Recurrent RET Gene Rearrangements in Intraductal Carcinomas of Salivary Gland

Abstract

Intraductal carcinoma (IC) is the World Health Organization designation for lesions previously called low-grade cribriform cystadenocarcinoma. The relationship of IC to salivary duct carcinoma (SDC) is controversial, but currently these are considered distinct entities. It is hypothesized that IC and SDC should have different genomic signatures that may be identifiable by next-generation sequencing. A total of 23 ICs were identified: 14 pure IC and 9 invasive carcinomas with an intraductal component. Five invasive carcinomas were subjected to next-generation paired-end RNA sequencing. Data analysis was performed using FusionSeq and Mutation detection algorithms (MuTect and VarScan) for variant callers. Gene fusion candidates were validated by fluorescence in situ hybridization and reverse transcription polymerase chain reaction, and mutations by Sanger sequencing. Among the 9 invasive carcinomas, all except 1 were apocrine SDCs with an intraductal component. The remaining case showed typical intercalated duct type IC with invasive adenocarcinoma. The 14 pure ICs had typical intercalated duct features (2 showed hybrid intercalated/apocrine features). RNA sequencing predicted a NCOA4-RET fusion, confirmed by reverse transcription polymerase chain reaction, in the intercalated duct type IC invasive component. Six additional cases of pure IC showed RET rearrangement by fluorescence in situ hybridization (7/15=47%). No apocrine carcinomas showed RET rearrangement. RNA sequencing and Sanger sequencing identified PIK3CA (p.E545K/p.H1047R) and/or HRAS (p.Q61R) hotspot mutations in 6 of 8 (75%) apocrine carcinomas. In conclusion, 2 distinctive types of intraductal lesions are emerging based on molecular analysis. Classic intercalated type ICs commonly harbor fusions involving RET and rarely show widespread invasion. Apocrine intraductal lesions are typically associated with widespread invasion with no pure examples and show similar PIK3CA and HRAS mutations to SDC.

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

Low‐grade intraductal carcinoma of the salivary gland with prominent oncocytic change: a newly described variant

“…Both oncocytic change and apocrine differentiation are characterised by eosinophilic cytoplasm, but they are obviously distinct phenotypes in terms of histological and immunohistochemical features . In LG‐IDC, while apocrine differentiation has been described as a common phenomenon, oncocytic change has not been reported . All five of our cases exhibited tumour areas with histological features consistent with classical LG‐IDC.…”

“…In the newest version of the WHO classification of head and neck tumours, LG‐IDC is classified as the new and independent disease entity ‘intraductal carcinoma (IDC)’ . IDC includes both low‐grade and high‐grade intraductal carcinomas such as salivary duct carcinoma in situ …”

“…Its intraductal nature is demonstrated by the presence of a myoepithelial layer in the surrounding ductal epithelium . Although oncocytic change is a well‐recognised phenomenon in various salivary gland tumours, oncocytic LG‐IDC has not been described in textbooks or the literature . Herein, we present five cases of LG‐IDC showing prominent oncocytic change.…”

Cytopathology approach to rare salivary gland lesions with oncocytic features

“…This variant should be differentiated from intra‐ductal carcinoma with apocrine change, because, unlike the latter, it shows positivity for anti‐mitochondria antibody and S100p, and is negative for AR, with a low Ki‐67 proliferation index (less than 15%) . Based on differences in morphologic and biologic features, a recent study of 23 cases of intraductal carcinoma of the salivary glands demonstrated that this neoplasm can be divided into two types: The intercalated duct type (a possible equivalent of low‐grade intraductal carcinoma) and the apocrine type (a possible equivalent of high‐grade intraductal carcinoma) . The neoplastic cells in the intercalated duct type are small with a moderate amount of eosinophilic cytoplasm, and do not exhibit nuclear atypia.…”