Head and Neck Mesenchymal Neoplasms With GLI1 Gene Alterations

Abstract

Soft tissue tumors with GLI1 gene fusions or amplifications have been recently described as a unique pathologic entity with an established risk of malignancy. We herein expand these findings by investigating a cohort of 11 head and neck lesions with GLI1 alterations, including 8 from the tongue, for their clinicopathologic and molecular features. The tumors commonly affected males in their 30s (male:female ratio 2.7:1; range: 1 to 65). Tumors showed a multinodular growth pattern, nested architecture separated by a delicate, arborizing vascular network, monotonous round to ovoid nuclei, and clear cytoplasm. Tumor protrusion into vascular spaces was common. Genetic alterations were investigated by fluorescence in situ hybridization and/or targeted RNA sequencing. Seven tumors harbored GLI1 fusions with the following partners: ACTB (n=4), PTCH1 (n=2), or MALAT1 (n=1). The remaining 4 cases showed coamplifications of GLI1 with CDK4 and MDM2 genes. Tumors were commonly positive for S100 protein and CD56. CDK4, MDM2, and STAT6 were positive in GLI1-amplified tumors. Two of 6 patients with available follow-up (1 each with GLI1 amplification and PTCH1-GLI1 fusion) developed distant metastases. Both tumors showed a high mitotic index and tumor necrosis. The head and neck region, particularly tongue, is a common location for GLI1-related mesenchymal tumors. Although a morphologic overlap was noted with the previously reported “pericytoma with t(7,12) translocation,” often occurring in the tongue, our findings expand the original findings, to include a more variable immunophenotype, propensity for late distant metastases, and alternative mechanisms of GLI1 oncogenic activation, such as various GLI1 fusion partners or GLI1 coamplifications with MDM2 and CDK4 genes.

GLI1 Immunohistochemistry Distinguishes Mesenchymal Neoplasms With GLI1 Alterations From Morphologic Mimics

“…The spectrum of GLI1-altered mesenchymal neoplasms has expanded in recent years to include soft tissue neoplasms with a range of appearances, including nested glomoid neoplasms. [5][6][7][8]10,11,[16][17][18] Despite their distinctive appearance, nested glomoid neoplasms and pericytomas with t(7;12) can be challenging to diagnose in some cases, in part due to nonspecific immunophenotypes. 6 GLI1 IHC has been shown to be sensitive and specific for gastroblastoma, 11 and a recent case report demonstrated GLI1 IHC expression in a mesenchymal neoplasm with MALAT1::GLI1 fusion, 12 suggesting that GLI1 IHC might be diagnostically useful to identify neoplasms driven by GLI1 alterations.…”

“…The latter include "nested glomoid neoplasm", a recently described tumor type that shows the nested architecture and glomus tumor-like perivascular proliferation, as well as other low-grade neoplasms with variable morphology, and high-grade neoplasms, some of which resemble myoepithelial carcinoma. [5][6][7][8][9][10] Pericytomas with t(7;12) and nested glomoid neoplasms have distinctive morphology and a variable immunohistochemical profile, with subsets of cases expressing S100, SMA, CDK4, and MDM2. 6,8 GLI1 immunohistochemistry (IHC) has the potential to facilitate the diagnosis of these rare tumor types without the need for molecular testing.…”

“…GLI1 amplification is present in gliomas and a subset of alveolar rhabdomyosarcomas and osteosarcomas,3,4 and GLI1 amplification and gene fusions have been identified in multiple mesenchymal tumor types, including pericytoma with t(7;12), gastroblastoma, plexiform fibromyxoma, and an emerging class of GLI1 -altered mesenchymal neoplasms. The latter include “nested glomoid neoplasm”, a recently described tumor type that shows the nested architecture and glomus tumor-like perivascular proliferation, as well as other low-grade neoplasms with variable morphology, and high-grade neoplasms, some of which resemble myoepithelial carcinoma 5–10…”

GLI activated epithelioid cell tumour: report of a case and proposed new terminology

“…In contrast to the cases characterised by chromosomal translocations involving GLI1, amplification of the GLI1 gene as the defining molecular event has been previously described in only two case series, in a total of 12 patients. 2,12 The first included 10 cases that showed histological similarities to our case and the malignant epithelioid tumours previously reported by Antonescu and colleagues, but lacked GLI1 rearrangements. 2 These cases did not show any consistent morphological features or immunophenotypes, occurred at a variety of anatomical sites, and showed variable clinical behaviour.…”

“…It is possible that the chromosomal instability inherent to unbalanced translocations resulted in amplification, the latter being responsible for some of the morphological features seen. The second series, 12 from the same group, contributed eight new cases (and three previously reported cases) from the head and neck region. Two of the new cases showed GLI1 amplification, the rest being characterised by GLI1 fusions.…”