Expanding the Molecular Spectrum of Secretory Carcinoma of Salivary Glands With a Novel VIM-RET Fusion

Abstract

Background: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET, ETV6-MAML3, and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements. Design: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6, RET, and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction. Results: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients’ age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts. Conclusions: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV6 5′ fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.

Dedifferentiated secretory breast carcinoma with fibrosarcomatous features harboring an ETV6‐NTRK3 fusion in both components

“…Interestingly, the sarcomatous component in this case shared several histologic and immunophenotypic features in common with infantile fibrosarcomas (IFS) 15,16 . Given the fact that secretory carcinomas also harbor the same gene fusions as IFS, 17‐21 this case demonstrates that sarcomatous dedifferentiation in secretory carcinomas may occasionally result in tumors that are histologically and molecularly indistinguishable from IFS. In this report, we discuss the diagnostic and theragnostic implications of this variant morphology.…”

“…At extramammary sites, a dedifferentiated secretory carcinoma with this morphology could mimic a kinase‐rearranged infantile or adult fibrosarcoma, especially if there is overgrowth of the sarcomatous component. In addition to the canonical ETV6‐NTRK3 gene fusion, secretory carcinomas may also harbor a number of alternative gene fusions involving other kinase‐encoding genes such as RET , MET or ALK 17‐21 . Many of these gene rearrangements have also been reported in infantile fibrosarcomas, infantile fibrosarcoma‐like pediatric spindle cell sarcomas and adult fibrosarcomas 15 .…”

MUC4 is a valuable marker for distinguishing secretory carcinoma of the salivary glands from its mimics

“…Molecular analyses were performed in two laboratories using established methods. All 17 SC cases from Plzen were tested using a combination of FISH, NGS or PCR as detailed earlier (11). Eleven SC cases from Erlangen were tested for ETV6 fusions using the TruSight RNA Fusion panel (Illumina Inc., San Diego, CA) as described recently (30).…”

“…Like its mammary counterpart, SC harbours a recurrent balanced chromosomal translocation, t(12;15) (p13;q25), leading to fusion of ETV6 on chromosome 12 with NTRK3 on chromosome 15 1 . Alternative fusion variants have been reported, including ETV6 – RET , 8 ETV6 – MET , 9 and, more recently, concurrent ETV6 – RET and EGFR – SEPT14 10 and VIM – RET 11 fusions.…”

Women’s Views about Breast Cancer Prevention at Mammography Screening Units and Well Women’s Clinics

“…Secretory carcinomas of the salivary gland were first described in 2010 and make up approximately 4-5% of salivary gland carcinomas [7,113,114]. The majority of secretory carcinomas have NTRK3 gene fusions (most often ETV6-NTRK3) [7], but there are reports of other ETV6 fusion partners, such as RET, MET, and MAML3 [115][116][117][118].…”