / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D016609:Neoplasms, Second Primary / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C530104:CCND1 protein, human; D047428:Protein Kinase Inhibitors; D019938:Cyclin D1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF V600E; BRAFi therapy; Dermatologic toxicity; Melanomas; Nevi