DIAGNOSTIC UTILITY OF FISH FOR MDM2 IN ADIPOCYTIC NEOPLASMS

Authors

  • Saud Sarwar Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore-Pakistan
  • Sajid Mushtaq Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore-Pakistan
  • Usman Hassan Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore-Pakistan
  • Hina Maqbool Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore-Pakistan
  • Romena Qazi Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore-Pakistan

Abstract

Background: The 2013 World Health Organization (WHO) classification of soft tissue and bone tumours recognizes benign entities such as lipoma and four major liposarcoma subtypes: atypical lipomatous tumour/well differentiated liposarcomas (ALT/WDL), dedifferentiated liposarcomas (DDL), myxoid liposarcoma and pleomorphic liposarcoma. This classification of atypical and malignant adipocytic tumours has evolved significantly over the past few decades owing to contributions from cytogenetics, molecular genetics and Immunohistochemical correlates. Most ALT/WDLs can be diagnosed on histology, however, some of the biopsies may be underdiagnosed due to focal atypia or limited nature of tissue for the biopsy. Fluorescence in situ hybridization (FISH) for MDM2 (located at 12q14-15) gene amplification has emerged as gold standard for diagnosis in cases with limiting histological factors. Methods: We studied MDM2 amplification by FISH in 55 such problematic adipocytic tumours with overlapping morphological features and a retrospective analysis was made against their corresponding histological features. Results:  MDM2 amplification correctly identified 11 of 17 ALT/WDLs (64.71% concordance) and 8 of 10 Lipomas (80% concordance). We were able to differentiate liposarcomas from other high grade sarcomatous lesions and sub-classified these lesions into pleomorphic and dedifferentiated types. Conclusion: FISH for MDM2 amplification should be used as a gold standard in adjunction with morphology and immunohistochemistry for problematic adipocytic neoplasms

References

Cloutier JM, Charville GW. Diagnostic classification of soft tissue malignancies: a review and update from a surgical pathology perspective. Curr Probl Cancer 2019;43(4):250–72.

Jo VY, Doyle LA. Refinements in sarcoma classification in the current 2013 World Health Organization classification of tumours of soft tissue and bone. Surg Oncol Clin N Am 2016;25(4):621–43.

Clay MR, Martinez AP, Weiss SW, Edgar MA. MDM2 amplification in problematic lipomatous tumours: Analysis of FISH Testing Criteria. Am J Surg Pathol 2015;39(10):1433–9. Ref no 3,24&28 are same

Bill KL, Seligson ND, Hays JL, Awasthi A, Demoret B, Stets CW, et al. Degree of MDM2 Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma. Oncologist 2019;24(7):989–96.

Cornillie J, Wozniak A, Li H, Gebreyohannes YK, Wellens J, Hompes D, et al. Anti-tumour activity of the MDM2-TP53 inhibitor BI-907828 in dedifferentiated liposarcoma patient-derived xenograft models harboring MDM2 amplification. Clin Transl Oncol 2020;22(4):546–54.

Kammerer-Jacquet SF, Thierry S, Cabillic F, Lannes M, Burtin F, Henno S, et al. Differential diagnosis of atypical lipomatous tumour/well-differentiated liposarcoma and dedifferentiated liposarcoma: utility of p16 in combination with MDM2 and CDK4 immunohistochemistry. Hum Pathol 2017;59:34–40.

Casadei L, Calore F, Braggio DA, Zewdu A, Deshmukh AA, Fadda P, et al. MDM2 derived from dedifferentiated liposarcoma extracellular vesicles induces MMP2 production from preadipocytes. Cancer Res 2019;79(19):4911–22.

Wang GY, Lucas DR. Dedifferentiated Liposarcoma with Myofibroblastic Differentiation. Arch Pathol Lab Med 2018;142(10):1159–63.

Beird HC, Wu CC, Ingram DR, Wang WL, Alimohamed A, Gumbs C, et al. Genomic profiling of dedifferentiated liposarcoma compared to matched well-differentiated liposarcoma reveals higher genomic complexity and a common origin. Cold Spring Harb Mol Case Stud 2018;4(2):a002386.

Mandahl N, Magnusson L, Nilsson J, Viklund B, Arbajian E, Von Steyern FV, et al. Scattered genomic amplification in dedifferentiated liposarcoma. Mol Cytogenet 2017;10(1):25.

Guérin M, Thariat J, Ouali M, Bouvier C, Decouvelaere AV, Cassagnau E, et al. A new subtype of high-grade mandibular osteosarcoma with RASAL1/MDM2 amplification. Hum Pathol 2016;50:70–8.

Yamashita K, Kohashi K, Yamada Y, Nishida Y, Urakawa H, Oda Y, et al. Primary extraskeletal osteosarcoma: a clinicopathological study of 18 cases focusing on MDM2 amplification status. Hum Pathol 2017;63:63–9.

