GLI1 -altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1 -altered mesenchymal neoplasms to date, including 23 GLI1- amplified and 15 GLI1 -rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1- rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1 -amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1 -amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1- amplified tumors. GLI1 -amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1 -amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1 -rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1 -amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1- rearranged group. Despite comparable progression rates, GLI1 -amplified tumors had a shorter median progression-free survival compared with GLI1 -rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1 -altered mesenchymal tumors.

Adolescent and Young Adult Oncology Cook Children's Medical Center Fort Worth TX

Bioptical Laboratory Ltd Plzeň Czech Republic

Department of Laboratory Medicine and Pathology Mount Sinai Hospital University of Toronto Toronto Ontario Canada

Department of Pathology and Laboratory Medicine Aga Khan University Hospital Karachi Pakistan

Department of Pathology and Laboratory Medicine Geisel School of Medicine at Dartmouth Dartmouth Hitchcock Medical Center Lebanon New Hampshire

Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY

Department of Pathology Charles University Faculty of Medicine in Plzeň Czech Republic; Bioptical Laboratory Ltd Plzeň Czech Republic

Department of Pathology Hacettepe University Ankara Turkey

Institute of Pathology Erlangen University Hospital Comprehensive Cancer Center European Metropolitan Area Erlangen Nuremberg Friedrich Alexander University of Erlangen Nuremberg Erlangen Germany

Robert J Tomsich Pathology and Laboratory Medicine Institute Cleveland Clinic Cleveland OH

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Chetty R Gene of the month: GLI-1. J Clin Pathol. 2020;73:228–230. PubMed

Carpenter RL, Lo HW. Identification, functional characterization, and pathobiological significance of GLI1 isoforms in human cancers. Vitam Horm. 2012;88:115–140. PubMed PMC

Dahlén A, Fletcher CD, Mertens F, et al. Activation of the GLI oncogene through fusion with the beta-actin gene (ACTB) in a group of distinctive pericytic neoplasms: pericytoma with t(7;12). Am J Pathol. 2004;164:1645–1653. PubMed PMC

Spans L, Fletcher CD, Antonescu CR, et al. Recurrent MALAT1-GLI1 oncogenic fusion and GLI1 up-regulation define a subset of plexiform fibromyxoma. J Pathol. 2016;239:335–343. PubMed PMC

Graham RP, Nair AA, Davila JI, et al. Gastroblastoma harbors a recurrent somatic MALAT1-GLI1 fusion gene. Mod Pathol. 2017;30:1443–1452. PubMed

Antonescu CR, Agaram NP, Sung YS, et al. A Distinct Malignant Epithelioid Neoplasm With GLI1 Gene Rearrangements, Frequent S100 Protein Expression, and Metastatic Potential: Expanding the Spectrum of Pathologic Entities With ACTB/MALAT1/PTCH1-GLI1 Fusions. Am J Surg Pathol. 2018;42:553–560. PubMed PMC

Agaram NP, Zhang L, Sung YS, et al. GLI1-amplifications expand the spectrum of soft tissue neoplasms defined by GLI1 gene fusions. Mod Pathol. 2019;32:1617–1626. PubMed PMC

Argani P, Boyraz B, Oliva E, et al. GLI1 Gene Alterations in Neoplasms of the Genitourinary and Gynecologic Tract. Am J Surg Pathol. 2022;46:677–687. PubMed PMC

Liu J, Mao R, Lao IW, et al. GLI1-altered mesenchymal tumor: a clinicopathological and molecular analysis of ten additional cases of an emerging entity. Virchows Arch. 2022;480:1087–1099. PubMed

Kerr DA, Cloutier JM, Margolis M, et al. GLI1-Altered Mesenchymal Tumors With ACTB or PTCH1 Fusion: A Molecular and Clinicopathologic Analysis. Mod Pathol. 2023;37:100386. PubMed

Zheng Z, Liebers M, Zhelyazkova B, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014;20:1479–1484. PubMed

Cheng DT, Mitchell TN, Zehir A, et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. J Mol Diagn. 2015;17:251–264. PubMed PMC

Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31:1023–1031. PubMed PMC

Xu B, Chang K, Folpe AL, et al. Head and Neck Mesenchymal Neoplasms With GLI1 Gene Alterations: A Pathologic Entity With Distinct Histologic Features and Potential for Distant Metastasis. Am J Surg Pathol. 2020;44:729–737. PubMed PMC

Jessurun J, Orr C, McNulty SN, et al. GLI1 -Rearranged Enteric Tumor : Expanding the Spectrum of Gastrointestinal Neoplasms With GLI1 Gene Fusions. Am J Surg Pathol. 2023;47:65–73. PubMed

Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32:2847–2849. PubMed

Skidmore ZL, Wagner AH, Lesurf R, et al. GenVisR: Genomic Visualizations in R. Bioinformatics. 2016;32:3012–3014. PubMed PMC

Prall OWJ, McEvoy CRE, Byrne DJ, et al. A Malignant Neoplasm From the Jejunum With a MALAT1-GLI1 Fusion and 26-Year Survival History. Int J Surg Pathol. 2020;28:553–562. PubMed

Kerr DA, Pinto A, Subhawong TK, et al. Pericytoma With t(7;12) and ACTB-GLI1 Fusion: Reevaluation of an Unusual Entity and its Relationship to the Spectrum of GLI1 Fusion-related Neoplasms. Am J Surg Pathol. 2019;43:1682–1692. PubMed PMC

