GLI1-Altered Tumors of the Ovary A Report of Four Cases of an Underrecognized Neoplasm That May Mimic Sex Cord-Stromal Tumors.

GLI1-altered neoplasms are an emerging group of tumors of presumed mesenchymal derivation which occur mostly in the head and neck or soft tissues of the trunk and extremities. We have recently identified four ovarian neoplasms with GLI1 gene fusions; all were initially diagnosed as unusual sex cord stromal tumors (n=3) or endometrioid adenocarcinoma with sex cord-like morphology (n=1). Patients ranged from 11-70 years and tumors from 3-15 cm; all were confined to the ovary. Three displayed dominant patterns of large irregular aggregates and smaller well-delineated nests of round cells with minimal to moderate amounts of clear to eosinophilic cytoplasm and monotonous round to ovoid nuclei divided by collagenous septae and focal myxoid areas. The final tumor showed alternating hypocellular and cellular areas composed of a loose, haphazard arrangement of spindled cells associated with myxoid stroma, imparting a "lace-like" reticular appearance, with only focal nested round cell morphology (20%). Additional minor patterns included tubules (n=3), trabeculae (n=2), follicle-like macrocysts (n=2), cords (n=1), microcysts (n=1), and rosette-like formations (n=1). Mitotic activity was minimal (<1-2/10 high power fields). All tumors had a network of numerous capillary-sized vessels. Two tumors had some positivity for markers of sex cord-stromal differentiation, with focal, strong calretinin expression in one and diffuse, weak SF1 in another. RNA-based next-generation sequencing revealed PTCH1::GLI1 fusions in all three tumors with round cells and an ACTB::GLI1 fusion in the predominantly spindled tumor. Our experience with these tumors, particularly the discovery of three of the cases in a relatively short time frame, suggests they are underrecognized in the ovary, where their morphologic features often mimic those of sex cord-stromal neoplasms. Awareness of their morphologic features and appropriate use of genetic testing will ensure accurate diagnosis and lead to greater understanding of these rare neoplasms.