The Role of Molecular Testing in the Differential Diagnosis of Salivary Gland Carcinomas

Abstract

Salivary gland neoplasms are a morphologically heterogenous group of lesions that are often diagnostically challenging. In recent years, considerable progress in salivary gland taxonomy has been reached by the discovery of tumor type-specific fusion oncogenes generated by chromosome translocations. This review describes the clinicopathologic features of a selected group of salivary gland carcinomas with a focus on their distinctive genomic characteristics. Mammary analog secretory carcinoma is a recently described entity characterized by a t(12;15)(p13;q25) translocation resulting in an ETV6-NTRK3 fusion. Hyalinizing clear cell carcinoma is a low-grade tumor with infrequent nodal and distant metastasis, recently shown to harbor an EWSR1-ATF1 gene fusion. The CRTC1-MAML2 fusion gene resulting from a t(11;19)(q21;p13) translocation, is now known to be a feature of both low-grade and high-grade mucoepidermoid carcinomas associated with improved survival. A t(6;9)(q22-23;p23-34) translocation resulting in a MYB-NFIB gene fusion has been identified in the majority of adenoid cystic carcinomas. Polymorphous (low-grade) adenocarcinoma and cribriform adenocarcinoma of (minor) salivary gland origin are related entities with partly differing clinicopathologic and genomic profiles; they are the subject of an ongoing taxonomic debate. Polymorphous (low-grade) adenocarcinomas are characterized by hot spot point E710D mutations in the PRKD1 gene, whereas cribriform adenocarcinoma of (minor) salivary glands origin are characterized by translocations involving the PRKD1-3 genes. Salivary duct carcinoma (SDC) is a high-grade adenocarcinoma with morphologic and molecular features akin to invasive ductal carcinoma of the breast, including HER2 gene amplification, mutations of TP53, PIK3CA, and HRAS and loss or mutation of PTEN. Notably, a recurrent NCOA4-RET fusion has also been found in SDC. A subset of SDC with apocrine morphology is associated with overexpression of androgen receptors. As these genetic aberrations are recurrent they serve as powerful diagnostic tools in salivary gland tumor diagnosis, and therefore also in refinement of salivary gland cancer classification. Moreover, they are promising as prognostic biomarkers and targets of therapy.

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

“…With >250 extramammary secretory carcinomas having been described in the literature since its delineation as a distinct entity in 2010, 1,22 these tumours are now known to arise most commonly in the parotid gland, and rarely at other sites, including other major and minor salivary glands, and the thyroid, sinonasal region, skin, and lung. [1][2][3][4][5][6][7][8][9][10][11][12] Most secretory carcinomas are characterised by the ETV6-NTRK3 fusion, 1,2 whereas the remainder harbour the ETV6- RET fusion.…”

Subtyping salivary gland neoplasm of uncertain malignant potential based on cell type demonstrates differential risk of malignancy

“…Recent molecular advances reveal several typespecific genetic alterations in salivary gland tumors. 37 Ancillary testing, such as immunocytochemistry, fluorescence in situ hybridization, or polymerase chain reaction, has emerged and has been used increasingly in cytopathology. 32,38,39 Nonetheless, more studies are still required to validate the performance of these tests on cytologic specimens.…”

The key radiologic and cytomorphologic features of oncocytic and oncocytoid lesions of the salivary gland

“…A number of molecular alterations have been described in SDC. Commonly mutated genes in SDC include TP53 , PIK3CA , and HRAS as well as PTEN , which also may be lost . A subset of SDCs will demonstrate ERBB2 amplification .…”