Lessons learnt from MDM2 fluorescence in‐situ hybridisation analysis of 439 mature lipomatous lesions with an emphasis on atypical lipomatous tumour/well‐differentiated liposarcoma lacking cytological atypia

Abstract

Aims Amplification of the murine double minute‐2 (MDM2) gene, which is usually detected with fluorescence in‐situ hybridisation (FISH), is the key driving event for atypical lipomatous tumours (ALTs)/well‐differentiated liposarcomas (WDLs). We sought to determine the concordance between the histopathological findings and MDM2 FISH in the diagnosis of ALT/WDL, and to identify the histological features of MDM2‐amplified tumours lacking classic atypia. Methods and results We performed a retrospective analysis of all mature lipomatous lesions subjected to MDM2 FISH analysis at our institution. MDM2 FISH analysis was performed on 439 mature lipomatous lesions: 364 (82.9%) were negative and 75 (17%) were positive. In 17 of 75 (22.6%) ALTs/WDLs, cytological atypia was not identified on initial histological assessment, thus favouring lipoma. On review, these cases shared common histological features, consisting of a very low number of relatively small stromal cells within the tumour lobules, with mildly coarse chromatin and oval nuclei, admixed with unremarkable adipocytes in a tumour background devoid of fibroconnective septa, areas of fibrosis, or blood vessels. These cells matched the cells in which FISH showed MDM2 amplification. In contrast, 13 cases (3.5%) regarded as suspicious for ALT/WDL on the basis of histology lacked MDM2 amplification and were reclassified following the FISH findings. Conclusions We conclude that a subset of lipoma‐like ALTs/WDLs are not associated with any of the features typically described in ALT/WDL. Our study also showed that tumours >100 mm are more likely to be ALT/WDL; however, a history of recurrence or concerning clinical/radiological features was not significantly associated with classification as ALT/WDL.

Soft Tissue Sarcomas with Chromosomal Alterations in the 12q13-15 Region: Differential Diagnosis and Therapeutic Implications

“…This emphasizes that FISH remains the ideal technique for detecting this genetic alteration. In a recent series of adipocytic tumor cases reported in a study by Vargas et al [113], later confirmed by Machado et al [103], instances of well-differentiated liposarcomas with isolated nuclear atypia were identified. Despite this, they exhibited immunohistochemical expression for MDM2/CDK4 and p16, alongside confirmation of MDM2 amplification by FISH [103,113].…”

“…In a recent series of adipocytic tumor cases reported in a study by Vargas et al [113], later confirmed by Machado et al [103], instances of well-differentiated liposarcomas with isolated nuclear atypia were identified. Despite this, they exhibited immunohistochemical expression for MDM2/CDK4 and p16, alongside confirmation of MDM2 amplification by FISH [103,113]. Similar situations can arise in neoplasms with GLI1 alterations (Figure 6), where immunohistochemistry for GLI1 is not always sufficient, necessitating molecular confirmation [104][105][106][107][108].…”

“…On the other hand, the DDIT3 gene is known to be rearranged in myxoid/round cell liposarcomas, which can fuse with either EWSR1 or FUS, and these fusions serve as diagnostic markers for this entity [112]. The amplification of DDIT3 and STAT6 may vary depending on the amplicon length in cases of mesenchymal neoplasms with 12q13-15 amplification [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115].…”

“…This drug exhibits a favorable safety profile, with reported toxicities in 88% of patients. The most common side effect was nausea (66%), and 41% of patients experienced equal to or greater than grade 3 toxicity, primarily including neutropenia (20%), thrombocytopenia (19%), and anemia (10%) (113). BI 907828 is an orally administered drug with a long half-life and is being evaluated in various types of sarcomas characterized by MDM2 overexpression [119,120].…”

FISH Diagnostic Assessment of MDM2 Amplification in Liposarcoma: Potential Pitfalls and Troubleshooting Recommendations

“…Considering the clinical consequences of misdiagnosing these lesions, the molecular analysis of MDM2 is essential, and it is usually performed with Fluorescence In Situ Hybridization (FISH) [ 30 ]. Indeed, the MDM2 amplification evaluation by FISH is a crucial and well-established assay for liposarcoma diagnostic work-up and, nowadays, is considered as a diagnostic gold standard [ 31 , 32 , 33 ]. However, despite its diagnostic relevance, no definitive consensus has ever been defined for determining the MDM2 gene status.…”