We examined whether MDM2 and/or CDK4 cause WDLPS/DDLPS, using two types of transformed human bone marrow stem cells (BMSCs), 2H and 5H, with five oncogenic hits (overexpression of hTERT, TP53 degradation, RB inactivation, c-MYC stabilization, and overexpression of HRAS<sup>v12</sup>).
Patients with well-differentiated lipomatous tumors (n = 113), of which 66 were diagnosed as lipoma (mean age 53 years (range, 13-82); 47% women) and 47 as atypical lipomatous tumor (ALT; mean age 60 years (range, 28-88); 64% women), were included into this study using histology and MDM2 amplification status by fluorescence in situ hybridization (FISH) as standard of reference.
Patients with an MDM2-negative lipoma or MDM2-positive WDLPS and a pretreatment T1-weighted MRI scan who were referred to Erasmus MC between 2009 and 2018 were included.
This tumor warrants separation from ordinary lipoma with fat necrosis, fat-rich spindle cell lipoma and the conventional form of atypical lipomatous tumor that features MDM2 gene amplification.
Commonly used immunomarkers, MDM2 and p16, have proven useful in diagnosing WDLS and dedifferentiated liposarcoma (DDLS), while HMB45 and Melan-A are melanocyte-related markers characteristically expressed in AML.
MDM2 and CDK4 were never coexpressed and FISH for MDM2 amplification was consistently negative, highlighting critical biological differences from atypical lipomatous tumor/dedifferentiated liposarcoma.
Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are closely related tumors commonly characterized by MDM2/CDK4 gene amplification, and lack clinically effective treatment options when inoperable.
Differential diagnosis of atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma: utility of p16 in combination with MDM2 and CDK4 immunohistochemistry.
Molecular chromosome analysis was performed on fluorescence in situ hybridization in tissue sections from the tissue blocks in all cases for the purpose of this study; a ratio greater than 2 was considered to represent murine double-minute 2 (MDM2) amplification consistent with a diagnosis of ALT/WDL.
Lipoblastoma (LB) is a rare benign adipocytic tumor of childhood occasionally showing histological similarities to myxoid liposarcoma (ML) or well-differentiated liposarcoma (WDL). p16 immunohistochemistry has proved to be useful in distinguishing various types of liposarcomas, in particular WDL from lipoma, with higher sensitivity and specificity than MDM2 and CDK4 immunohistochemistry.
Despite indistinguishable morphology all cases of malignant PT with WDLS-like liposarcomatous differentiation were negative forMDM2 and CDK4 IHC and FISH, supporting different underlying pathogenesis.
Atypical lipomatous tumor/well-differentiated liposarcoma (ALT-WDLPS) and dedifferentiated liposarcoma (DDLPS) are characterized cytogenetically by a 12q13-15 amplification involving the mouse double minute 2 (MDM2) oncogene.
Four cases of atypical lipomatous tumor/well-differentiated liposarcoma (4/26, 15%) with a low MDM2 and CDK4 amplification level (MDM2-CDK4/CEP12 ratio ranging between 2 and 2.5) detected by FISH showed no amplification by MLPA, although gain of MDM2 and CDK4 (ratios ranging between 1.6 and 1.9) was seen with MLPA.
FISH was performed in two cases of well-differentiated liposarcoma and high levels of amplification of MDM2 at 12q13-15 were observed; the CHOP translocation at 12q13.1-q13.2 was absent in both cases.
HMGA2, CDK4, and JUN genes have been described as frequently coamplified with MDM2 in atypical lipomatous tumor, well-differentiated liposarcoma, and dedifferentiated liposarcoma.
We present 2 cases of liposarcoma arising in the vulva: a myxoid liposarcoma harboring DDIT3 and FUS rearrangements and a well differentiated liposarcoma/atypical lipomatous tumor harboring MDM2 amplification detected by fluorescence in situ hybridization.
Dedifferentiated liposarcoma (DDLPS) has been defined as a tumor composed of well-differentiated liposarcoma associated with a nonlipogenic undifferentiated sarcoma and is genetically characterized by a 12q13-15 amplicon with MDM2 amplification.
In conclusion, this work is the first to report the entire genome of a well-differentiated liposarcoma with novel chromosomal rearrangements associated with amplification of therapeutically targetable genes such as MDM2 and DDR2.