Journal of Gastrointestinal Cancer

, Volume 43, Issue 4, pp 521–525

Diagnostic and Therapeutic Challenges in Hepatic Epithelioid Hemangioendothelioma

  • Akshitkumar M. Mistry
  • D. Lee Gorden
  • Jacob F. Busler
  • Alice C. Coogan
  • Beau S. Kelly
Review Article



Epithelioid hemangioendothelioma is a very rare, low-grade vascular tumor known to arise in soft tissues and visceral organs. Clinical diagnosis of hepatic epithelioid hemangioendothelioma remains a challenge, and although it is frequently managed with a liver transplant due to its multifocal nature, recurrence is a common complication.


We review recent advances in the diagnosis of hepatic epithelioid hemangioendothelioma, including major genetic breakthroughs, and discuss efforts to reduce post-liver transplant recurrence of hepatic epithelioid hemangioendothelioma.


Hepatic epithelioid hemangioendothelioma Epithelioid hemangioendothelioma HEHE EHE 


  1. 1.
    Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer. 1982;50(5):970–81.PubMedCrossRefGoogle Scholar
  2. 2.
    Fletcher CD, Unni KK, Mertens F. Other intermediate vascular neoplasm. In: WHO classification of tumours. Pathology & genetics. Tumours of soft tissue and bone. Lyon: IARC Press; 2002. p. 173.Google Scholar
  3. 3.
    Weiss SW, Goldblum JR. Hemangioendothelioma: vascular tumors of intermediate malignancy. In: Weiss SW, Goldblum JR, editors. Enzinger and Weiss’s soft tissue tumors. 5th ed. St. Louis, MO: Mosby Elsevier; 2008. p. 681–8.Google Scholar
  4. 4.
    Mehrabi A, Kashfi A, Fonouni H, Schemmer P, Schmied BM, Hallscheidt P, Schirmacher P, Weitz J, Friess H, Buchler MW, Schmidt J. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy. Cancer. 2006;107(9):2108–21. doi:10.1002/cncr.22225.PubMedCrossRefGoogle Scholar
  5. 5.
    Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer. 1999;85(3):562–82.PubMedCrossRefGoogle Scholar
  6. 6.
    Ishak KG, Sesterhenn IA, Goodman ZD, Rabin L, Stromeyer FW. Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow-up study of 32 cases. Hum Pathol. 1984;15(9):839–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Scoazec JY, Lamy P, Degott C, Reynes M, Feldmann G, Bismuth H, Benhamou JP. Epithelioid hemangioendothelioma of the liver. Diagnostic features and role of liver transplantation. Gastroenterology. 1988;94(6):1447–53.PubMedGoogle Scholar
  8. 8.
    Bancel B, Patricot LM, Caillon P, Ducerf C, Pouyet M. Hepatic epithelioid hemangioendothelioma. A case with liver transplantation. Review of the literature. Ann Pathol. 1993;13(1):23–8.PubMedGoogle Scholar
  9. 9.
    Ishak KG, Goodman ZD, Stocker JT. Epithelioid haemangioendothelioma. In: Ishak KG, Goodman ZD, Stocker JT, editors. Tumors of the liver and intrahepatic bile ducts. Washington, DC: Armed Forces Institute of Pathology; 2001. p. 282–93.Google Scholar
  10. 10.
    Hertl M, Cosimi AB. Liver transplantation for malignancy. Oncologist. 2005;10(4):269–81. doi:10.1634/theoncologist.10-4-269.PubMedCrossRefGoogle Scholar
  11. 11.
    Lauffer JM, Zimmermann A, Krahenbuhl L, Triller J, Baer HU. Epithelioid hemangioendothelioma of the liver. A rare hepatic tumor. Cancer. 1996;78(11):2318–27.PubMedCrossRefGoogle Scholar
  12. 12.
    Hayashi Y, Inagaki K, Hirota S, Yoshikawa T, Ikawa H. Epithelioid hemangioendothelioma with marked liver deformity and secondary Budd-Chiari syndrome: pathological and radiological correlation. Pathol Int. 1999;49(6):547–52.PubMedCrossRefGoogle Scholar
  13. 13.
