title: A Comparison of Morphologic and Molecular Features of BRAF, ALK, and NTRK1 Fusion Spitzoid Neoplasms.
abstract: Recent studies have identified translocations involving the kinase domains of ALK, NTRK1, BRAF, RET, and ROS in spitzoid neoplasms. Subsequent studies have also characterized morphologic features corresponding to ALK and NTRK1 translocations. In this study, we sought to further compare morphologic features across a range of 49 genetically defined spitzoid neoplasms with ALK, NTRK1, BRAF, or RET fusions to determine discriminating features. We also compared them with a group of 22 spitzoid neoplasms, which were confirmed to be negative for fusions in ALK, NTRK1, BRAF, and RET. Features with the highest discriminatory value included diameter of the lesion, dermal architecture, and certain cytomorphologic features. Specifically, cases with a large diameter (≥9 mm) and wedge-shaped, plexiform dermal architecture of nests of large, spindle-shaped cells were most likely to have an ALK fusion. NTRK1-fused cases were most likely of the fusions to have Kamino bodies and were typically arranged in smaller nests with smaller predominantly spindle-shaped cells, occasionally forming rosettes. BRAF fusion cases were the only fusion subtype to have a predominance of epithelioid cells, were less organized in nests, and commonly had a sheet-like growth pattern or dysplastic Spitz architecture. BRAF fusion cases were most likely to have high-grade nuclear atypia, to be diagnosed as spitzoid melanoma, to have a positive result by melanoma fluorescence in situ hybridization assay, and to develop copy number gains in the kinase domain of the fusion protein. On the basis of experience from this cohort, BRAF-fused cases appear most likely to progress to melanoma.
authors: *Department of Dermatology, Feinberg School of Medicine †The Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL.
authors: Sapna M
authors: SM
authors: Amin
authors: Alexandra M
authors: AM
authors: Haugh
authors: Christina Y
authors: CY
authors: Lee
authors: Bin
authors: B
authors: Zhang
authors: Jeffrey A
authors: JA
authors: Bubley
authors: Emily A
authors: EA
authors: Merkel
authors: Anna Elisa
authors: AE
authors: Verzì
authors: Pedram
authors: P
authors: Gerami
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D050939:Gene Fusion; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D060787:Neoplasm Grading; D018332:Nevus, Epithelioid and Spindle Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011237:Predictive Value of Tests; D048493:Proto-Oncogene Proteins B-raf / Q000032:analysis / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D020917:Receptor, trkA / Q000032:analysis / Q000235:genetics*; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014178:Translocation, Genetic; D047368:Tumor Burden; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000611485:NTRK1 protein, human; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf