Myxoid pleomorphic liposarcoma is a recently defined subtype of liposarcoma, which preferentially involves the mediastinum of young patients and shows mixed histological features of conventional myxoid liposarcoma and pleomorphic liposarcoma. While myxoid pleomorphic liposarcoma is known to lack the EWSR1/FUS-DDIT3 fusions characteristic of the former, additional genetic data are limited. To further understand this tumor type, we extensively examined a series of myxoid pleomorphic liposarcomas by fluorescence in situ hybridization (FISH), shallow whole genome sequencing (sWGS) and genome-wide DNA methylation profiling. The 12 tumors occurred in 6 females and 6 males, ranging from 17 to 58 years of age (mean 33 years, median 35 years), and were located in the mediastinum (n = 5), back, neck, cheek and leg, including thigh. Histologically, all cases consisted of relatively, bland, abundantly myxoid areas with a prominent capillary vasculature, admixed with much more cellular and less myxoid foci containing markedly pleomorphic spindled cells, numerous pleomorphic lipoblasts and elevated mitotic activity. Using sWGS, myxoid pleomorphic liposarcomas were found to have complex chromosomal alterations, including recurrent large chromosomal gains involving chromosomes 1, 6–8, 18–21 and losses involving chromosomes 13, 16 and 17. Losses in chromosome 13, in particular loss in 13q14 (including RB1, RCTB2, DLEU1, and ITM2B genes), were observed in 4 out of 8 cases analyzed. Additional FISH analyses confirmed the presence of a monoallelic RB1 deletion in 8/12 cases. Moreover, nuclear Rb expression was deficient in all studied cases. None showed DDIT3 gene rearrangement or MDM2 gene amplification. Using genome-wide DNA methylation profiling, myxoid pleomorphic liposarcomas and conventional pleomorphic liposarcomas formed a common methylation cluster, which segregated from conventional myxoid liposarcomas. While the morphologic, genetic and epigenetic characteristics of myxoid pleomorphic liposarcoma suggest a link with conventional pleomorphic liposarcoma, its distinctive clinical features support continued separate classification for the time being.
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Alaggio R, Coffin CM, Weiss SW, Bridge JA, Issakov J, Oliveira AM, et al. Liposarcomas in young patients. A study of 82 cases occurring patients younger than 22 years of age. Am J Surg Pathol. 2009;33:645–58.
WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. Lyon, France: IARC Press; 2020
Alaggio R, Creytens D. Myxoid pleomorphic liposarcoma. In: WHO Classification of Tumours of Soft tissue and Bone. 5th ed. Lyon, France: IARC; 2020
Boland JM, Colby TV, Folpe AL. 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. 2012;36:1395–403.
Creytens D, van Gorp J, Ferdinande L, Van Roy N, Libbrecht L. Array-based comparative genomic hybridisation analysis of a pleomorphic myxoid liposarcoma. J Clin Pathol. 2014;67:834–5.
Hofvander J, Jo VY, Ghanei I, Gisselsson D, Martensson E, Mertens F. Comprehensive genetic analysis of paediatric pleomorphic myxoid liposarcoma reveals near-haploidization and loss of RB1 gene. Histopathology. 2016;69:141–7.
Evans HL. Liposarcoma. A study of 55 cases with reassessment of its classification. Am J Surg Pathol. 1979;3:507–23.
Evans HL, Soule EH, Winkelmann RK. Atypical lipoma, atypical intramuscular lipoma, and well differentiated retroperitoneal liposarcoma. A reappraisal of 30 cases formerly classified as well differentiated liposarcoma. Cancer. 1979;43:574–84.
Demicco EG. Molecular updates in adipocytic neoplasms. Semin Diagn Pathol. 2019;36:85–94.
Creytens D. A contemporary review of myxoid adipocytic tumors. Semin Diagn Pathol. 2019;36:129–41.
Putra J, Al-Ibraheemi A. Adipocytic tumors in children: a contemporary review. Semin Diagn Pathol. 2019;36:95–104.
Creytens D. What’s new in adipocytic neoplasia? Virchows Arch. 2020;476:29–39.
Creytens D, van Gorp J, Savola S, Ferdinande L, Mentzel T, Libbrecht L. Atypical spindle cell lipoma: a clinicopathologic, immunohistochemical, and molecular study emphasizing its relationship to classical spindle cell lipoma. Virchows Arch. 2014;465:97–108.
