FluorescenceIn SituHybridization forMDM2Amplification as a Routine Ancillary Diagnostic Tool for Suspected Well-Differentiated and Dedifferentiated Liposarcomas: Experience at a Tertiary Center

Abstract

Background. The assessment of MDM2 gene amplification by fluorescence in situ hybridization (FISH) has become a routine ancillary tool for diagnosing atypical lipomatous tumor (ALT)/well-differentiated liposarcoma and dedifferentiated liposarcoma (WDL/DDL) in specialist sarcoma units. We describe our experience of its utility at our tertiary institute. Methods. All routine histology samples in which MDM2 amplification was assessed with FISH over a 2-year period were included, and FISH results were correlated with clinical and histologic findings. Results. 365 samples from 347 patients had FISH for MDM2 gene amplification. 170 were positive (i.e., showed MDM2 gene amplification), 192 were negative, and 3 were technically unsatisfactory. There were 122 histologically benign cases showing a histology:FISH concordance rate of 92.6%, 142 WDL/DDL (concordance 96.5%), and 34 cases histologically equivocal for WDL (concordance 50%). Of 64 spindle cell/pleomorphic neoplasms (in which DDL was a differential diagnosis), 21.9% showed MDM2 amplification. Of the cases with discrepant histology and FISH, all but 3 had diagnoses amended following FISH results. For discrepancies of benign histology but positive FISH, lesions were on average larger, more frequently in “classical” (intra-abdominal or inguinal) sites for WDL/DDL and more frequently core biopsies. Discrepancies of malignant histology but negative FISH were smaller, less frequently in “classical” sites but again more frequently core biopsies. Conclusions. FISH has a high correlation rate with histology for cases with firm histologic diagnoses of lipoma or WDL/DDL. It is a useful ancillary diagnostic tool in histologically equivocal cases, particularly in WDL lacking significant histologic atypia or DDL without corresponding WDL component, especially in larger tumors, those from intra-abdominal or inguinal sites or core biopsies. There is a significant group of well-differentiated adipocytic neoplasms which are difficult to diagnose on morphology alone, in which FISH for MDM2 amplification is diagnostically contributory.

Diagnostic performance of MRI and histology in assessment of deep lipomatous tumours

“…This study is distinct from most other large case series in that every patient underwent cytogenetic testing for the MDM 2 gene – currently the test for ALT. Only around 30 per cent of deep lipomatous tumours referred as lesions suspicious for soft tissue sarcoma proved to be ALT, which is consistent with other series.…”

“…The histopathological similarity between lipomas and ALTs has prompted the development of alternative cytogenetic and molecular tests to improve diagnostic accuracy. Fluorescence in situ hybridization (FISH) analysis for amplification of the MDM2 gene is highly sensitive in distinguishing ALT from lipoma and has become the standard. The gene is present throughout an ALT so the analysis is not subject to sampling error.…”

Esophageal carcinosarcoma comprised of minimally invasive squamous cell carcinoma and undifferentiated pleomorphic sarcoma: A collision cancer?

“…MDM2, a highly specific marker of welldifferentiated and dedifferentiated subtypes of liposarcoma, 15 was focally positive in some stromal tumor cells, but fluorescence in situ hybridization analysis of the MDM2 gene did not establish the diagnosis of liposarcoma: although a slightly increased number of MDM2 signals (4 to 10 dots) were observed in the sarcoma cells, chromosome 12 centromere probe signals were also increased in number (3 to 8 dots), which indicated the aneuploidy of the DNA rather than the specific amplification of the MDM2 gene. 16 Based on these findings and tumor histology, the sarcomatous component was finally diagnosed as an undifferentiated pleomorphic sarcoma (previously called malignant fibrous histiocytoma) as has been described in other cases of esophageal carcinosarcoma. 1,4,9 Mutations in the TP53 gene are present in squamous cell carcinomas of the esophagus in approximately 50% of cases.…”

“…Other cell lineage markers tested were all negative in the sarcoma cells: these include the markers of dendritic cells/Langerhans cells (CD1a, S100 protein), follicular dendritic cells (CD21, CD23, CD35), myeloid hematopoietic cells (myeloperoxidase, CD13, CD33), T/NK‐ and B‐lymphoid cells (CD3, CD5, CD8, CD20, CD79a, CD30, CD45, CD45RO, CD56), melanocytes (HMB45, Melan‐A), neuroendocrine cells (chromogranin A, synaptophysin) and other mesenchymal cells (neuron specific enolase, desmin, α‐smooth muscle actin, HHF35, myoglobin, CD31). MDM2, a highly specific marker of well‐differentiated and dedifferentiated subtypes of liposarcoma, was focally positive in some stromal tumor cells, but fluorescence in situ hybridization analysis of the MDM2 gene did not establish the diagnosis of liposarcoma: although a slightly increased number of MDM2 signals (4 to 10 dots) were observed in the sarcoma cells, chromosome 12 centromere probe signals were also increased in number (3 to 8 dots), which indicated the aneuploidy of the DNA rather than the specific amplification of the MDM2 gene . Based on these findings and tumor histology, the sarcomatous component was finally diagnosed as an undifferentiated pleomorphic sarcoma (previously called malignant fibrous histiocytoma) as has been described in other cases of esophageal carcinosarcoma …”

Diagnosis and management of spermatic cord tumors

“…Immunostaining with MDM2 and CDK4 can help to differentiate the lesion from benign lipoma. Pathological changes in less differentiated liposarcomas are represented by round cells with a high nucleus-to-cytoplasm ratio and prominent nucleoli that can be observed back-to-back with little intervening stroma or vascular network [13,14].…”