A subset of cutaneous and soft tissue mixed tumors are genetically linked to their salivary gland counterpart

Abstract

Neoplasms morphologically similar to mixed tumors and myoepitheliomas of the salivary glands, under the broad concept of myoepithelial neoplasia, have recently been defined in the skin and soft tissue; however, to date, no data have supported a shared genetic background with their salivary gland counterpart. From a large body of research, it has been well established that rearrangement of pleomorphic adenoma gene 1 (PLAG1) leads to aberrant expression of its protein and is pathogenically relevant in the development of salivary mixed tumors. On the other hand, in soft tissue lesions, compelling evidence suggests that EWSR1 is involved in a significant subset. To examine the hypothesis that there is a genetic link between these histologically similar tumors at different sites, we randomly selected 20 benign myoepitheliomas/mixed tumors of skin and soft tissue (10 cases each). Nineteen cases could be immunostained for PLAG1, of which 11 cases showed distinct nuclear staining with moderate or strong intensity in a significant number of cells. Interphase fluorescence in situ hybridization (FISH) for PLAG1 was successfully performed in 11 cases (7 in skin, 4 in soft tissue) and was positive for gene rearrangement in 8 cases (5 in skin, 3 in soft tissue). All PLAG1-rearranged tumors, except one, had clear-cut ductal structures and were immunoreactive for PLAG1. In our series, tumors with PLAG1 alteration shared a common morphologic phenotype characterized by prominent tubuloductal differentiation, suggesting that myoepithelial neoplasms with genuine salivary gland-like morphology, so-called soft tissue/cutaneous mixed tumors, are genetically related to their salivary gland counterpart.

Hyalinizing Clear Cell Carcinoma of Salivary Gland: A Review and Update

“…SMET is a somewhat morphologically heterogeneous group of tumors with benign and malignant variants. Some are identical to their salivary counterparts and may show PLAG1 rearrangement [19] but these are not the tumors with EWSR1 rearrangement. The EWSR1 rearranged SMETs are distinct from myoepithelial tumors of salivary gland [18] and typically stain with S100 and/or GFAP, as well as keratins and/or EMA.…”

Angiomatoid Fibrous Histiocytoma: The Current Status of Pathology and Genetics

“…81,86 The association of myoepithelial tumors with EWSR1-CREB1, EWSR1-ATF1, or FUS-ATF1 fusions has not been documented, except in one case of a pelvic myoepithelioma, which was described as having the EWSR1-ATF1 fusion. 75 A proportion of myoepithelial tumors of the skin and soft tissue with tubuloductal differentiation show recurrent PLAG1 rearrangements similar to those in mixed tumors of the salivary glands (pleomorphic adenomas), 87,88 which have not been described in AFH.…”

Myoepithelial Neoplasms of Soft Tissue: An Updated Review of the Clinicopathologic, Immunophenotypic, and Genetic Features

“…Notably, cutaneous syncytial myoepithelioma has a distinct immunophenotype of EMA and S-100 positivity but infrequent cytokeratin staining [7]. PLAG1 immunostaining is positive in 58-100 % of mixed tumors [15,16] (Fig. 2b), but is negative in myoepitheliomas lacking ductal differentiation [16].…”

“…Mixed tumors show PLAG1 gene rearrangement in 37-72 % of cases [15,29], suggesting a genetic relationship to their salivary gland counterparts, as up to 88 % of salivary pleomorphic adenoma [30] and up to 63-75 % of carcinoma ex pleomorphic adenoma have PLAG1 gene alterations [19,30].…”