Molecular Profiling of Salivary Gland Intraductal Carcinoma Revealed a Subset of Tumors Harboring NCOA4-RET and Novel TRIM27-RET Fusions

Abstract

Intraductal carcinoma (IC) is the new World Health Organization designation for tumors previously called "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma is controversial, but they now are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in situ, that shows diffuse S100 protein and mammaglobin positivity and is only partially defined genetically. (Mammary analogue) secretory carcinoma harboring ETV6-NTRK3, and in rare cases ETV6-RET fusion, shares histomorphologic and immunophenotypical features with IC. Recently, RET rearrangements and NCOA4-RET have been described in IC, suggesting a partial genetic overlap with mammary analogue secretory carcinoma. Here, we genetically characterize the largest cohort of IC to date to further explore this relationship. Seventeen cases of IC were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). Identified fusions were confirmed using fluorescence in situ hybridization break apart and, in some cases, fusion probes, and a reverse transcription polymerase chain reaction designed specifically to the detected breakpoints. All analyzed cases were known to be negative for ETV6 rearrangement by fluorescence in situ hybridization and for ETV6-NTRK3 fusion by reverse transcription polymerase chain reaction. Next-generation sequencing analysis detected a NCOA4-RET fusion transcript joining exon 7 or 8 of NCOA4 gene and exon 12 of RET gene in 6 cases of intercalated duct type IC; and a novel TRIM27-RET fusion transcript between exons 3 and 12 in 2 cases of salivary gland tumors displaying histologic and immunohistochemical features typical of apocrine IC. A total of 47% of IC harbored a fusion involving RET. In conclusion, we have confirmed the presence of NCOA4-RET as the dominant fusion in intercalated duct type IC. A novel finding in our study has been a discovery of a subset of IC patients with apocrine variant IC harboring a novel TRIM27-RET.

Immunohistochemistry with a pan‐TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma

“…Intraductal carcinoma, specifically the ‘classic’ example showing low‐grade morphology and intercalated duct‐type differentiation with S100 expression, can also closely mimic secretory carcinoma. However, this tumour type is remarkably rare (~0.3%) . Intraductal carcinoma commonly harbours RET fusions and characteristically shows an intraductal growth pattern with intact myoepithelial cells, which can be highlighted by p63 staining …”

“…However, this tumour type is remarkably rare (~0.3%). 30 Intraductal carcinoma commonly harbours RET fusions and characteristically shows an intraductal growth pattern with intact myoepithelial cells, which can be highlighted by p63 staining. 30,31 The detection of NTRK3 rearrangement among salivary gland tumours has both diagnostic and therapeutic significance.…”

Cytopathology approach to rare salivary gland lesions with oncocytic features

“…Similar to salivary duct carcinoma, the apocrine type may harbor mutations in PIK3CA and HRAS, and it demonstrates a worse prognosis in general . RET rearrangements are not commonly reported, although TRIM27‐RET is a novel mutation that has been recently detected in the apocrine type . Approximately 10% to 25% only of salivary glands intraductal carcinoma cases reported in literature displayed microinvasion .…”

“…Intra-ductal carcinoma of the salivary gland has been controversial since its conception, mainly because it bears morphologic and biologic resemblance to other neoplasms in the salivary glands, such as salivary duct carcinoma and mammary analogue secretory carcinoma (MASC), to name a few. 37 The first nomenclatures of this entity were "intra-ductal carcinoma" 38 and "low-grade salivary duct carcinoma". 39 In 2005, the WHO considered it as a variant of cystadenocarcinoma, and the term low-grade cribriform cystadenocarcinoma was adopted to refer to it.…”

“…44 RET rearrangements are not commonly reported, 54 although TRIM27-RET is a novel mutation that has been recently detected in the apocrine type. 37,55 Approximately 10% to 25% only of salivary glands intraductal carcinoma cases reported in literature displayed microinvasion. 54 In addition, surgical management of intraductal carcinomas is confined to surgical excision of the mass without neck dissection or chemo and radiotherapy.…”