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.
Your institute does not have access to this article
Subscribe to Journal
Get full journal access for 1 year
We are sorry, but there is no personal subscription option available for your country.
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
Alaggio R., Coffin C.M., Weiss S.W., Bridge J.A., Issakov J., Oliveira A.M. & Folpe A.L. Liposarcomas in young patients: a study of 82 cases occurring in patients younger than 22 years of age. Am. J. Surg. Pathol. 33, 645-–658 (2009).
Boland J.M., Colby T.V. & Folpe A.L. Liposarcomas of the mediastinum and thorax: a clinicopathologic and molecular cytogenetic study of 24 cases, emphasizing unusual and diverse histologic features. Am. J. Surg. Pathol. 36, 1395–1403 (2012).
Creytens D., Folpe A.L., Koelsche C., Mentzel T., Ferdinande L., van Gorp J.M., et al. Myxoid pleomorphic liposarcoma-a clinicopathologic, immunohistochemical, molecular genetic and epigenetic study of 12 cases, suggesting a possible relationship with conventional pleomorphic liposarcoma. Mod. Pathol. 34, 2043–2049 (2021).
Creytens D., van Gorp J., Ferdinande L., Van Roy N. & Libbrecht L. Array-based comparative genomic hybridization analysis of a pleomorphic myxoid liposarcoma. J. Clin. Pathol. 67, 834–835 (2014).
Hofvander J., Jo V.Y., Ghanei I., Gisselsson D., Mårtensson E. & Mertens F. Comprehensive genetic analysis of a paediatric pleomorphic myxoid liposarcoma reveals near-haploidization and loss of the RB1 gene. Histopathology. 69, 141–147 (2016).
Cheng D.T., Mitchell T.N., Zehir A., Shah R.H., Benayed R., Syed 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. 17, 251–264 (2015).
Mayakonda A., Lin D., Assenov Y., Plass C. & Koeffler P.H. “Maftools: efficient and comprehensive analysis of somatic variants in cancer.” Genome Res. 28, 1747–1756 (2018).
Zhang J. (2021). CNTools: Convert segment data into a region by sample matrix to allow for other high level computational analyses. R package version 1.50.0.
Wang, S., Li, H., Song, M., Tao, Z., Wu, T. & He, Z. et al. Copy number signature analysis tool and its application in prostate cancer reveals distinct mutational processes and clinical outcomes. PLoS Genet 17, e1009557 (2021).
Gu, Z. Circlize implements and enhances circular visualization in R. Bioinformatics. 30, 2811–2812 (2014).
Shen, R. & Seshan, V. E. FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res 44, e131 (2016).
Plukker, J.T., Joosten, H.J., Rensing, J.B. & Van Haelst U.J. Primary liposarcoma of the mediastinum in a child. J. Surg. Oncol. 37, 257–263 (1988).
Greif J., Marmor S., Merimsky O., Kovner F. & Inbar M. Primary liposarcoma of the mediastinum. Sarcoma. 2, 205–257 (1998).
Hahn H.P. & Fletcher C.D. Primary mediastinal liposarcoma: clinicopathologic analysis of 24 cases. Am. J. Surg. Pathol. 31, 1868–1874 (2007).
von Mehren M., Randall R.L., Benjamin R.S., Boles S., Bui M.M., Ganjoo K.N., et al. Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Canc. Netw. 16, 536–563 (2018).
Gronchi A., Miah A.B., Dei Tos A.P., Abecassis N., Bajpai J., Bauer S., Biagini R., et al. Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 32, 1348–1365 (2021).
Bode-Lesniewska B., Frigerio S., Exner U., Abdou M.T, Moch H. & Zimmermann DR. Relevance of translocation type in myxoid liposarcoma and identification of a novel EWSR1-DDIT3 fusion. Genes Chromosomes Cancer. 46, 961–971 (2007).
Hornick J.L., Bosenberg M.W., Mentzel T., McMenamin M.E., Oliveira A.M. & Fletcher C.D. Pleomorphic liposarcoma: clinicopathologic analysis of 57 cases. Am. J. Surg. Pathol. 28, 1257–1267 (2004).
Koelsche C., Renner M., Hartmann W., Brandt R., Lehner B., Waldburger N., et al. TERT promoter hotspot mutations are recurrent in myxoid liposarcomas but rare in other soft tissue sarcoma entities. J. Exp. Clin. Cancer Res. 33, 33 (2014).
Barretina J., Taylor B.S., Banerji S., Ramos A.H., Lagos-Quintana M., Decarolis P.L., et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat. Genet. 42, 715–721 (2010).
Demicco E.G., Torres K.E., Ghadimi M.P., Colombo C., Bolshakov S., Hoffman A., et al. Involvement of the PI3K/Akt pathway in myxoid/round cell liposarcoma. Mod. Pathol. 25, 212–221 (2012).
Trautmann M., Cyra M., Isfort I., Jeiler B., Krüger A., Grünewald I., et al. Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in Myxoid Liposarcoma. Mol. Cancer Ther. 18, 834–844 (2019).
Ghadimi M.P., Liu P., Peng T., Bolshakov S., Young E.D., Torres K.E., et al. Pleomorphic liposarcoma: clinical observations and molecular variables. Cancer. 117, 5359–5369 (2011).
Sinclair T.J., Thorson CM., Alvarez E., Tan S., Spunt S.L. & Chao S.D. Pleomorphic myxoid liposarcoma in an adolescent with Li-Fraumeni syndrome. Pediatr. Surg. Int. 33, 631–635 (2017).
Yoshikawa Y., Emi M., Hashimoto-Tamaoki T., Ohmuraya M., Sato A., Tsujimura T., et al. High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. Proc. Natl. Acad. Sci. U. S. A. 113, 13432–13437 (2016).
Dal Cin P., Sciot R., Fletcher C.D., Samson I., De Vos R., Mandahl N., et al. Inflammatory leiomyosarcoma may be characterized by specific near-haploid chromosome changes. J. Pathol. 185, 112–115 (1998).
Arbajian E., Köster J., Vult von Steyern F. & Mertens F. Inflammatory leiomyosarcoma is a distinct tumor characterized by near-haploidization, few somatic mutations, and a primitive myogenic gene expression signature. Mod. Pathol. 31, 93–100 (2018).
Cloutier J.M., Charville G.W., Mertens F., Sukov W., Fritchie K., Perry K.D., et al. “Inflammatory Leiomyosarcoma” and “Histiocyte-rich Rhabdomyoblastic Tumor”: a clinicopathological, immunohistochemical and genetic study of 13 cases, with a proposal for reclassification as “Inflammatory Rhabdomyoblastic Tumor”. Mod Pathol. 34, 758–769 (2021).
Bielski C.M., Zehir A., Penson A.V., Donoghue M.T.A., Chatila W., Armenia J., et al. Genome doubling shapes the evolution and prognosis of advanced cancers. Nat. Genet. 50, 1189–1195 (2018).
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.
The authors declare no competing interests.
Ethics approval/consent to participate
This study was approved by the Memorial Sloan Kettering Cancer Institute Institutional Review Board.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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