title: A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression.
abstract: We recently reported that germline mutations in BAP1 cause a familial tumor syndrome characterized by high penetrance for melanocytic tumors with distinct clinical and histologic features. Melanocytic neoplasms in affected individuals harbored BRAF mutations, showed loss of BAP1 expression, and histologically resembled so-called "atypical Spitz tumors" (ASTs). ASTs are an ill-defined and probably heterogenous group of melanocytic tumors that display histologic features seen in both Spitz nevi and melanomas. Their biological behavior cannot be reliably predicted. In view of the histologic similarities of the familial tumors and ASTs, we hypothesized that a subset of ASTs might harbor genetic alterations seen in the familial tumors. To address this hypothesis, we analyzed 32 sporadic ASTs for BRAF mutations and for BAP1 expression. Nine (28%) sporadic ASTs showed loss of BAP1 expression, of which 8 (89%) had concomitant BRAF mutations. Only 1 of the BAP1-positive ASTs (4%) had a BRAF mutation (P<0.0001). BRAF-mutated, BAP1-negative tumors were primarily located in the dermis and were composed entirely or predominantly of epithelioid melanocytes with abundant amphophilic cytoplasm and well-defined cytoplasmic borders. Nuclei were commonly vesicular and exhibited substantial pleomorphism and conspicuous nucleoli. The combination of BRAF mutation and loss of nuclear BAP1 expression thus characterizes a subset of ASTs with distinct histologic features. The typical morphology of these tumors and BAP1 immunohistochemistry provide pathologic clues that will enable accurate identification of this subset. Future studies are necessary to determine whether this subset has a predictable clinical behavior.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiesner
authors.forename: Rajmohan
authors.initials: R
authors.lastname: Murali
authors.forename: Isabella
authors.initials: I
authors.lastname: Fried
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cerroni
authors.forename: Klaus
authors.initials: K
authors.lastname: Busam
authors.forename: Heinz
authors.initials: H
authors.lastname: Kutzner
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D015622:Epithelioid Cells / Q000378:metabolism / Q000473:pathology; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D018332:Nevus, Epithelioid and Spindle Cell / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D043222:Ubiquitin Thiolesterase