NTRK Gene Fusion Detection in Atypical Spitz Tumors

Rocco Cappellesso,Filippo Nozzoli,Giandomenico Roviello,Carlo Cota,Federica Zito Marino,Barbara Corti,Vincenzo De Giorgi,Giosuè Scognamiglio,Angelo Paolo Dei Tos,Sara Simi,Rebecca Senetta,Mario Mandalà,Francesca Castiglione,Renato Franco,Anna Maria Anniciello,Daniela Massi,Barbara Valeri,Costantino Ricci,Angela Rita Sementa,Maria Gabriella Valente,Anna Maria Cesinaro,Andrea Gianatti

doi:10.3390/ijms222212332

Abstract

Atypical Spitz tumors (AST) deviate from stereotypical Spitz nevi for one or more atypical features and are now regarded as an intermediate category of melanocytic tumors with uncertain malignant potential. Activating NTRK1/NTRK3 fusions elicit oncogenic events in Spitz lesions and are targetable with kinase inhibitors. However, their prevalence among ASTs and the optimal approach for their detection is yet to be determined. A series of 180 ASTs were screened with pan-TRK immunohistochemistry and the presence of NTRK fusions was confirmed using FISH, two different RNA-based NGS panels for solid tumors, and a specific real time RT-PCR panel. Overall, 26 ASTs showed pan-TRK immunostaining. NTRK1 fusions were detected in 15 of these cases showing cytoplasmic immunoreaction, whereas NTRK3 was detected in one case showing nuclear immunoreaction. Molecular tests resulted all positive in only two ASTs (included the NTRK3 translocated), RNA-based NGS and real time RT-PCR were both positive in three cases, and FISH and real time RT-PCR in another two cases. In seven ASTs NTRK1 fusions were detected only by FISH and in two cases only by real time RT-PCR. The frequency of NTRK fusions in ASTs is 9%, with a clear prevalence of NTRK1 compared to NTRK3 alterations. Pan-TRK immunohistochemistry is an excellent screening test. Confirmation of NTRK fusions may require the use of different molecular techniques.

Highlights

The term atypical Spitz tumor (AST) identifies a heterogeneous group of melanocytic lesions with clinical, histopathological, and molecular features overlapping those of benignSpitz nevus and Spitz melanoma [1]
The detection of appropriate molecular alterations allows identification of Spitz melanomas among the heterogeneous category of spitzoid melanomas, which includes lesions ranging from melanomas with tumor cells with spitzoid cytological features to melanomas showing epidermal hyperplasia and clefting around the melanocytic nests
It must be highlighted that many Spitz melanomas are diagnosed as such because of known synchronous metastasis or are initially diagnosed as Atypical Spitz tumors (AST) and classified as fully malignant after the detection of distant metastasis during clinical followup

Summary

Introduction

The term atypical Spitz tumor (AST) identifies a heterogeneous group of melanocytic lesions with clinical, histopathological, and molecular features overlapping those of benignSpitz nevus and Spitz melanoma [1]. The term atypical Spitz tumor (AST) identifies a heterogeneous group of melanocytic lesions with clinical, histopathological, and molecular features overlapping those of benign. The real incidence of ASTs is currently unknown, probably because of the lack of standardized terminology and the blurred interpretative criteria used in the past. ASTs are regarded as an intermediate category of melanocytic lesions composed of epithelioid or spindle melanocytes with ground-glass cytoplasm, showing some additional worrisome features such as increased size, asymmetry, ulceration, partial or complete lack of maturation, solid growth, greater pagetoid spread and deeper extension than in Spitz nevus, cytological pleomorphism, increased mitotic activity, and deep and atypical mitoses [2,3,4]. The high inter-observer discrepancy in AST diagnosis, even among internationally recognized dermatopathology experts, is due to the possible different interpretations of these variables [3,4]

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