KRAS codon 12 mutations characterize a subset of de novo proliferating “metaplastic” Warthin tumors

Abstract

Warthin tumor (WT; synonym: cystadenolymphoma) represents one of the most frequent salivary gland tumors with a frequency equaling or even outnumbering that of pleomorphic adenomas in some series. Histologically, the tumor displays tall columnar oncocytic cells, arranged into two cell-thick layers lining variably cystic glands within an organoid lymphoid stroma. Tumors with exuberant squamous metaplasia in response to FNA-induced or other types of tissue injury/infarction have been referred to as “metaplastic WTs.” However, the same terminology was used for tumors with variable mucinous cell and solid or stratified epidermoid proliferations (occasionally mimicking mucoepidermoid carcinoma), although the “metaplasia concept” has never been proven for the latter. We herein investigated 22 WTs showing prominent mucoepidermoid-like or solid oncocytoma-like proliferations without prior FNA or histological evidence of infarction/ trauma using the TruSight Tumor 15 gene panel and KRAS pyrosequencing. As a control, we tested 11 conventional WTs. No statistically significant differences were observed between the two subcohorts regarding patient’s age and tumor size. Six of 22 (27%) proliferating/ metaplastic WTs revealed oncogenic KRAS mutations clustering at codon 12 (exon 2), while all conventional tumors lacked these mutations. Our findings are in line with a neoplastic nature of the epidermoid/ mucoepidermoid proliferations in non-injured “metaplastic” Warthin tumors. We propose the descriptive term “de novo proliferating Warthin tumor” for this variant to distinguish it from infarcted/inflamed genuine metaplastic Warthin tumor.

Molecular testing in salivary gland cytopathology: A practical overview in conjunction with the Milan system

“…Similarly, PLAG1 or HMGA2 gene fusions support the diagnosis of a neoplasm from the pleomorphic adenoma spectrum (including myoepithelial‐rich PA and myoepitheliomas), despite a small residual risk for an unrecognized or cytomorphologically undetectable low‐grade CXPA. As mentioned above, KRAS mutations may occasionally be detected in metaplastic mucinous WT 12 . Finally, in SDCs, which may sometimes show quite bland oncocytic differentiation, TP53 mutations or ERBB2 amplifications may be found 6,83 ; both are not typically found in low‐grade carcinomas.…”

“…As mentioned above, KRAS mutations may occasionally be detected in metaplastic mucinous WT. 12 Finally, in SDCs, which may sometimes show quite bland oncocytic differentiation, TP53 mutations or ERBB2 amplifications may be found 6,83 ; both are not typically found in low-grade carcinomas.…”

“…Lastly, another confounding factor that may lead to misdiagnosis is that a small subset of proliferating metaplastic WTs harbour activating KRAS mutations, which are rarely retrieved in salivary gland tumours. 12 Being rare in salivary gland neoplasms, such mutations might also point to other types of metastatic cancers. 13,14…”