Cutaneous Non-Neural Granular Cell Tumors Harbor Recurrent ALK Gene Fusions

Abstract

Non-neural granular cell tumor (NNGCT; also known as primitive polypoid granular cell tumor) is a rare neoplasm composed of large ovoid cells with abundant granular cytoplasm, variable nuclear pleomorphism, and the potential for regional lymph node spread. In contrast to conventional granular cell tumor (GCT), NNGCT lacks S100 expression and can exhibit greater nuclear atypia and mitotic activity. Therefore, we investigated clinicopathologic features of 12 NNGCT, and also used next-generation sequencing to identify potential driver events in a subset of NNGCT and 6 GCT. NNGCT demonstrated mild-to-moderate nuclear pleomorphism, variable mitotic activity (0 to 10/10 high-power fields), and were S100. Genetic analysis of 5 cutaneous NNGCT revealed gene fusions involving the anaplastic lymphoma kinase gene (ALK) in 3 cases (60%). Specifically, an interstitial deletion of chromosome 2 resulting in an in-frame fusion of dyanactin 1 (DCTN1) to ALK was identified in 2 cases, and a translocation resulting in a fusion between sequestosome 1 (SQSTM1) on chromosome 5 and ALK was identified in one case. Two of 6 GCT (33%) showed gains of chromosome 7. No other molecular or chromosomal alterations were detected in NNGCT and GCT. ALK immunohistochemistry revealed weak-to-moderate positivity in 4/9 cutaneous NNCGT (44%) including all 3 tumors with ALK fusions. Three oral NNGCT lacked ALK expression. NNGCT with ALK immunostaining did not have morphologic features distinguishing them from those without ALK staining. Our results demonstrate that a subset of NNGCT harbor ALK fusions, suggest that NNGCT are molecularly diverse, and further substantiate NNGCT as distinct from GCT.

Epithelioid Cutaneous Mesenchymal Neoplasms: A Practical Diagnostic Approach

“…Immunohistochemically, the tumor cells are diffusely positive for S100 protein. Granular cell tumors in subcutaneous tissue express higher levels of TFE3 than those in other sites [73].…”

“…The differential diagnoses of granular cell tumor include primitive non-neural granular cell tumor, adult rhabdomyoma, and malignant melanoma. Primitive non-neural granular cell tumors have a polypoid configuration with an epithelial collarette and are negative for S100 protein [73]. Adult rhabdomyomas show sheets of polygonal cells and are positive for desmin and myogenin.…”

Three additional cases of non‐neural granular cell tumor with novel immunohistochemical findings

“…Positivity for ALK 14 has been recently demonstrated in almost half of cutaneous NNGCT cases; this finding is correlated with underlying ALK gene fusions studied by next‐generation sequencing 28 . However, no phenotypical or behavioral differences were noted between ALK‐positive and ‐negative NNGCTs.…”

“…It was recently described that cyclin D1 plays a role in differentiating neoplastic from reactive Langerhans cell proliferation, as this protein is frequently expressed in the neoplastic cells of Langerhans cell histiocytosis. 27Positivity for ALK14 has been recently demonstrated in almost half of cutaneous NNGCT cases; this finding is correlated with underlying ALK gene fusions studied by next-generation sequencing 28. However, no phenotypical or behavioral differences were noted between ALK-positive and -negative NNGCTs.…”

Desmoplastic stromal changes in cutaneous neural granular cell tumors: An under‐recognized histopathologic feature of diagnostic and prognostic importance

“…Unlike conventional GCTs, these tumors are S100‐negative, do not have a recognizable line of differentiation and are presumed to be nonneural (hence the name “nonneural GCT”) . Recently, these tumors have been shown to harbor recurrent anaplastic lymphoma kinase ( ALK ) gene fusions …”