GLI1 Coamplification in Well-Differentiated/Dedifferentiated Liposarcomas: Clinicopathologic and Molecular Analysis of 92 Cases

Overview

Journal Mod Pathol

Specialty Pathology

Date 2024 Apr 15

PMID 38621503

Authors

Aarti E Sharma

Mark Dickson

Samuel Singer

Meera R Hameed

Narasimhan P Agaram

Affiliations

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Abstract

GLI1(12q13.3) amplification is identified in a subset of mesenchymal neoplasms with a distinct nested round cell/epithelioid phenotype. MDM2 and CDK4 genes are situated along the oncogenic 12q13-15 segment, amplification of which defines well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). The 12q amplicon can occasionally include GLI1, a gene in close proximity to CDK4. We hereby describe the first cohort of GLI1/MDM2/CDK4 coamplified WD/DDLPS. The departmental database was queried retrospectively for all cases of WD/DDLPS having undergone next-generation (MSK-IMPACT) sequencing with confirmed MDM2, CDK4, and GLI1 coamplification. Clinicopathologic data was obtained from a review of the medical chart and available histologic material. Four hundred eighty-six WD/DDLPS cases underwent DNA sequencing, 92 (19%) of which harbored amplification of the GLI1 locus in addition to that of MDM2 and CDK4. These included primary tumors (n = 60), local recurrences (n = 29), and metastases (n = 3). Primary tumors were most frequently retroperitoneal (47/60, 78%), mediastinal (4/60, 7%), and paratesticular (3/60, 5%). Average age was 63 years, with a male:female ratio of 3:2. The cohort was comprised of DDLPS (86/92 [93%], 6 of which were WDLPS with early dedifferentiation) and WDLPS without any longitudinal evidence of dedifferentiation (6/92, 7%). One-fifth (13/86, 17%) of DDLPS cases showed no evidence of a well-differentiated component in any of the primary, recurrent, or metastatic specimens. Dedifferentiated areas mostly showed high-grade undifferentiated pleomorphic sarcoma-like (26/86,30%) and high-grade myxofibrosarcoma-like (13/86,16%) morphologies. A disproportionately increased incidence of meningothelial whorls with/without osseous metaplasia was observed as the predominant pattern in 16/86 (19%) cases, and GLI1-altered morphology as described was identified in a total of 10/86 (12%) tumors. JUN (1p32.1), also implicated in the pathogenesis of WD/DDLPS, was coamplified with all 3 of MDM2, CDK4, and GLI1 in 7/91 (8%) cases. Additional loci along chromosomal arms 1p and 6q, including TNFAIP3, LATS1, and ESR1, were also amplified in a subset of cases. In this large-scale cohort of GLI1 coamplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorl-like and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and coamplification of other spatially discrete genomic segments (1p and 6q) might aid in distinction from tumors with true driver GLI1 alterations.

References

Folpe A, Weiss S . Lipoleiomyosarcoma (well-differentiated liposarcoma with leiomyosarcomatous differentiation): a clinicopathologic study of nine cases including one with dedifferentiation. Am J Surg Pathol. 2002; 26(6):742-9. DOI: 10.1097/00000478-200206000-00007. View

Yan Y, Xia S, Teng D, Hu S, Li S, Wang Y . Resection outcomes for primary and local recurrent retroperitoneal liposarcoma patients. Ann Transl Med. 2020; 8(21):1450. PMC: 7723604. DOI: 10.21037/atm-20-6316. View

Zhu H, Lo H . The Human Glioma-Associated Oncogene Homolog 1 (GLI1) Family of Transcription Factors in Gene Regulation and Diseases. Curr Genomics. 2010; 11(4):238-45. PMC: 2930663. DOI: 10.2174/138920210791233108. View

Scapa J, Cloutier J, Raghavan S, Peters-Schulze G, Varma S, Charville G . DDIT3 Immunohistochemistry Is a Useful Tool for the Diagnosis of Myxoid Liposarcoma. Am J Surg Pathol. 2020; 45(2):230-239. PMC: 7796975. DOI: 10.1097/PAS.0000000000001564. View

Dahlen A, Fletcher C, Mertens F, Fletcher J, Perez-Atayde A, Hicks M . 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(5):1645-53. PMC: 1615655. DOI: 10.1016/s0002-9440(10)63723-6. View

Mantilla J, Ricciotti R, Chen E, Liu Y, Hoch B . Amplification of DNA damage-inducible transcript 3 (DDIT3) is associated with myxoid liposarcoma-like morphology and homologous lipoblastic differentiation in dedifferentiated liposarcoma. Mod Pathol. 2018; 32(4):585-592. DOI: 10.1038/s41379-018-0171-y. View