Creytens D, Mentzel T, Ferdinande L, Lecoutere E, van Gorp J, Atanesyan L, et al. ‘Atypical’ pleomorphic lipomatous tumor: a clinicopathologic, immunohistochemical and molecular study of 21 cases, emphasizing its relationship to atypical spindle cell lipomatous tumor and suggesting a morphologic spectrum (atypical spindle cell/pleomorphic lipomatous tumor). Am J Surg Pathol. 2017;41:1443–55.
Agaimy A. Anisometric cell lipoma: insight from a case series and review of the literature on adipocytic neoplasms in survivors of retinoblastoma suggest a role for RB1 loss and possible relationship to fat-predominant (“fat-only”) spindle cell lipoma. Ann Diagn Pathol. 2017;29:52–6.
Agaimy A, Michal M, Giedl J, Hadravsky L, Michal M. Superficial acral fibromyxoma: clinicopathological, immunohistochemical, and molecular study of 11 cases highlighting frequent Rb1 loss/deletions. Hum Pathol. 2017;60:192–98.
Weaver J, Downs-Kelly E, Goldblum JR, Turner S, Kulkarni S, Tubbs RR, et al. Fluorescence in situ hybridization for MDM2 gene amplification as a diagnostic tool in lipomatous neoplasms. Mod Pathol. 2008;21:943–9.
Creytens D, van Gorp J, Ferdinande L, Speel EJ, Libbrecht L. Detection of MDM2/CDK4 amplification in lipomatous soft tissue tumors from formalin-fixed, paraffin-embedded tissue: comparison of multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH). Appl Immunohistochem Mol Morphol. 2015;23:126–33.
Downs-Kelly E, Goldblum JR, Patel RM, Weiss SW, Folpe AL, Mertens F, et al. The utility of fluorescence in situ hybridization (FISH) in the diagnosis of myxoid soft tissue neoplasms. Am J Surg Pathol. 2008;31:8–13.
Langmead B, Trapnell C, Pop M, Salzberg SL. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009;10:R25.
Tischler G, Leonard S. Biobambam: tools for read pair collation based algorithms on BAM files. Source Code Biol Med. 2014;9:13.
Li H, Handsaker B, Wysoker A, Fenell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–9.
Raman L, Van der Linden M, De Vriendt C, Van den Broeck B, Muylle K, Deeren D, et al. Shallow-depth sequencing of cell-free DNA for Hodgkin and diffuse large B-cell lymphoma (differential) diagnosis: a standardized approach with underappreciated potential. Haematologica. (2020). https://doi.org/10.3324/haematol.2020.268813
Raman L, Dheedene A, De Smet M, Van Dorpe J, Menten B. WisecondorX: improved copy number detection for routine shallow whole-genome sequencing. Nucleic Acids Res. 2019;47:1605–14.
Van der Linden M, Raman L, Vander Trappen A, Dheedene A, De Smet M, Sante T, et al. Detection of copy number alterations by shallow whole-genome sequencing of formalin-fixed, paraffin-embedded tumor tissue. Arch Pathol Lab Med. (2019). https://doi.org/10.5858/arpa.2019-0010-OA
Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555:469–74.
Capper D, Stichel D, Sahm F, Jones DTW, Schrimpf D, Sill M, et al. Practical implementation of DNA methylation and copy‑number‑based CNS tumor diagnostics: the Heidelberg experience. Acta Neuropathologica. 2018;136:181–210.
Koelsche C, Schrimpf D, Stichel D, Sill M, Sahm F, Reuss DE, et al. Sarcoma classification by DNA methylation profiling. Nat Commun. 2021;12:498.
Sinclair TJ, Thorson CM, Alvarez E, Tan S, Spunt SL, Chao SD. Pleomorphic myxoid liposarcoma in an adolescent with Li-Fraumeni syndrome. Pediatr Surg Int. 2017;33:631–5.
Francom CR, Leoniak SM, Lovell MA, Herrmann BW. Head and neck pleomorphic myxoid liposarcoma in a child with Li-Fraumeni syndrome. Int J Pediatr Otorhinolaryngol. 2019;123:191–4.
Zare SY, Leivo M, Fadare O. Recurrent pleomorphic myxoid liposarcoma in a patient with Li-Fraumeni syndrome. Int J Surg Pathol. 2020;28:225–8.
