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Myxoid pleomorphic liposarcoma is distinguished from other liposarcomas by widespread loss of heterozygosity and significantly worse overall survival: a genomic and clinicopathologic study

Abstract

Myxoid pleomorphic liposarcoma (MPLPS) is a recently described and extremely rare subtype of liposarcoma with a predilection for the mediastinum. However, the genomic features of MPLPS remain poorly understood. We performed comprehensive genomic profiling of MPLPS in comparison with pleomorphic liposarcoma (PLPS) and myxoid/round cell liposarcoma (MRLPS). Of the 8 patients with MPLPS, 5 were female and 3 were male, with a median age of 32 years old (range 10–68). All except one were located in the mediastinum, with invasion of surrounding anatomic structures, including chest wall, pleura, spine, and large vessels. All cases showed an admixture of morphologies reminiscent of PLPS and MRLPS, including myxoid areas with plexiform vasculature admixed with uni- and/or multivacuolated pleomorphic lipoblasts. Less common features included well-differentiated liposarcoma-like areas, and in one case fascicular spindle cell sarcoma reminiscent of dedifferentiated LPS. Clinically, 4 experienced local recurrence, 4 had distant metastases and 5 died of disease. Compared to PLPS and MRLPS, patients with MPLPS had worse overall and progression-free survival. Recurrent TP53 mutations were present in all 8 MPLPS cases. In contrast, in PLPS, which also showed recurrent TP53 mutations (83%), RB1 and ATRX losses were more common. MRLPS was highly enriched in TERT promoter mutations (88%) and PI3K/AKT pathway mutations. Copy number profiling in MPLPS revealed multiple chromosomal gains with recurrent amplifications of chromosomes 1, 19 and 21. Importantly, allele-specific copy number analysis revealed widespread loss of heterozygosity (80% of the genome on average) in MPLPS, but not in PLPS or MRLPS. Our findings revealed genome-wide loss of heterozygosity co-existing with TP53 mutations as a characteristic genomic signature distinct from other liposarcoma subtypes, which supports the current classification of MPLPS as a stand-alone pathologic entity. These results further expand the clinicopathologic features of MPLPS, including older age, extra-mediastinal sites, and a highly aggressive outcome.

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Fig. 1: Radiologic, gross pathologic and histologic features of myxoid pleomorphic liposarcoma.
Fig. 2: Histopathologic features of myxoid pleomorphic liposarcoma (MPLPS).
Fig. 3: Recurrent gene-level mutations and copy number alterations across different liposarcoma subtypes.
Fig. 4: Genome-wide copy number alterations in myxoid pleomorphic liposarcoma.
Fig. 5: Widespread loss of heterozygosity in myxoid pleomorphic liposarcoma (MPLPS).
Fig. 6: Overall and progression-free survival among different liposarcoma subtypes.

Data availability

The raw data generated are not publicly available due to lack of access to indefinite hosting capabilities, but are available from the corresponding author on reasonable request.

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Acknowledgements

We gratefully acknowledge the members of the Molecular Diagnostics Service in the Department of Pathology and would like to acknowledge the Center Core grant (P30 CA008748) and the Marie-Josee and Henry R. Kravis Center for Molecular Oncology for use of MSK-IMPACT data. This work was supported by P50 CA217694 (SS, WT, CRA), P30 CA008748 (SS, WT, CRA), Kristin Ann Carr Foundation (CRA). All other authors report no funding sources related to this study.

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J.K.D performed study design, data acquisition, data analysis and interpretation, writing and revision of the paper. SCH, L.W., W.D.T., S.S. performed acquisition, analysis, and/or interpretation of data, and review of the paper. C.M.V. and C.R.A. performed study design and conception, analysis and interpretation of data, writing, review and revision of paper. All authors read and approved the final manuscript.

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Correspondence to Cristina R. Antonescu.

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This study was approved by the Memorial Sloan Kettering Cancer Institute Institutional Review Board.

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Dermawan, J.K., Hwang, S., Wexler, L. et al. Myxoid pleomorphic liposarcoma is distinguished from other liposarcomas by widespread loss of heterozygosity and significantly worse overall survival: a genomic and clinicopathologic study. Mod Pathol (2022). https://doi.org/10.1038/s41379-022-01107-6

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