Skip to main content
Log in

Nuclear expression of MDM2 in hibernoma: a potential diagnostic pitfall

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript


Hibernoma is a rare benign adipocytic tumor composed of a proliferation of brown and white fat cells varying in their proportions. The tumor may also contain fat cells resembling lipoblasts, which makes it difficult to distinguish it from atypical lipomatous tumor/well differentiated liposarcoma (ALT/WDLS). Although nuclear expressions of murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) are widely used as immunohistochemical surrogate markers for ALT/WDLS, the utility of these proteins in distinguishing between hibernoma and ALT/WDLS still remains to be elucidated. We evaluated immunohistochemical expressions of MDM2 and CDK4 in 10 hibernomas expressing uncoupling protein-1 (UCP-1), a mitochondrial protein transporter consistently expressed in brown fat cells, and lacking MDM2 gene amplification, which was analyzed by fluorescence in situ hybridization (FISH). In contrast to the data previously obtained, nuclear expression of MDM2 was observed in 100% (10/10 cases) of the hibernomas irrespective of the proportion of brown fat cells, whereas no cases were positive for CDK4. The tumors also showed almost concurrent expression of p53 (in 9/10 cases) and ubiquitin-specific-processing protease 7 (USP7) (in 10/10 cases), which deubiquitinates and stabilizes MDM2, potentially resulting in its nuclear expression without MDM2 gene amplification. MDM2 expression may thus be a diagnostic pitfall for hibernoma particularly in differentiating it from ALT/WDLS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others


  1. Furlong MA, Fanburg-Smith JC, Miettinen M (2001) The morphologic spectrum of hibernoma: a clinicopathologic study of 170 cases. Am J Surg Pathol 25:809–814.

    Article  CAS  PubMed  Google Scholar 

  2. Vassos N, Lell M, Hohenberger W, Croner RS, Agaimy A (2013) Deep-seated huge hibernoma of soft tissue: a rare differential diagnosis of atypical lipomatous tumor/well differentiated liposarcoma. Int J Clin Exp Pathol 6:2178–2184

    PubMed  PubMed Central  Google Scholar 

  3. Val-Bernal JF, Azueta A, Ortiz-Rivas LA, Fuentes J, Ballestero R (2013) Incidental lipoma-like hibernoma arising from the adrenal gland: a well-differentiated liposarcoma mimicker. Pathol Res Pract 209:812–816.

    Article  PubMed  Google Scholar 

  4. Al Hmada Y, Schaefer I-M, Fletcher CDM (2018) Hibernoma mimicking atypical lipomatous tumor: 64 cases of a morphologically distinct subset. Am J Surg Pathol 42:951–957.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hallin M, Schneider N, Thway K (2016) Well-differentiated liposarcoma with hibernoma-like morphology. Int J Surg Pathol 24:620–622.

    Article  PubMed  Google Scholar 

  6. 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.

    Article  PubMed  Google Scholar 

  7. Manieri M, Murano I, Fianchini A, Brunelli A, Cinti S (2010) Morphological and immunohistochemical features of brown adipocytes and preadipocytes in a case of human hibernoma. Nutr Metab Cardiovasc Dis 20:567–574.

    Article  CAS  PubMed  Google Scholar 

  8. Malzahn J, Kastrenopoulou A, Papadimitriou-Olivgeri I, Papachristou DJ, Brown JM, Oppermann U, Athanasou NA (2019) Immunophenotypic expression of UCP1 in hibernoma and other adipose/non adipose soft tissue tumours. Clin Sarcoma Res 9:1–8.

