Rare MDM2 amplification in a fat-predominant angiomyolipoma

Abstract

Angiomyolipomas (AMLs) are triphasic tumors (smooth muscle, vascular and adipocytic components) with myomelanocytic differentiation, arising most commonly in the kidneys, which can show predominant epithelioid morphology and fat-predominant or fat-poor variants. Fat-predominant AMLs can show areas of hypercellularity and lipoblast-like cells, and these features can mimic well-differentiated liposarcoma (WDLS). To date, only one documented metastatic epithelioid AML showed unequivocal MDM2 amplification by fluorescence in situ hybridization. We describe our findings in a series of 35 AMLs including epithelioid, fat-poor, and fat-predominant variants, following interrogation of the MDM2 locus by FISH and CISH assays. MDM2 amplification was detected in 1 fat-predominant AML. Our findings demonstrate that rare MDM2 amplifications can occur in AMLs. We favor that this finding likely represents a “molecular bystander” event since these tumors are mainly driven by aberrations in the TSC1/TSC2 genes. Nevertheless, the presence of MDM2 amplification in a fat-predominant AML could present a potential diagnostic pitfall, particularly when confronted with the differential diagnosis of fat-predominant AML and WDLS in limited material from the retroperitoneum.

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References

  1. 1.

    Martignoni G, Pea M, Reghellin D, Zamboni G, Bonetti F (2008) PEComas: the past, the present and the future. Virchows Arch 452:119–132. https://doi.org/10.1007/s00428-007-0509-1

    Article  PubMed  Google Scholar 

  2. 2.

    Folpe AL, Kwiatkowski DJ (2010) Perivascular epithelioid cell neoplasms: pathology and pathogenesis. Hum Pathol 41:1–15. https://doi.org/10.1016/j.humpath.2009.05.011

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Martignoni GCJ, Fletcher CDM et al (2016) Mesenchymal tumours occurring mainly in adults. In: Moch HHP, Ulbright TM, Reuter VE (eds) WHO Classification of Tumours of the Urinary System and Male Genital Organs, 4th edn. IARC, Lyon, pp 62–65

    Google Scholar 

  4. 4.

    Tsui WM, Colombari R, Portmann BC, Bonetti F, Thung SN, Ferrell LD, Nakanuma Y, Snover DC, Bioulac-Sage P, Dhillon AP (1999) Hepatic angiomyolipoma: a clinicopathologic study of 30 cases and delineation of unusual morphologic variants. Am J Surg Pathol 23:34–48

    CAS  Article  Google Scholar 

  5. 5.

    Hruban RH, Bhagavan BS, Epstein JI (1989) Massive retroperitoneal angiomyolipoma. A lesion that may be confused with well-differentiated liposarcoma. Am J Clin Pathol 92:805–808. https://doi.org/10.1093/ajcp/92.6.805

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Shimada S, Harada H, Ishizawa K, Hirose T (2006) Retroperitoneal lipomatous angiomyolipoma associated with amyloid deposition masquerading as well-differentiated liposarcoma. Pathol Int 56:638–641. https://doi.org/10.1111/j.1440-1827.2006.02021.x

    Article  PubMed  Google Scholar 

  7. 7.

    Asch-Kendrick RJ, Shetty S, Goldblum JR, Sharma R, Epstein JI, Argani P, Cimino-Mathews A (2016) A subset of fat-predominant angiomyolipomas label for MDM2: a potential diagnostic pitfall. Hum Pathol 57:7–12. https://doi.org/10.1016/j.humpath.2016.06.014

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Creytens D (2017) A subset of fat-predominant angiomyolipomas label for MDM2: a potential diagnostic pitfall; comment on Asch-Kendrick et al. 2016. Hum Pathol 64:232–233. https://doi.org/10.1016/j.humpath.2016.12.033

    Article  PubMed  Google Scholar 

  9. 9.

    Lin X, Laskin WB, Lu X, Zhang Y (2018) Expression of MDM2 and p16 in angiomyolipoma. Hum Pathol 75:34–40. https://doi.org/10.1016/j.humpath.2018.01.022

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Inoue C, Saito R, Nakanishi W, Kumata H, Eba S, Fujishima F, Watanabe M, Sasano H (2019) Renal epithelioid angiomyolipoma undergoing aggressive clinical outcome: the MDM2 expression in tumor cells of two cases. Tohoku J Exp Med 247:119–127. https://doi.org/10.1620/tjem.247.119

    Article  PubMed  Google Scholar 

  11. 11.

    Mardekian SK, Solomides CC, Gong JZ, Peiper SC, Wang ZX, Bajaj R (2015) Comparison of chromogenic in situ hybridization and fluorescence in situ hybridization for the evaluation of MDM2 amplification in adipocytic tumors. J Clin Lab Anal 29:462–468. https://doi.org/10.1002/jcla.21794

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Sirvent N, Coindre JM, Maire G, Hostein I, Keslair F, Guillou L, Ranchere-Vince D, Terrier P, Pedeutour F (2007) Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am J Surg Pathol 31:1476–1489. https://doi.org/10.1097/PAS.0b013e3180581fff

    Article  PubMed  Google Scholar 

  13. 13.