    d’Annibale M, Piovanello P, Carlini P, Del Nonno F, Sciarretta F, Rossi M, Berloco P, Iappelli M, Lonardo MT, Perrone R, Donnorso R. Epithelioid hemangioendothelioma of the liver: case report and review of the literature. Transplant Proc. 2002;34(4):1248–51.PubMedCrossRefGoogle Scholar
  14. 14.
    Radin DR, Craig JR, Colletti PM, Ralls PW, Halls JM. Hepatic epithelioid hemangioendothelioma. Radiology. 1988;169(1):145–8.PubMedGoogle Scholar
  15. 15.
    Furui S, Itai Y, Ohtomo K, Yamauchi T, Takenaka E, Iio M, Ibukuro K, Shichijo Y, Inoue Y. Hepatic epithelioid hemangioendothelioma: report of five cases. Radiology. 1989;171(1):63–8.PubMedGoogle Scholar
  16. 16.
    Miller WJ, Dodd GD, Federle MP, Baron RL. Epithelioid hemangioendothelioma of the liver: imaging findings with pathologic correlation. AJR Am J Roentgenol. 1992;159(1):53–7.PubMedGoogle Scholar
  17. 17.
    Lin J, Ji Y. CT and MRI diagnosis of hepatic epithelioid hemangioendothelioma. Hepatobiliary Pancreat Dis Int. 2010;9(2):154–8.PubMedGoogle Scholar
  18. 18.
    Fukayama M, Nihei Z, Takizawa T, Kawaguchi K, Harada H, Koike M. Malignant epithelioid hemangioendothelioma of the liver, spreading through the hepatic veins. Virchows Arch A Pathol Anat Histopathol. 1984;404(3):275–87.PubMedCrossRefGoogle Scholar
  19. 19.
    Goodman ZD, Terraciano LM. Tumours and tumour-like lesions of the liver. In: Burt AD, Portmann B, Ferrell LD, editors. MacSween’s pathology of the liver. 5th ed. Oxford: Elsevier Churchill Livingstone; 2007. p. 761–814.Google Scholar
  20. 20.
    Bioulac-Sage P, Laumonier H, Laurent C, Blanc JF, Balabaud C. Benign and malignant vascular tumors of the liver in adults. Semin Liver Dis. 2008;28(3):302–14. doi:10.1055/s-0028-1085098.PubMedCrossRefGoogle Scholar
  21. 21.
    Deyrup AT, Tighiouart M, Montag AG, Weiss SW. Epithelioid hemangioendothelioma of soft tissue: a proposal for risk stratification based on 49 cases. Am J Surg Pathol. 2008;32(6):924–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Otrock ZK, Al-Kutoubi A, Kattar MM, Zaatari G, Soweid A. Spontaneous complete regression of hepatic epithelioid haemangioendothelioma. Lancet Oncol. 2006;7(5):439–41. doi:10.1016/s1470-2045(06)70697-0.PubMedCrossRefGoogle Scholar
  23. 23.
    Komatsu Y, Koizumi T, Yasuo M, Urushihata K, Yamamoto H, Hanaoka M, Kubo K, Kawakami S, Honda T, Fujimoto K, Hachiya T. Malignant hepatic epithelioid hemangioendothelioma with rapid progression and fatal outcome. Intern Med. 2010;49(12):1149–53.PubMedCrossRefGoogle Scholar
  24. 24.
    Mentzel T, Beham A, Calonje E, Katenkamp D, Fletcher CD. Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Am J Surg Pathol. 1997;21(4):363–74.PubMedCrossRefGoogle Scholar
  25. 25.
    Folpe AL, Chand EM, Goldblum JR, Weiss SW. Expression of Fli-1, a nuclear transcription factor, distinguishes vascular neoplasms from potential mimics. Am J Surg Pathol. 2001;25(8):1061–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Fujii T, Zen Y, Sato Y, Sasaki M, Enomae M, Minato H, Masuda S, Uehara T, Katsuyama T, Nakanuma Y. Podoplanin is a useful diagnostic marker for epithelioid hemangioendothelioma of the liver. Mod Pathol. 2008;21(2):125–30. doi:10.1038/modpathol.3800986.PubMedGoogle Scholar
  27. 27.
    Emamaullee JA, Edgar R, Toso C, Thiesen A, Bain V, Bigam D, Kneteman N, Shapiro AM. Vascular endothelial growth factor expression in hepatic epithelioid hemangioendothelioma: implications for treatment and surgical management. Liver Transpl. 2010;16(2):191–7. doi:10.1002/lt.21964.PubMedCrossRefGoogle Scholar
