A morphologic and molecular reappraisal of myoepithelial tumors of soft tissue, bone, and viscera with EWSR1 and FUS gene rearrangements

Abstract

Myoepithelial tumors (MET) represent a clinicopathologically heterogeneous group of tumors, ranging from benign to highly aggressive lesions. Although MET arising in soft tissue, bone, or viscera share morphologic and immunophenotypic overlap with their salivary gland and cutaneous counterparts, there is still controversy regarding their genetic relationship. Half of MET of soft tissue and bone harbor EWSR1 or FUS related fusions, while MET arising in the salivary gland and skin often show PLAG1 and HMGA2 gene rearrangements. Regardless of the site of origin, the gold standard in diagnosing a MET relies on demonstrating its "myoepithelial immunophenotype" of positivity for EMA/CK and S100 protein or GFAP. However, the morphologic spectrum of MET in soft tissue and bone is quite broad and the above immunoprofile is nonspecific, being shared by other pathogenetically unrelated neoplasms. Moreover, rare MET lack a diagnostic immunoprofile but shows instead the characteristic gene fusions. In this study, we analyzed a large cohort of 66 MET with EWSR1 and FUS gene rearrangements spanning various clinical presentations, to better define their morphologic spectrum and establish relevant pathologic-molecular correlations. Genetic analysis was carried out by FISH for EWSR1/FUS rearrangements and potential partners, and/or by targeted RNA sequencing. Then, 82% showed EWSR1 rearrangement, while 18% had FUS abnormalities. EWSR1-POU5F1 occurred with predilection in malignant MET in children and young adults and these tumors had nested epithelioid morphology and clear cytoplasm. In contrast, EWSR1/FUS-PBX1/3 fusions were associated with benign and sclerotic spindle cell morphology. Tumors with EWSR1-KLF17 showed chordoma-like morphology. Our results demonstrate striking morphologic-molecular correlations in MET of bone, soft tissue and viscera, which might have implications in their clinical behavior.

Keywords: EWSR1; FUS; PBX1; PBX3; POU5F1; myoepithelial tumors.

Figure 1.

Distribution of gene fusions in the present cohort of 66 MET of soft tissue, bone, and visceral organs.

Figure 2.. Morphologic spectrum of MET with POU5F1 gene rearrangements.

A-H. MET with EWSR1-POU5F1 showing at low power a lobulated growth within a prominent myxochondroid stroma (A), often a well-defined nested pattern (B-D), being composed of epithelioid cells with overtly malignant features and lightly eosinophilic cytoplasm (C) or clear cytoplasm (D). These classic examples often show diffuse positivity for cytokeratin (E) and S100 protein (F). Rare examples showed unusual features such as more solid growth of epithelioid cells with scant clear cell cytoplasm (G) or an infiltrative growth pattern within subcutaneous fat, with ill-defined cell borders (H). Rare FUS-POU5F1 positive cases showed epithelioid morphology with light eosinophilic to clear cytoplasm organized in nests or linear arrangements (I).

Figure 3.. Pathologic features of MET harboring EWSR1-PBX1/3 fusions.

Tumors with EWSR1-PBX1 fusions often show a bland epithelioid to ovoid phenotype, with scant clear cytoplasm, embedded in a delicate fibrous collagenous stroma (A,B). Tumors are frequently positive for EMA (C) and S100 protein (D). MET with EWSR1-PBX3 fusions display a more ovoid to spindle cell appearance, with benign histologic features (E,F).

Figure 4.. Morphologic appearances of rare genetic subtypes of MET.

FUS-KLF17-positive MET show often a diffusely myxoid or fibromyxoid stromal component with ovoid to epithelioid cells arranged in cords and a reticular pattern, reminiscent of chordoma phenotype (parachordoma) (A-D). These tumors are often S100 protein positive (E). MET with EWSR1-ZNF444 are often malignant and may display an undifferentiated round to spindle cell phenotype (F,G), with variable stromal component, ranging from very scant to prominent and desmoplastic (H). A rare tumor with EWSR1-KLF15 fusions showing cords of epithelioid cells embedded in a variably myxoid or fibromyxoid stroma (I).