Papke DJ Jr., Dickson BC, Oliveira AM, et al. Distinctive Nested Glomoid Neoplasm: Clinicopathologic Analysis of 20 Cases of a Mesenchymal Neoplasm With Frequent GLI1 Alterations and Indolent Behavior. Am J Surg Pathol. 2023;47:12–24. PubMed

Castri F, Ravegnini G, Lodoli C, et al. Gastroblastoma in old age. Histopathology. 2019;75:778–782. PubMed

Shabbir J, Earle J, Glomski K, et al. Gastroblastoma with a novel ACTB::GLI1 gene fusion in a 19-year-old male. Virchows Arch. 2024. PubMed

Liu Y, Wu H, Wu X, et al. Gastroblastoma Treated by Endoscopic Submucosal Excavation with a Novel PTCH1::GLI2 Fusion: A Rare Case Report and Literature Review. Curr Oncol. 2022;29:8862–8873. PubMed PMC

Koo SC, LaHaye S, Kovari BP, et al. Gastroblastoma with a novel EWSR1-CTBP1 fusion presenting in adolescence. Genes Chromosomes Cancer. 2021;60:640–646. PubMed

Doyle LA, Tao D, Mariño-Enríquez A. STAT6 is amplified in a subset of dedifferentiated liposarcoma. Mod Pathol. 2014;27:1231–1237. PubMed

Demicco EG, Harms PW, Patel RM, et al. Extensive survey of STAT6 expression in a large series of mesenchymal tumors. Am J Clin Pathol. 2015;143:672–682. PubMed PMC

Palsgrove DN, Rooper LM, Stevens TM, et al. GLI1-Altered Soft Tissue Tumors of the Head and Neck: Frequent Oropharyngeal Involvement, p16 Immunoreactivity, and Detectable Alterations by DDIT3 Break Apart FISH. Head Neck Pathol. 2022;16:1146–1156. PubMed PMC

Parrack PH, Mariño-Enríquez A, Fletcher CDM, et al. GLI1 Immunohistochemistry Distinguishes Mesenchymal Neoplasms With GLI1 Alterations From Morphologic Mimics. Am J Surg Pathol. 2023;47:453–460. PubMed

Machado I, Agaimy A, Giner F, et al. The value of GLI1 and p16 immunohistochemistry in the premolecular screening for GLI1-altered mesenchymal neoplasms. Virchows Arch. 2023. PubMed PMC

Kotake Y, Naemura M, Murasaki C, et al. Transcriptional Regulation of the p16 Tumor Suppressor Gene. Anticancer Res. 2015;35:4397–4401. PubMed

Machado I, Hosler GA, Traves V, et al. Superficial GLI1-amplified mesenchymal neoplasms: Expanding the spectrum of an emerging entity which reaches the realm of dermatopathology. J Cutan Pathol. 2023;50:487–499. PubMed

Sioletic S, Dal Cin P, Fletcher CD, Hornick JL. Well-differentiated and dedifferentiated liposarcomas with prominent myxoid stroma: analysis of 56 cases. Histopathology. 2013;62:287–293. PubMed

Giner F, Machado I, Rubio-Martínez LA, et al. Intimal Sarcoma with MDM2/CDK4 Amplification and p16 Overexpression: A Review of Histological Features in Primary Tumor and Xenograft, with Immunophenotype and Molecular Profiling. Int J Mol Sci. 2023;24. PubMed PMC

Ji P, Diederichs S, Wang W, et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22:8031–8041. PubMed

Kasper M, Schnidar H, Neill GW, et al. Selective modulation of Hedgehog/GLI target gene expression by epidermal growth factor signaling in human keratinocytes. Mol Cell Biol. 2006;26:6283–6298. PubMed PMC

Mendelson NL, Al Assaad M, Hadi K, et al. Whole-genome Analysis Elucidates Complex Genomic Events in GLI1 -rearranged Enteric Tumor. Am J Surg Pathol. 2023;47:1192–1193. PubMed

Lopez-Nunez O, Surrey LF, Alaggio R, et al. Novel APOD-GLI1 rearrangement in a sarcoma of unknown lineage. Histopathology. 2021;78:338–340. PubMed

Nitta Y, Takeda M, Fujii T, et al. A case of pericytic neoplasm in the shoulder with a novel DERA-GLI1 gene fusion. Histopathology. 2021;78:466–469. PubMed

Punjabi LS, Goh CHR, Sittampalam K. Expanding the spectrum of GLI1-altered mesenchymal tumors-A high-grade uterine sarcoma harboring a novel PAMR1::GLI1 fusion and literature review of GLI1-altered mesenchymal neoplasms of the gynecologic tract. Genes Chromosomes Cancer. 2023;62:107–114. PubMed

Wang Z, Wang DZ, Pipes GC, Olson EN. Myocardin is a master regulator of smooth muscle gene expression. Proc Natl Acad Sci U S A. 2003;100:7129–7134. PubMed PMC

Whitson RJ, Lee A, Urman NM, et al. Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas. Nat Med. 2018;24:271–281. PubMed PMC

Didiasova M, Schaefer L, Wygrecka M. Targeting GLI Transcription Factors in Cancer. Molecules. 2018;23. PubMed PMC

Cutaneous/subcutaneous RREB1::MRTFB fusion-positive extra-glossal mesenchymal neoplasm-two cases expanding the anatomical spectrum of an emerging entity