    Article  Google Scholar 

  9. Fletcher CDM, Akerman M, Dal Cin P, De Wever I, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Sciot R, Tallini G, van den Berghe H, van de Ven W, Vanni R, Willen H (1996) Correlation between clinicopathological features and karyotype in lipomatous tumors: a report of 178 cases from the chromosomes and morphology (CHAMP) collaborative study group. Am J Pathol 148:623–630

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Gisselsson D, Höglund M, Mertens F, Dal Cin P, Mandahl N (1999) Hibernomas are characterized by homozygous deletions in the multiple endocrine neoplasia type region: metaphase fluorescence in situ hybridization reveals complex rearrangements not detected by conventional cytogenetics. Am J Pathol 155:61–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nord KH, Magnusson L, Isaksson M, Nilsson J, Lilljebjörn H, Domanski HA, Kindblom LG, Mandahl N (2010) Mertens F (2010) concomitant deletions of tumor suppressor genes MEN1 and AIP are essential for the pathogenesis of the brown fat tumor hibernoma. Proc Natl Acad Sci U S A 107:21122–21127.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Brooks CL, Li M, Hu M, Shi Y, Gu W (2007) The p53--Mdm2--HAUSP complex is involved in p53 stabilization by HAUSP. Oncogene 26:7262–7266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Weaver J, Rao P, Goldblum JR, Joyce MJ, Turner SL, Lazar AJF, López-Terada D, Tubbs RR, Rubin BP (2010) Can MDM2 analytical tests performed on core needle biopsy be relied upon to diagnose well-differentiated liposarcoma? Mod Pathol 23:1301–1306.

    Article  CAS  PubMed  Google Scholar 

  14. Clay MR, Martinez AP, Weiss SW, Edgar MA (2016) MDM2 and CDK4 immunohistochemistry: should it be used in problematic differentiated lipomatous tumors?: a new perspective. Am J Surg Pathol 40:1647–1652.

    Article  PubMed  Google Scholar 

  15. Ishibashi N, Maebayashi T, Aizawa T, Sakaguchi M, Nishimaki H, Masuda S (2017) Correlation between the Ki-67 proliferation index and response to radiation therapy in small cell lung cancer. Radiat Oncol 12:16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pekmezci M, Reuss DE, Hirbe AC, Dahiya S, Gutmann DH, von Deimling A, Horvai AE, Perry A (2015) Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas. Mod Pathol 28:187–200.

    Article  CAS  PubMed  Google Scholar 

  17. Masuya D, Huang C, Liu D, Nakashima T, Yokomise H, Ueno M, Nakashima N, Sumitomo S (2006) The HAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways. J Pathol 208:724–732.

    Article  CAS  PubMed  Google Scholar 

  18. Binh MBN, Sastre-Garau X, Guillou L, de Pinieux G, Terrier P, Lagace R, Aurias A, Hostein I, Coindre JM (2005) MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 29:1340–1347.

    Article  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. Lin X, Laskin WB, Lu X, Zhang Y (2018) Expression of MDM2 and p16 in angiomyolipoma. Hum Pathol 75:34–40.

    Article  CAS  PubMed  Google Scholar 

  21. Chen KT (1999) Uterine leiomyohibernoma. Int J Gynecol Pathol 18:96–97.

    Article  CAS  PubMed  Google Scholar 

Download references

Availability of data and material

All data generated or analyzed during this study are included in this published article.


This study was partially funded by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (KAKENHI) (grant number JP18K07704).

Author information

Authors and Affiliations



All authors read and approved the final manuscript. Yojiro Tsuda is responsible for data curation, investigation, writing—original draft, and writing—review and editing. Atsuji Matsuyama is responsible for methodology and investigation. Koichi Higaki, Toru Motoi, Kosuke Makihara, and Tomotake Okuma are responsible for investigation and resources. Masanori Hisaoka is responsible for conceptualization, methodology, and supervision.

Corresponding author

Correspondence to Yojiro Tsuda.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

The Ethics Committee of Medical Research, University of Occupational and Environmental Health, Japan approved this study (No. H25-169).

Code availability

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Quality in Pathology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsuda, Y., Matsuyama, A., Makihara, K. et al. Nuclear expression of MDM2 in hibernoma: a potential diagnostic pitfall. Virchows Arch 478, 527–534 (2021).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: