Myxoid pleomorphic liposarcoma—a clinicopathologic, immunohistochemical, molecular genetic and epigenetic study of 12 cases, suggesting a possible relationship with conventional pleomorphic liposarcoma

Abstract

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.

Update of Pediatric Lipomatous Lesions: A Clinicopathological, Immunohistochemical and Molecular Overview

“…Molecular findings are in line with those of the adult PLPS and are associated with a complex karyotype with multiple (whole chromosomal) gains and losses, with the most frequent mutations being in TP53 and NF1 (see also Table 1 ) [ 77 , 105 , 107 , 108 , 109 ]. Peng et al found loss of chromosomes 17 and 22, with deletion of RB1 [ 77 ].…”

“…MPLPS is a new entity within pediatric liposarcomas, first described in 2009 by Allagio et al and genomically seen as a distinct subtype of liposarcoma in the current WHO (5th edition, 2020) [ 79 , 83 , 93 , 107 ]. These lesions are rare, although they have a higher incidence in the pediatric population in comparison to adults [ 77 ].…”

“…MPLPS occurs as a large, non-encapsulated, deep-seated soft tissue lesion with ill-defined margins [ 107 ]. It is typically a multinodular growth with infiltration into the surrounding soft tissue [ 107 ].…”

“…Histologically, MPLPS is a high-grade lesion with areas of pleomorphic sarcoma (with severe cytological atypia, pleomorphic lipoblasts, brisk mitotic activity and occasional necrosis) combined with low-grade myxoid components (abundant myxoid matrix with bland, round to oval cells, scattered lipoblasts and a curvilinear, to plexiform capillary network) ( Figure 5 ) [ 77 , 79 , 107 ]. Differentiation from PLPS can be challenging on small biopsies where the MLPS-like pattern is not prominent [ 77 ].…”

“…Immunohistochemically, MPLPS lacks expression of MDM2 and shows a loss of expression for RB1 [ 107 ]. MPLPS does not show a DDIT3 -rearrangement, nor does it have an MDM2 amplification, therefore, differing from MLPS and WDLPS/ALT, respectively [ 77 , 91 ].…”