GLI2::CREBBP fusions define a subset of potentially aggressive nested-hyalinizing epithelioid soft tissue neoplams

The classification of mesenchymal neoplasms is undergoing a period of punctuated equilibrium thanks to the increasing availability and routine application of next-generation sequencing. This is especially true for the characterization of undifferentiated/ unclassified mesenchymal tumors, which have historically been grouped morphologically as spindle cell, epithelioid cell, round cell and pleomorphic neoplasms. Herein, we report four undifferentiated epithelioid mesenchymal neoplasms harboring a novel GLI2::CREBBP gene fusion. All patients were adult males who presented with a small superficial mass. Histologically, the tumors were composed of nests or sheets of bland epithelioid cells often embedded within prominent collagenous stroma. One case contained metaplastic bone, and dystrophic calcification in a region of prior ischemia. Immunohistochemistry showed variable keratin expression in three cases, but was otherwise non-contributory. Targeted next generation sequencing revealed a GLI2::CREBBP fusion in all cases. Clinically, three of the tumors followed an indolent clinical course; however, one patient ultimately died as a result of metastatic disease, suggesting GLI2::CREBBP-rearranged nested-hyalinizing epithelioid neoplasms may behave potentially aggressive. Further study is necessary to characterize the biological potential and molecular-pathologic spectrum of this potentially novel entity.