Genomic analysis of recurrences and high‐grade forms of polymorphous adenocarcinoma

Abstract

Aims Polymorphous adenocarcinoma (PAC) usually follows an indolent course, but some cases may show recurrences and high‐grade features. The genetic events associated with recurrences and high‐grade versions are yet to be defined. Our aim was to determine the genetic underpinning of recurrent PACs of the salivary gland and the repertoire of somatic genetic alterations in cases with high‐grade histology. Methods and results Four PACs from three patients, including one case with matching primary and recurrent tumours, one de‐novo high‐grade PAC, and a PAC that transformed to a high‐grade tumour following multiple recurrences, were subjected to targeted sequencing (Memorial Sloan Kettering Mutation Profiling of Actionable Cancer Targets assay) or whole‐exome sequencing. Both matching primary and recurrent tumours, and the de‐novo high‐grade PAC, harboured clonal PRKD1 E710D hotspot mutations, whereas the PAC that underwent high‐grade transformation upon recurrence, which was wild‐type for PRKD1, harboured a PRKD2 rearrangement. The PACs analysed here also harboured mutations targeting cancer genes such as PIK3CA, SETD2, ARID1A, and NOTCH2. A clonal decomposition analysis of the matching primary and recurrent PACs revealed that a minor subclone from the primary tumour became dominant in the recurrent tumour following a clonal selection evolutionary pattern. Conclusions Our findings demonstrate that recurrent and high‐grade PACs are underpinned by PRKD1 E710D hotspot mutations or PRKD2 rearrangements, and that recurrences of PACs may stem from the selection of pre‐existing subclones in the primary tumour.

A novel STRN3::PRKD1 fusion in a cribriform adenocarcinoma of salivary gland with high‐grade transformation

“…High-grade transformation (HGT) has been reported in several salivary gland malignancies and even in PAC. [11][12][13] In this report, the tumor consisted of areas predominately solid nests of high-grade carcinoma with central necrosis arranged in lobules delineated with prominent stromal septa and areas of classic/ conventional CASG morphologic features. The biologic significance of HGT in CASG is yet to be understood.…”

“…The presence of a high‐grade component led us to carry out a salivary NGS fusion panel analysis to confirm the diagnosis. High‐grade transformation (HGT) has been reported in several salivary gland malignancies and even in PAC 11–13 . In this report, the tumor consisted of areas predominately solid nests of high‐grade carcinoma with central necrosis arranged in lobules delineated with prominent stromal septa and areas of classic/conventional CASG morphologic features.…”

New Insights into Tumor Heterogeneity: A Case of Solid-Oncocytic Epithelial-Myoepithelial Carcinoma of the Parotid Gland Harboring a HRAS and Heterogeneous Terminating ARID1A Mutation

“…ARID1A mutations have been very well characterized in ovarian clear cell carcinoma and endometrioid adenocarcinoma [11], whereas aberrations in ARID1A have been described only very rarely in salivary gland tumors: a ARID1A-PRKD1 fusion has been reported in cribriform adenocarcinoma of salivary gland origin by Weinreb et al [12]. Moreover, Sebastiao et al recently showed a terminating p.Q288Pfs*71 frameshift ARID1A deletion in a polymorphous adenocarcinoma [13]. Terminating mutations and frameshift mutations leading to early termination of ARID1A protein translation and thereby to a loss of function, have been described previously in salivary gland carcinomas (12/114 sequenced salivary gland tumors) encompassing in addition salivary duct carcinoma (2/18 samples) and adenoid cystic carcinoma (10/73 samples) [14].…”

Salivary gland polymorphous adenocarcinoma: Clinicopathological features and gene alterations in 36 Japanese patients

“…The definition and terminology of PAC have changed with the times. PAC has long been called polymorphous low‐grade adenocarcinoma (PLGA); however, the term “low‐grade” was eliminated in the current WHO Classification of Head and Neck Tumors published in 2017 because of the presence of rare aggressive cases 1,4–6 . On the other hand, a tumor entity named cribriform adenocarcinoma of salivary gland (CASG) was proposed as an independent tumor type from PAC 7,8 .…”

“…PAC has long been called polymorphous low-grade adenocarcinoma (PLGA); however, the term "low-grade" was eliminated in the current WHO Classification of Head and Neck Tumors published in 2017 because of the presence of rare aggressive cases. 1,[4][5][6] On the other hand, a tumor entity named cribriform adenocarcinoma of salivary gland (CASG) was proposed as an independent tumor type from PAC. 7,8 CASG has a propensity to occur at the base of tongue, with a lobulated architecture, a predominant solid, microcystic and cribriform growth pattern, and a uniform type of tumor cells with ground-glass, optically clear nuclei.…”