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.

The role of anaplastic lymphoma kinase in pediatric cancers

“…(39) Furthermore, ALK rearrangements occur in approximately 10-20% of spitzoid tumors (Spitz nevi, atypical Spitz tumors, and spitzoid melanomas), which are melanocytic neoplasms with distinctive histopathological features such as increased cell size and an epithelioid or spindle morphology. (52) Spitzoid tumors are more common in children and adolescents, but can occur at all ages. Those with ALK fusions show unique histopathologic features, which promise to improve the classification of these diagnostically challenging tumors.…”

First Japanese case of atypical Spitz tumor exhibiting ROS1 rearrangement

“…However, their cytological morphologies were different because the tumor cells of spitzoid neoplasms involving ALK rearrangement are predominantly spindle-shaped. 4,5 Herein, we present the first Japanese case of AST involving rearrangement of the ROS1 gene and hope that this case will contribute to our knowledge about such lesions.…”

“…However, at the present time no specific cytological or histological features of spitzoid neoplasms with ROS1 fusions have been reported, making the identification of such lesions difficult. 2,4 Recently, we reported the first Japanese case of AST involving rearrangement of the ALK gene. 5 At low magnification, both the latter and present cases exhibited similar histological architectures; namely both lesions had wedge-shaped silhouettes, were composed of nests and short fascicles, and displayed infiltrative borders.…”

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

“…Rearrangement of receptor tyrosine kinases like anaplastic lymphoma kinase (ALK), ROS1, neurotrophic tyrosine kinase receptor type 1 (NTRK1), hepatocyte growth factor receptor (MET), RET, and serine-threonine kinase BRAF are identifi ed in almost half of all Spitzoid tumours (6).…”

“…Recent studies report the presence of kinase fusions within this class of neoplasm, efforts being made to identify new markers with prognostic signifi cance in these melanocytic tumors (3)(4)(5). Rearrangement of receptor tyrosine kinases like anaplastic lymphoma kinase (ALK), ROS1, neurotrophic tyrosine kinase receptor type 1 (NTRK1), hepatocyte growth factor receptor (MET), RET, and serine-threonine kinase BRAF are identifi ed in almost half of all Spitzoid tumours (6).…”