Histologic Subvariants of Retroperitoneal Well-Differentiated Liposarcoma Show Evidence of Clinical and Genomic Progression Toward Dedifferentiated Liposarcoma

PURPOSE Several histologic subvariants of retroperitoneal well-differentiated liposarcoma (WDLS) have been described, but their associations with clinical outcomes, underlying genomic differences, and transformation to dedifferentiated liposarcoma (DDLS) are not well-defined. METHODS We identified 276 patients with primary retroperitoneal WDLS and 353 patients with primary retroperitoneal DDLS who underwent resection between July 1982 and July 2021 at our institution. WDLS histology was reviewed by a sarcoma pathologist and divided into three subvariants: lipoma-like, sclerosing/myxoid, or incipient/early dedifferentiated WDLS. We also performed an exploratory genomic analysis on a subset of 140 patients with available next-generation targeted sequencing data generated using the MSK-IMPACT platform. RESULTS Compared with the lipoma-like subvariant, the sclerosing/myxoid (hazard ratio [HR], 3.2) and incipient/early dedifferentiated subvariants (HR, 5.3) and DDLS (HR, 9.6) were independently associated with higher incidence of disease-specific death after controlling for other prognostic factors such as tumor size and resection margins. Both the sclerosing/myxoid (HR, 2.9) and incipient/early dedifferentiated (HR, 5.4) subvariants were also associated with a higher incidence of subsequent dedifferentiation compared with the lipoma-like subvariant. On genomic exploratory analysis, compared with the lipoma-like samples, the sclerosing/myxoid and incipient/early dedifferentiated samples had significantly higher copy number log ratios (CNLRs) of MDM2 and CDK4 , with the incipient/early dedifferentiated samples having similar CNLRs of MDM2 and CDK4 to DDLS samples. CONCLUSION WDLS subvariants exhibit both a morphological and genomic progression along the WDLS to DDLS disease spectrum. Distinguishing between them is clinically meaningful for accurate patient counseling and enrollment and stratification in future clinical trials.