Dyson NJ. RB1: a prototype tumor suppressor and an enigma. Genes Dev. 2016;30:1492–502.
Dal Cin P, Sciot R, Polito P, Stas M, de Wever I, Cornelis A, et al. Lesions of 13q may occur independently of deletion of 16q in spindle cell/pleomorphic lipomas. Histopathology. 1997;31:222–5.
Schneider-Stock R, Walter H, Radig K, Rys J, Bosse A, Kuhnen C, et al. MDM2 amplification and loss of heterozygosity at RB and p53 genes: no simultaneous alterations in the oncogenesis of liposarcomas. J Cancer Res Clin Oncol. 1998;124:532–40.
Barretina J, Taylor BS, Banerji S, Ramos AH, Lagos-Quintana M, Decarolis PL, et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet. 2010;42:715–21.
Mentzel T, Palmedo G, Kuhnen C. Well-differentiated spindle cell liposarcoma (‘atypical spindle cell lipomatous tumor’) does not belong to the spectrum of atypical lipomatous tumor but has a close relationship to spindle cell lipoma: clinicopathologic, immunohistochemical, and molecular analysis of six cases. Mod Pathol. 2010;23:729–36.
Ghadimi MP, Liu P, Peng T, Bolshakov S, Young ED, Torres KE, et al. Pleomorphic liposarcoma: clinical observations and molecular variables. Cancer. 2011;117:5359–69.
Marino-Enriquez A, Nascimento AF, Ligon AH, Liang C, Fletcher CDM. Atypical spindle cell lipomatous tumor: clinicopathologic characterization of 232 cases demonstrating a morphologic spectrum. Am J Surg Pathol. 2017;41:234–44.
Lecoutere E, Creytens D. Atypical spindle cell/pleomorphic lipomatous tumor. Histol Histopathol. 2020;35:769–78.
Latil A, Chêne L, Mangin P, Fournier G, Berthon P, Cussenot O. Extensive analysis of the 13q14 region in human prostate tumors: DNA analysis and quantitative expression of genes lying in the interval of deletion. Prostate. 2003;57:39–50.
Garding A, Bhattacharya N, Claus R, Ruppel M, Tschuch C, Filarsky K, et al. Epigenetic upregulation of IncRNAs at 13q14.3 in leukemia is linked to the In Cis downregulation of a gene cluster that targets NF-kB. PLoS Genet. 2013;9:e1003373.
Gebhard S, Coindre JM, Michels JJ, Terrier P, Bertrand G, Trassard M, et al. Pleomorphic liposarcoma: clinicopathologic, immunohistochemical, and follow-up analysis of 63 cases. Am J Surg Pathol. 2002;26:601–16.
Hornick JL, Bosenberg MW, Mentzel T, McMenamin ME, Oliveira AM, Fletcher CD. Pleomorphic liposarcoma: clinicopathologic analysis of 57 cases. Am J Surg Pathol. 2004;28:1257–67.
Pedeutour F, Montgomery EA. Pleomorphic liposarcoma. In: WHO Classification of Tumours of Soft tissue and Bone. 5th ed. Lyon, France: IARC; 2020
Anderson WJ, Jo VY. Pleomorphic liposarcoma: updates and current differential diagnosis. Semin Diagn Pathol. 2019;36:122–8.
We are very grateful for technical assistance to Isabelle Rottiers and Lynn Supply (Department of Pathology, University Hospital Ghent, Belgium) and Tamara De Clercq (Center for Medical Genetics, Ghent University, Ghent, Belgium). We thank the Microarray unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ) for providing excellent DNA methylation services. This work was supported by the German Cancer Aid (Grant no. 70112499).
The DNA methylation profiling part in this study was supported by the German Cancer Aid (Grant no. 70112499). Other authors received no specific funding for this work.
Ethics approval and consent to participate
This study was approved by the Institutional Review Board of the Ghent University Hospital/Ghent University (approval number/ID B670201938578). This study was performed in accordance with the Declaration of Helsinki and with the Code of Conduct of the Federation of Medical Scientific Societies in the United States of America, Belgium, the Netherlands, and Germany.
The authors declare no competing interests.
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Creytens, D., Folpe, A.L., Koelsche, C. 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 (2021). https://doi.org/10.1038/s41379-021-00862-2