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.

Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy

“…25,59 ALK fusions have been described in other tumours, including anaplastic large cell lymphoma, 60 lung cancer, 61 inflammatory myofibroblastic tumours 62 and acral melanoma. 63 ALK positive Spitz tumours are usually solitary, dome-shaped lesions and occur slightly more frequently on the extremities.…”

“…63 ALK positive Spitz tumours are usually solitary, dome-shaped lesions and occur slightly more frequently on the extremities. 59,64 The majority of tumours are amelanotic, but they can occasionally be heavily pigmented. The lesions are often clinically suspected to be irritated melanocytic naevi, virus induced lesions (verruca, molluscum contagiosum), or vascular lesions (angioma, pyogenic granuloma).…”

Spitzoid Melanoma-Case Report; Potential Role of Alk Expression in the Diagnosis of Spitzoid Melanocytic Lesions

“…Later, it was identifi ed in other neoplasms, either benign or malignant, such as lung adenocarcinoma, Ewing sarcoma, infl ammatory myofbroblastic tumor, epithelioid fi brous histiocytomas (22). ALK was also detected in approximately 10-15% of all spitzoid tumors; ALK fusions are found in benign Spitz naevi, atypical Spitz tumors, and less commonly in spitzoid melanoma (23)(24)(25)(26). Immunohistochemistry is widely considered a good surrogate for ALK rearrangement (5,27).…”

“…Immunohistochemistry is widely considered a good surrogate for ALK rearrangement (5,27). There are evidences that spitzoid melanocytic tumors with ALK imunoreactivity have specifi c histopathological features (25,26,28). In a previous study, we analyzed several spitzoid tumors for ALK expression.…”

Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects

“…125 CAP-Gly domain-containing linker protein 1 (CLIP1) and general transcription factor IIIC subunit 2 (GTF3C2) were identified as new partners in Spitz tumors. 126 ALK immunohistochemistry plays a central role in the diagnosis of ALK-positive tumors. As ALK expression is …”