He X, Pang Z, Zhang X, Lan T, Chen H, Chen M, et al. Consistent amplification of FRS2 and MDM2 in low-grade osteosarcoma. Am J Surg Pathol 2018;42(9):1143–55.

Chow LT. Giant cell rich osteosarcoma revisited—diagnostic criteria and histopathologic patterns, Ki67, CDK4, and MDM2 expression, changes in response to bisphosphonate and denosumab treatment. Virchows Arch 2016;468(6):741–55.

Chen PC, Yen CC, Hung GY, Pan CC, Chen WM. Gene amplification and tumour grading in parosteal osteosarcoma. J Chin Med Assoc 2019;82(12):889–94.

Kobayashi A, Sakuma T, Fujimoto M, Jimbo N, Hirose T. Diagnostic utility and limitations of immunohistochemistry of p16, CDK4, and MDM2 and automated dual-color in situ hybridization of MDM2 for the diagnosis of challenging cases of dedifferentiated liposarcoma. Appl Immunohistochem Mol Morphol 2019;27(10):758–63.

Yoshimoto M, Yamada Y, Ishihara S, Kohashi K, Toda Y, Ito Y, et al. Comparative Study of Myxofibrosarcoma With Undifferentiated Pleomorphic Sarcoma: Histopathologic and Clinicopathologic Review. Am J Surg Pathol 2020;44(1):87–97.

Suster D, Ronen S, Peterson JF, Mackinnon AC, Hes O, Suster S, et al. MDM2 amplification and immunohistochemical expression in sarcomatoid renal cell carcinoma. Hum Pathol 2019;87:28–36.

Makise N, Sekimizu M, Kubo T, Wakai S, Hiraoka N, Komiyama M, et al. Clarifying the distinction between malignant peripheral nerve sheath tumour and dedifferentiated liposarcoma: A critical reappraisal of the diagnostic utility of MDM2 and H3K2me3 status. Am J Surg Pathol 2018;42(5):656–64.

Høland M, Kolberg M, Danielsen SA, Bjerkehagen B, Eilertsen IA, Hektoen M, et al. Inferior survival for patients with malignant peripheral nerve sheath tumours defined by aberrant TP53. Mod Pathol 2018;31(11):1694–707.

Le Guellec S, Decouvelaere AV, Filleron T, Valo I, Charon-Barra C, Robin YM, et al. Malignant peripheral nerve sheath tumour is a challenging diagnosis: A systematic pathology review, Immunohistochemistry, and Molecular analysis in 160 patients from the French sarcoma group database. Am J Surg Pathol 2016;40(7):896–908.

Di Mauro I, Mescam-Mancini L, Chetaille B, Lae M, Pierron G, Dadone-Montaudie B, et al. MDM2 amplification and fusion gene ss18-ssx in a poorly differentiated synovial sarcoma: A rare but puzzling conjunction. Neoplasia 2020;22(8):311–21.

Stojanov IJ, Mariño-Enriquez A, Bahri N, Jo VY, Woo SB. Lipomas of the oral cavity: utility of MDM2 and CDK4 in avoiding overdiagnosis as atypical lipomatous tumour. Head Neck Pathol 2019;13(2):169–76.

Clay MR, Martinez AP, Weiss SW, Edgar MA. MDM2 amplification in problematic lipomatous tumours: Analysis of FISH Testing Criteria. Am J Surg Pathol 2015;39(10):1433–9. Ref no 3,24&28 are same

Clay MR, Martinez AP, Weiss SW, Edgar MA. MDM2 and CDK4 Immunohistochemistry: Should It Be Used in Problematic Differentiated Lipomatous Tumours? Am J Surg Pathol 2016;40(12):1647–52.

Wong DD, Low IC, Peverall J, Robbins PD, Spagnolo DV, Nairn R, Carey-Smith RL, Wood D. MDM2/CDK4 gene amplification in large/deep-seated ‘lipomas’: incidence, predictors and clinical significance. Pathology 2016;48(3):203–9.

McCarthy AJ, Chetty R. Tumours composed of fat are no longer a simple diagnosis: an overview of fatty tumours with a spindle cell component. J Clin Pathol 2018;71(6):483–92.

Clay MR, Martinez AP, Weiss SW, Edgar MA. MDM2 amplification in problematic lipomatous tumours: Analysis of FISH Testing Criteria. Am J Surg Pathol 2015;39(10):1433–9. Ref no 3,24&28 are same

Thway K, Wang J, Swansbury J, Min T, Fisher C. Fluorescence in situ hybridization for MDM2 amplification as a routine ancillary diagnostic tool for suspected well-differentiated and dedifferentiated liposarcomas: experience at a tertiary center. Sarcoma 2015;2015:812089.

Weaver J, Downs-Kelly E, Goldblum JR, Turner S, Kulkarni S, Tubbs RR, et al. Fluorescence in situ hybridization for MDM2 gene amplification as a diagnostic tool in lipomatous neoplasms. Mod Pathol 2008;21(8):943–9.

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Published

2021-10-06

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