    Weaver J, Downs-Kelly E, Goldblum JR, Turner S, Kulkarni S, Tubbs RR, Rubin BP, Skacel M (2008) Fluorescence in situ hybridization for MDM2 gene amplification as a diagnostic tool in lipomatous neoplasms. Mod Pathol 21:943–949. https://doi.org/10.1038/modpathol.2008.84

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Zhang H, Macdonald WD, Erickson-Johnson M, Wang X, Jenkins RB, Oliveira AM (2007) Cytogenetic and molecular cytogenetic findings of intimal sarcoma. Cancer Genet Cytogenet 179:146–149. https://doi.org/10.1016/j.cancergencyto.2007.08.013

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Neuville A, Collin F, Bruneval P, Parrens M, Thivolet F, Gomez-Brouchet A, Terrier P, de Montpreville VT, Le Gall F, Hostein I, Lagarde P, Chibon F, Coindre JM (2014) Intimal sarcoma is the most frequent primary cardiac sarcoma: clinicopathologic and molecular retrospective analysis of 100 primary cardiac sarcomas. Am J Surg Pathol 38:461–469. https://doi.org/10.1097/pas.0000000000000184

    Article  PubMed  Google Scholar 

  16. 16.

    Ito Y, Maeda D, Yoshida M, Yoshida A, Kudo-Asabe Y, Nanjyo H, Izumi C, Yamamoto F, Inoue M, Shibata H, Katoh H, Ishikawa S, Nakamura H, Totoki Y, Shibata T, Yachida S, Goto A (2017) Cardiac intimal sarcoma with PDGFRbeta mutation and co-amplification of PDGFRalpha and MDM2: an autopsy case analyzed by whole-exome sequencing. Virchows Arch 471:423–428. https://doi.org/10.1007/s00428-017-2135-x

    Article  PubMed  Google Scholar 

  17. 17.

    Makise N, Sekimizu M, Kubo T, Wakai S, Hiraoka N, Komiyama M, Fukayama M, Kawai A, Ichikawa H, Yoshida A (2018) Clarifying the distinction between malignant peripheral nerve sheath tumor and dedifferentiated liposarcoma: a critical reappraisal of the diagnostic utility of MDM2 and H3K27me3 status. Am J Surg Pathol 42:656–664. https://doi.org/10.1097/pas.0000000000001014

    Article  PubMed  Google Scholar 

  18. 18.

    Makise N, Sekimizu M, Kubo T, Wakai S, Watanabe SI, Kato T, Kinoshita T, Hiraoka N, Fukayama M, Kawai A, Ichikawa H, Yoshida A (2018) Extraskeletal osteosarcoma: MDM2 and H3K27me3 analysis of 19 cases suggest disease heterogeneity. Histopathology 73:147–156. https://doi.org/10.1111/his.13506

    Article  PubMed  Google Scholar 

  19. 19.

    Schoolmeester JK, Sciallis AP, Greipp PT, Hodge JC, Dal Cin P, Keeney GL, Nucci MR (2015) Analysis of MDM2 amplification in 43 endometrial stromal tumors: a potential diagnostic pitfall. Int J Gynecol Pathol 34:576–583. https://doi.org/10.1097/pgp.0000000000000187

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Brimo F, Robinson B, Guo C, Zhou M, Latour M, Epstein JI (2010) Renal epithelioid angiomyolipoma with atypia: a series of 40 cases with emphasis on clinicopathologic prognostic indicators of malignancy. Am J Surg Pathol 34:715–722. https://doi.org/10.1097/PAS.0b013e3181d90370

    Article  PubMed  Google Scholar 

  21. 21.

    Thway K, Flora R, Shah C, Olmos D, Fisher C (2012) Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol 36:462–469. https://doi.org/10.1097/PAS.0b013e3182417330

    Article  PubMed  Google Scholar 

  22. 22.

    Giannikou K, Malinowska IA, Pugh TJ, Yan R, Tseng YY, Oh C, Kim J, Tyburczy ME, Chekaluk Y, Liu Y, Alesi N, Finlay GA, Wu CL, Signoretti S, Meyerson M, Getz G, Boehm JS, Henske EP, Kwiatkowski DJ (2016) Whole exome sequencing identifies TSC1/TSC2 biallelic loss as the primary and sufficient driver event for renal angiomyolipoma development. PLoS Genet 12:e1006242. https://doi.org/10.1371/journal.pgen.1006242

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Jennifer Gooding, CG (ASCP) CM Technical Specialist II-Cytogenetics Laboratory, Division of Laboratory Genetics Mayo Clinic, Rochester MN.

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CNPG conceived and designed the study, edited and reviewed the manuscript, and collected and analyzed the data. MCRP wrote, edited, and reviewed the manuscript. SH collected and analyzed the data and reviewed and edited the manuscript. JG, PTG, SW, GM, and GJN reviewed and edited the manuscript. All authors gave final approval for publication. CNPG takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

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Correspondence to Maria Del Carmen Rodriguez Pena.

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The Institutional Review Board approved this study.

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Rodriguez Pena, M.D.C., Gordetsky, J., Greipp, P.T. et al. Rare MDM2 amplification in a fat-predominant angiomyolipoma. Virchows Arch 477, 661–666 (2020). https://doi.org/10.1007/s00428-020-02813-9

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Keywords

  • Renal angiomyolipoma
  • MDM2 amplification
  • Well-differentiated liposarcoma
  • Fluorescent in situ hybridization
  • Chromogenic in situ hybridization