  28. 28.
    Szymik-Kantorowicz S, Partyka L, Dembinska-Kiec A, Zdzienicka A. Vascular endothelial growth factor in monitoring therapy of hepatic haemangioendothelioma. Med Pediatr Oncol. 2003;40(3):196–7. doi:10.1002/mpo.10128.PubMedCrossRefGoogle Scholar
  29. 29.
    Miller MA, Sandler AD. Elevated plasma vascular endothelial growth factor levels in 2 patients with hemangioendothelioma. J Pediatr Surg. 2005;40(5):e17–9. doi:10.1016/j.jpedsurg.2005.02.014.PubMedCrossRefGoogle Scholar
  30. 30.
    Wicki A, Christofori G. The potential role of podoplanin in tumour invasion. Br J Cancer. 2007;96(1):1–5. doi:10.1038/sj.bjc.6603518.PubMedCrossRefGoogle Scholar
  31. 31.
    Boudousquie AC, Lawce HJ, Sherman R, Olson S, Magenis RE, Corless CL. Complex translocation [7;22] identified in an epithelioid hemangioendothelioma. Cancer Genet Cytogenet. 1996;92(2):116–21.PubMedCrossRefGoogle Scholar
  32. 32.
    He M, Das K, Blacksin M, Benevenia J, Hameed M. A translocation involving the placental growth factor gene is identified in an epithelioid hemangioendothelioma. Cancer Genet Cytogenet. 2006;168(2):150–4. doi:10.1016/j.cancergencyto.2006.02.010.PubMedCrossRefGoogle Scholar
  33. 33.
    Mendlick MR, Nelson M, Pickering D, Johansson SL, Seemayer TA, Neff JR, Vergara G, Rosenthal H, Bridge JA. Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma. Am J Surg Pathol. 2001;25(5):684–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Errani C, Zhang L, Sung YS, Hajdu M, Singer S, Maki RG, Healey JH, Antonescu CR. A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosom Cancer. 2011;50(8):644–53. doi:10.1002/gcc.20886.PubMedCrossRefGoogle Scholar
  35. 35.
    Tanas MR, Sboner A, Oliveira AM, Erickson-Johnson MR, Hespelt J, Hanwright PJ, Flanagan J, Luo Y, Fenwick K, Natrajan R, Mitsopoulos C, Zvelebil M, Hoch BL, Weiss SW, Debiec-Rychter M, Sciot R, West RB, Lazar AJ, Ashworth A, Reis-Filho JS, Lord CJ, Gerstein MB, Rubin MA, Rubin BP. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci Transl Med. 2011;3(98):98ra82. doi:10.1126/scitranslmed.3002409.PubMedCrossRefGoogle Scholar
  36. 36.
    Woelfel C, Liehr T, Weise A, Langrehr J, Kotb WA, Pacyna-Gengelbach M, Katenkamp D, Petersen I. Molecular cytogenetic characterization of epithelioid hemangioendothelioma. Cancer Genet. 2011;204(12):671–6. doi:10.1016/j.cancergen.2011.11.007.PubMedCrossRefGoogle Scholar
  37. 37.
    Grotz TE, Nagorney D, Donohue J, Que F, Kendrick M, Farnell M, Harmsen S, Mulligan D, Nguyen J, Rosen C, Reid-Lombardo KM. Hepatic epithelioid haemangioendothelioma: is transplantation the only treatment option? HPB (Oxford). 2010;12(8):546–53. doi:10.1111/j.1477-2574.2010.00213.x.CrossRefGoogle Scholar
  38. 38.
    Mosoia L, Mabrut JY, Adham M, Boillot O, Ducerf C, Partensky C, Baulieux J. Hepatic epithelioid hemangioendothelioma: long-term results of surgical management. J Surg Oncol. 2008;98(6):432–7. doi:10.1002/jso.21132.PubMedCrossRefGoogle Scholar
  39. 39.
    Langrehr JM, Petersen I, Pfitzmann R, Lopez-Hanninen E. Malignant epithelioid hemangioendothelioma of the liver. Results of surgical treatment strategies. Chirurg. 2005;76(12):1161–7. doi:10.1007/s00104-005-1070-6.PubMedCrossRefGoogle Scholar
  40. 40.
    Rodriguez JA, Becker NS, O’Mahony CA, Goss JA, Aloia TA. Long-term outcomes following liver transplantation for hepatic hemangioendothelioma: the UNOS experience from 1987 to 2005. J Gastrointest Surg. 2008;12(1):110–6. doi:10.1007/s11605-007-0247-3.PubMedCrossRefGoogle Scholar
