title: Clinical, histopathologic, and genomic features of Spitz tumors with ALK fusions.
abstract: Activating kinase fusions have recently been described as early oncogenic events that are mutually exclusive with HRAS and BRAF mutations in Spitz tumors. Here, we report a series of 32 Spitz tumors with ALK fusions (6 Spitz nevi, 22 atypical Spitz tumors, and 4 spitzoid melanomas) in patients ranging from 5 months to 64 years (median=12 y) of age. The tumors typically presented as exophytic papules on the extremities and were occasionally darkly pigmented. In addition to ALK fusions previously described in other tumor types (NPM1-ALK, TPR-ALK), we identified 2 novel ALK fusions (CLIP1-ALK and GTF3C2-ALK) in our cohort of Spitz tumors. Array comparative genomic hybridization of 19 of these tumors demonstrated a high frequency of chromosome 2 aberrations (where ALK resides, 63%) and chromosome 1p loss in 37% of the cases. Spitz tumors with ALK fusions demonstrated unique histopathologic features. Clefts and small vesicle-like spaces were arrayed between plump spindled melanocytes with fibrillar cytoplasm and enlarged nuclei. These melanocytes were typically arrayed in elongated and fusiform nests with radial orientation. The tumors often had extension into the dermis or subcutis with a wedge-shaped or bulbous lower border (45% and 17%, respectively). An infiltrative growth pattern was often present at the periphery of the tumor and was highlighted by ALK immunohistochemistry. In conclusion, Spitz tumors with ALK rearrangement show distinct histopathologic features that should aid in improving classification of these diagnostically challenging tumors.
authors.affiliation: *Departments of Dermatology and Pathology, University of California, San Francisco, CA ‡Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY †Department of Biopathologie, Centre Leon Berard, Leon, France.
authors.forename: Iwei
authors.initials: I
authors.lastname: Yeh
authors.forename: Arnaud
authors.initials: A
authors.lastname: de la Fouchardiere
authors.forename: Daniel
authors.initials: D
authors.lastname: Pissaloux
authors.forename: Thaddeus W
authors.initials: TW
authors.lastname: Mully
authors.forename: Maria C
authors.initials: MC
authors.lastname: Garrido
authors.forename: Swapna S
authors.initials: SS
authors.lastname: Vemula
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Busam
authors.forename: Philip E
authors.initials: PE
authors.lastname: LeBoit
authors.forename: Timothy H
authors.initials: TH
authors.lastname: McCalmont
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
mesh_terms: D000293:Adolescent; D000077548:Anaplastic Lymphoma Kinase; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D005260:Female; D023281:Genomics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D008875:Middle Aged; D018332:Nevus, Epithelioid and Spindle Cell / Q000235:genetics* / Q000473:pathology*; D000090243:Nucleophosmin; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult
chemical_list: C000716967:NPM1 protein, human; D015514:Oncogene Proteins, Fusion; D000090243:Nucleophosmin; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases