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We report the case of a "fat-rich" (spindle cell-poor) variant of an atypical spindle cell/pleomorphic lipomatous tumor in a 63-year-old female patient presenting with a firm, painless soft tissue mass on the right hip. Atypical spindle cell/pleomorphic lipomatous tumor is a very recently described low-grade adipocytic neoplasm, which occurs predominantly in adults with a predilection for the limbs and limb girdles. In the present case, the diagnosis of an atypical spindle cell/pleomorphic lipomatous tumor was challenging because the tumor was almost exclusively composed of an atypical adipocytic component (resembling "classical" atypical lipomatous tumor/well-differentiated tumor) with only very focal presence of the diagnostic atypical morphologic features (atypical spindle-shaped cells, floret-like multinucleated cells, and "bizarre" pleomorphic [multinucleated] cells). The possibility of a "classical" atypical lipomatous tumor/well-differentiated liposarcoma was ruled out by immunohistochemistry (lack of MDM2 expression and loss of Rb expression) and molecular genetic testing (no amplification of MDM2 and presence of monoallelic deletion of RB1 ). Another interesting morphologic observation in this case was the striking perivascular location of the atypical spindle/pleomorphic cells in some areas (so-called "pericytic mimicry"). To our knowledge, pericytic mimicry has not been reported in the setting of an atypical spindle cell/pleomorphic lipomatous tumor.

Background/aim: Well-differentiated liposarcoma (WDLPS) and de-differentiated liposarcoma (DDLPS) are characterized by amplified sequences derived from the long arm of chromosome 12. The goal of the present study was to identify, besides the well-known candidate genes, novel relevant genes in these large, complex 12q amplicons., Materials and Methods: Using multiplex ligation-dependent probe amplification, genetic alterations in 19 different genes of 12q12-24 were evaluated in 77 lipomatous soft tissue tumors (including lipomas, WDLPS, DDLPS and pleomorphic liposarcomas)., Results: We recorded several amplified genes of 12q13-15, including miR-26a-2, a gene not well studied in liposarcoma, and the well-known and previously described genes murine double minute 2 (MDM2), YEATS domain-containing protein 4 (YEATS4), high-mobility AT-hook 2 (HMGA2), cyclin-dependent kinase 4 (CDK4) and tetraspanin 31 (TSPAN31). Interestingly, the amplification profiles of these six genes were found to be significantly different between WDLPS and DDLPS, more frequently having a high-level status in DDLPS than in WDLPS. In addition, DDLPS were found to have significantly higher mean amplification ratios compared to WDLPS. Moreover, we identified additional genes exclusively amplified in DDLPS in 12q13, 12q21 and 12q24, including glioma-associated oncogene homolog 1 (GLI1), mitogen activated protein kinase kinase kinase 12 (MAP3K12), cyclin-dependent kinase 2 (CDK2), ALX homeobox 1 (ALX1) and T-box 5 (TBX5)., Conclusion: Differences in amplification profiles among WDLPS and DDLPS may be related to progression/de-differentiation in liposarcomas and show how in the future amplification profiles could provide an adjunctive tool in characterizing progression to DDLPS. In addition, we identified additional genes exclusively amplified in DDLPS, which may play a role in liposarcomagenesis, particularly in the de-differentiation process., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

In this study, the detection of MDM2 and CDK4 amplification was evaluated in lipomatous soft tissue tumors using multiplex ligation-dependent probe amplification (MLPA), a PCR-based technique, in comparison with fluorescence in situ hybridization (FISH). These 2 techniques were evaluated in a series of 77 formalin-fixed, paraffin-embedded lipomatous tumors (27 benign adipose tumors, 28 atypical lipomatous tumors/well-differentiated liposarcomas, 18 dedifferentiated liposarcomas, and 4 pleomorphic liposarcomas). Using MLPA, with a cut-off ratio of >2, 36/71 samples (22 atypical lipomatous tumors/well-differentiated liposarcomas, and 14 dedifferentiated liposarcomas) showed MDM2 and CDK4 amplification. Using FISH as gold standard, MLPA showed a sensitivity of 90% (36/40) and a specificity of 100% (31/31) in detecting amplification of MDM2 and CDK4 in lipomatous soft tissue tumors. In case of high-level amplification (MDM2-CDK4/CEP12 ratio >5), concordance was 100%. 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. No amplification was detected in benign lipomatous tumors and pleomorphic liposarcomas. Furthermore, there was a very high concordance between the ratios obtained by FISH and MLPA. In conclusion, MLPA proves to be an appropriate and straightforward technique for screening MDM2/CDK4 amplification in lipomatous tumors, especially when a correct cut-off value and reference samples are chosen, and could be considered a good alternative to FISH to determine MDM2 and CDK4 amplification in liposarcomas. Moreover, because MLPA, as a multiplex technique, allows simultaneous detection of multiple chromosomal changes of interest, it could be in the future a very reliable and fast molecular analysis on paraffin-embedded material to test for other diagnostically, prognostically, or therapeutically relevant genomic mutations in lipomatous tumors.

We studied a series of spindle cell lipomas arising in atypical sites and showing unusual morphologic features (which we called atypical spindle cell lipoma) to assess if these lesions have the same chromosomal alterations as classical spindle cell lipoma but different from those found in atypical lipomatous tumor/well-differentiated liposarcoma. We investigated alterations of different genes in the 13q14 region and the amplification status of the MDM2 and CDK4 genes at 12q14-15 by multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH) analysis. In the atypical spindle cell lipomas, MLPA revealed deletions in the two nearest flanking genes of RB1 (ITM2B and RCBTB2) and in multiple important exons of RB1. In contrast, in classical spindle cell lipomas, a less complex loss of RB1 exons was found but no deletion of ITM2B and RCBTB2. Moreover, MLPA identified a deletion of the DLEU1 gene, a finding which has not been reported earlier. We propose an immunohistochemical panel for lipomatous tumors which comprises of MDM2, CDK4, p16, Rb, which we have found useful in discriminating between atypical or classical spindle cell lipomas and other adipocytic neoplasms, especially atypical lipomatous tumor/well-differentiated liposarcoma. Our findings strengthen the link between atypical spindle cell lipoma and classical spindle cell lipoma, and differentiate them from atypical lipomatous tumor/well-differentiated liposarcoma.