  41. 41.
    Nudo CG, Yoshida EM, Bain VG, Marleau D, Wong P, Marotta PJ, Renner E, Watt KD, Deschenes M. Liver transplantation for hepatic epithelioid hemangioendothelioma: the Canadian multicentre experience. Can J Gastroenterol. 2008;22(10):821–4.PubMedGoogle Scholar
  42. 42.
    Lerut JP, Orlando G, Adam R, Schiavo M, Klempnauer J, Mirza D, Boleslawski E, Burroughs A, Selles CF, Jaeck D, Pfitzmann R, Salizzoni M, Soderdahl G, Steininger R, Wettergren A, Mazzaferro V, Le Treut YP, Karam V. The place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma: report of the European liver transplant registry. Ann Surg. 2007;246(6):949–57. doi:10.1097/SLA.0b013e31815c2a70.PubMedCrossRefGoogle Scholar
  43. 43.
    Cardinal J, de Vera ME, Marsh JW, Steel JL, Geller DA, Fontes P, Nalesnik M, Gamblin TC. Treatment of hepatic epithelioid hemangioendothelioma: a single-institution experience with 25 cases. Arch Surg. 2009;144(11):1035–9. doi:10.1001/archsurg.2009.121.PubMedCrossRefGoogle Scholar
  44. 44.
    Lerut JP, Orlando G, Sempoux C, Ciccarelli O, Van Beers BE, Danse E, Horsmans Y, Rahier J, Roggen F. Hepatic haemangioendothelioma in adults: excellent outcome following liver transplantation. Transpl Int. 2004;17(4):202–7. doi:10.1007/s00147-004-0697-4.PubMedCrossRefGoogle Scholar
  45. 45.
    Penn I. Hepatic transplantation for primary and metastatic cancers of the liver. Surgery. 1991;110(4):726–34.PubMedGoogle Scholar
  46. 46.
    Ben-Haim M, Roayaie S, Ye MQ, Thung SN, Emre S, Fishbein TA, Sheiner PM, Miller CM, Schwartz ME. Hepatic epithelioid hemangioendothelioma: resection or transplantation, which and when? Liver Transplant Surg. 1999;5(6):526–31.CrossRefGoogle Scholar
  47. 47.
    Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8(2):128–35. doi:10.1038/nm0202-128.PubMedCrossRefGoogle Scholar
  48. 48.
    Trautmann K, Bethke A, Ehninger G, Folprecht G. Bevacizumab for recurrent hemangioendothelioma. Acta Oncol. 2011;50(1):153–4. doi:10.3109/0284186x.2010.498829.PubMedCrossRefGoogle Scholar
  49. 49.
    Mizota A, Shitara K, Fukui T. Bevacizumab chemotherapy for pulmonary epithelioid hemangioendothelioma with severe dyspnea. J Thorac Oncol. 2011;6(3):651–2. doi:10.1097/JTO.0b013e31820b9e23.PubMedCrossRefGoogle Scholar
  50. 50.
    Lazarus A, Fuhrer G, Malekiani C, McKay S, Thurber J. Primary pleural epithelioid hemangioendothelioma (EHE—two cases and review of the literature. Clin Respir J. 2011;5(1):e1–5. doi:10.1111/j.1752-699X.2010.00221.x.PubMedCrossRefGoogle Scholar
  51. 51.
    Kim YH, Mishima M, Miyagawa-Hayashino A. Treatment of pulmonary epithelioid hemangioendothelioma with bevacizumab. J Thorac Oncol. 2010;5(7):1107–8. doi:10.1097/JTO.0b013e3181e2bc5d.PubMedCrossRefGoogle Scholar
  52. 52.
    Belmont L, Zemoura L, Couderc LJ. Pulmonary epithelioid haemangioendothelioma and bevacizumab. J Thorac Oncol. 2008;3(5):557–8. doi:10.1097/JTO.0b013e31816e2400.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Akshitkumar M. Mistry
    • 1
  • D. Lee Gorden
    • 2
  • Jacob F. Busler
    • 3
  • Alice C. Coogan
    • 3
  • Beau S. Kelly
    • 2
  1. 1.Department of MedicineVanderbilt University Medical CenterNashvilleUSA
  2. 2.Department of Surgery, Division of Hepatobiliary Surgery and Liver TransplantationVanderbilt University Medical CenterNashvilleUSA
  3. 3.Department of Pathology, Microbiology, and ImmunologyVanderbilt University Medical CenterNashvilleUSA

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