Xie H, Paradise B, Ma W, Fernandez-Zapico M . Recent Advances in the Clinical Targeting of Hedgehog/GLI Signaling in Cancer. Cells. 2019; 8(5). PMC: 6562674. DOI: 10.3390/cells8050394. View

Tap W, Eilber F, Ginther C, Dry S, Reese N, Barzan-Smith K . Evaluation of well-differentiated/de-differentiated liposarcomas by high-resolution oligonucleotide array-based comparative genomic hybridization. Genes Chromosomes Cancer. 2010; 50(2):95-112. DOI: 10.1002/gcc.20835. View

Nascimento A, Kurtin P, Guillou L, Fletcher C . Dedifferentiated liposarcoma: a report of nine cases with a peculiar neurallike whorling pattern associated with metaplastic bone formation. Am J Surg Pathol. 1998; 22(8):945-55. DOI: 10.1097/00000478-199808000-00004. View

10.

Alwaqfi R, Samuelson M, Guseva N, Ouyang M, Bossler A, Ma D . PTCH1-GLI1 Fusion-Positive Ovarian Tumor: Report of a Unique Case With Response to Tyrosine Kinase Inhibitor Pazopanib. J Natl Compr Canc Netw. 2021; 19(9):998-1004. DOI: 10.6004/jnccn.2021.7058. View

11.

Henricks W, Chu Y, Goldblum J, Weiss S . Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol. 1997; 21(3):271-81. DOI: 10.1097/00000478-199703000-00002. View

12.

Spans L, Fletcher C, Antonescu C, Rouquette A, Coindre J, Sciot R . Recurrent MALAT1-GLI1 oncogenic fusion and GLI1 up-regulation define a subset of plexiform fibromyxoma. J Pathol. 2016; 239(3):335-43. PMC: 5586099. DOI: 10.1002/path.4730. View

13.

Agaimy A, Michal M, Hadravsky L, Michal M . Dedifferentiated liposarcoma composed predominantly of rhabdoid/epithelioid cells: a frequently misdiagnosed highly aggressive variant. Hum Pathol. 2018; 77:20-27. DOI: 10.1016/j.humpath.2017.12.025. View

14.

Hasegawa T, Seki K, Hasegawa F, Matsuno Y, Shimodo T, Hirose T . Dedifferentiated liposarcoma of retroperitoneum and mesentery: varied growth patterns and histological grades--a clinicopathologic study of 32 cases. Hum Pathol. 2000; 31(6):717-27. DOI: 10.1053/hupa.2000.8222. View

15.

Kuczkiewicz-Siemion O, Wisniewski P, Dansonka-Mieszkowska A, Grabowska-Kieryl M, Olszewska K, Goryn T . The utility of fluorescence in situ hybridization (FISH) in determining DNA damage-inducible transcript 3 (DDIT3) amplification in dedifferentiated liposarcomas - an important diagnostic pitfall. Pathol Res Pract. 2021; 225:153555. DOI: 10.1016/j.prp.2021.153555. View

16.

Kerr D, Pinto A, Subhawong T, Wilky B, Schlumbrecht M, Antonescu C . 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(12):1682-1692. PMC: 6851481. DOI: 10.1097/PAS.0000000000001360. View

17.

Takahashi S, Fujiwara Y, Nakano K, Shimizu T, Tomomatsu J, Koyama T . Safety and pharmacokinetics of milademetan, a MDM2 inhibitor, in Japanese patients with solid tumors: A phase I study. Cancer Sci. 2021; 112(6):2361-2370. PMC: 8177775. DOI: 10.1111/cas.14875. View

18.

Xu B, Chang K, Folpe A, Kao Y, Wey S, Huang H . 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(6):729-737. PMC: 7225037. DOI: 10.1097/PAS.0000000000001439. View

19.

Yamashita K, Kohashi K, Yamada Y, Ishii T, Nishida Y, Urakawa H . Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. Histopathology. 2017; 72(5):729-738. DOI: 10.1111/his.13421. View

20.

Yu Z, Zhao X, Gao J, Zhou S, Li P, Liu N . Correlation Analysis Between Demographic, Surgical, and Pathological Characteristics with Local Recurrence-Free Survival for Surgical Resected Retroperitoneal Liposarcoma. World J Surg. 2023; 47(8):1946-1955. DOI: 10.1007/s00268-023-07009-1. View