GLI1-Altered neoplasms: From molecular alterations to morphologic and phenotypic features with formal recognition in the upcoming WHO Classification of soft tissue tumors.

Abstract

GLI1-altered mesenchymal tumors represent a recently defined group of neoplasms molecularly characterized by GLI1 gene fusions or amplifications. Although initially thought to share similar molecular alterations, including pericytoma with ACTB::GLI1 fusion, plexiform fibromyxoma, and gastroblastoma, these tumors are now recognized as distinct entities with specific clinicopathological features. Histologically, GLI1-altered mesenchymal tumors typically exhibit a multinodular growth pattern composed of relatively uniform epithelioid-to-ovoid cells arranged in nested formations. These nests are supported by a delicate arborizing capillary network and are often embedded in a myxoid stroma. Immunohistochemically, variable positivity for CD56, S100, CD10, smooth muscle actin, cyclin D1, and p16 has been reported. GLI1 immunohistochemistry is both highly sensitive and specific, serving as a valuable diagnostic marker in the appropriate context. Some GLI1-amplified tumors may show co-amplification of neighboring genes, including STAT6, MDM2, CDK4, and DDIT3, which can result in variable immunoreactivity depending on amplicon size. These tumors can arise at a broad range of anatomical sites and occur across all age groups. Although GLI1-altered mesenchymal neoplasms were initially considered indolent, malignant cases with metastatic potential have been reported. Necrosis, high mitotic index, and large tumor size are associated with an increased risk of metastasis. Tumors with GLI1 amplification generally demonstrate worse clinical outcomes than those driven by GLI1 fusions. Definitive diagnosis requires molecular confirmation via next-generation sequencing and/or fluorescence in situ hybridization. Accurate recognition of GLI1-altered mesenchymal tumors has important diagnostic, prognostic, and therapeutic implications. Herein, we describe the clinicopathologic features of GLI1-altered neoplasms, including their molecular findings and the differential diagnosis with other tumors exhibiting overlapping morphology and immunoprofile.