Skip to main content

Advertisement

SpringerLink
Log in

Infantile hepatic hemangioma: current state of the art, controversies, and perspectives

  • Review
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Infantile hepatic hemangioma (IHH) is a common vascular tumor, distinctive for its perinatal presentation, rapid growth during the first year of life, and subsequent involution. Although they generally follow a benign course, some tumors have been reported to undergo malignant transformation. The diagnosis of IHH is based on patient’s medical history, physical examination, and imaging. Moreover, the management of this vascular tumor is based on clinical presentation and includes observational, medical, surgical, and radiological interventional treatment options. The present review presents the currently available data in the literature on the diverse aspects of the terminology, epidemiology, clinical presentation, pathogenesis, diagnosis, indications for surgery, malignant potential, and long-term outcomes of these tumors.

Conclusion: No formal guidelines have yet been established for the treatment of these hepatic lesions, and the therapeutic strategies implemented vary widely from simple observation to medical, radiological, and surgical interventions in the prism of multidisciplinary teams.

What is Known:

• Infantile hepatic hemangioma is the most common benign tumor of the liver in infancy, but despite its benign nature, it can present with life-threatening complications.

• The treatment strategies range from simple observation to a series of medical, surgical, and radiological interventions.

What is New:

• This review gives an overview of the developments and current status about the management of IHH.

• The aim of this study is to clear up the confusion and controversy that exists about terminology, diagnosis, and treatment of IHH.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

CT:

Computed tomography

GLUT 1:

Glucose transporter isoform 1

IHH:

Infantile hepatic hemangioma

ISSVA:

International Society for the Study of Vascular Anomalies

MRI:

Magnetic resonance imaging

OLT:

Orthotopic liver transplantation

99mTc:

Technetium 99m-labeled

U/S:

Ultrasound

References

  1. Achilleos OA, Buist LJ, Kelly D, Raafat F, McMaster P, Mayer AD, Buckels JA (1996) Unresectable hepatic tumors in childhood and the role of liver transplantation. J Pediatr Surg 31:1563–1567

    CAS  PubMed  Google Scholar 

  2. Avagyan S, Klein M, Kerkar N, Demattia A, Blei F, Lee S, Rosenberg HK et al (2013) Propranolol as a first-line treatment for diffuse infantile hepatic hemangioendothelioma. J Pediatr Gastroenterol Nutr 56:17–20

    Google Scholar 

  3. Barlow CF, Priebe CJ, Mulliken JB, Barnes PD, Mac Donald D, Folkman J, Ezekowitz RA (1998) Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy. J Pediatr 132:527–530

    CAS  PubMed  Google Scholar 

  4. Barnés CM, Huang S, Kaipainen A, Sanoudou D, Chen EJ, Eichler GS, Guo Y, Yu Y, Ingber DE, Mulliken JB, Beggs AH, Folkman J, Fishman SJ (2005) Evidence by molecular profiling for a placenta origin of infantile hemangioma. Proc Natl Acad Sci U S A 102:19097–19102

    PubMed  PubMed Central  Google Scholar 

  5. Bielenberg DR, Bucana CD, Sanchez R et al (1999) Progressive growth of infantile cutaneous hemangioma is directed correlated with hyperplasia and angiogenesis of adjacent epidermis and inversely correlated with expression of the endogenous angiogenesis inhibitor, IFN-beta. Int J Oncol 4:401–408

    Google Scholar 

  6. Blei F, Walter J, Orlow SJ, Marshuk DA et al (1998) Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. Arch Dermatol 134:718–722

    CAS  PubMed  Google Scholar 

  7. Bosemani T, Puttgen K, Huisman TA, Tekes A (2012) Multifocal infantile hepatic hemangioma-Imaging strategy and response to treatment after propranolol and steroids including review of the literature. Eur J Pediatr 171:1023–1028

    PubMed  Google Scholar 

  8. Boye E, Yu Y, Paranya G, Muliken JB, Olsen BR, Bischoff J (2001) Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest 107:745–752

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Chioran L, Cui XW, Tannapfell A, Franke D, Stenzei M, Schreiber-Dietrich D et al (2015) Benign liver tumors in pediatric patients—review with emphasis on maging features. World J Gastroenterol 21:8541–8561

    Google Scholar 

  10. Christison-Lagay ER, Burrows PE, Alomari A, Dubois J, Kozakewich HP, Lane TS et al (2007) Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry. J Pediatr Surg 42:62–68

    PubMed  Google Scholar 

  11. Chung EM, Lattin GE Jr, Cube R, Lewia RB, Marichal-Hernadez C, Shawhan R et al (2010) Pediatric liver masses: radiologic–pathologic correlation. Part 1. Benign tumors. Radiographics 30:801–827

    PubMed  Google Scholar 

  12. Daller JA, Bueno J, Gutierrez J, Dvorchik I, Twobin RB, Dickman PS et al (1999) Hepatic hemangioendothelioma: clinical experience and management strategy. J Pediatr Surg 34:98–108

    CAS  PubMed  Google Scholar 

  13. Davenport M, Hansen L, Heaton ND, Howard ER (1995) Hemangioendothelioma of the liver in infants. J Pediatr Surg 33:44–48

    Google Scholar 

  14. De Lorimer AA, Simpson EB, Baum RS (1967) Hepatic artery ligation for hepatic hemangiomatosis. N Engl J Med 277:333–337

    Google Scholar 

  15. Dehner LP, Ishak KG (1971) Vascular tumours of the liver in infants and children. A study of 30 cases and review of the literature. Arch Pathol 92:101–110

    CAS  PubMed  Google Scholar 

  16. Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, Bauman NM, Chiu YE, Chun RH, Garzon MC, Holland KE, Liberman L, MacLellan-Tobert S, Mancini AJ, Metry D, Puttgen KB, Seefeldt M, Sidbury R, Ward KM, Blei F, Baselga E, Cassidy L, Darrow DH, Joachim S, Kwon EK, Martin K, Perkins J, Siegel DH, Boucek RJ, Frieden IJ (2013) Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics 131:128–140

    PubMed  PubMed Central  Google Scholar 

  17. Finegold MJ, Egler RA, Goss JA, Guillerman RP, Karen SJ, Krishnamurthy R et al (2008) Liver tumors: pediatric population. Liver Transpl 14:1545–1556

    PubMed  Google Scholar 

  18. Foot J (1919) Hemangio-endothelium of the liver. JAMA 73:1042

    Google Scholar 

  19. Garcia-Rodriguez E, Calderón-López G (2010) Neonatal fulminant Type 2 infantile hepatic hemangioendothelioma involving skin, viscera and soft tissue. Fetal Pediatr Pathol 29:338–343

    PubMed  Google Scholar 

  20. Gnarra M, Behr G, Kitajewski A, Wu JK, Anupindi SA, Shawber CJ, Zavras N, Schizas D, Salakos C, Economopoulos KP (2016) History of the infantile hepatic hemangioma: from imaging to generating a differential diagnosis. World J Clin Pediatr 5:273–280

    PubMed  PubMed Central  Google Scholar 

  21. Grabhorn E, Richter A, Fischer L, Krebs-Schmitt D, Ganschow R (2009) Neonates with severe infantile hepatic hemangioendothelioma: limitations of liver transplantation. Pediatr Transplant 13:560–564

    PubMed  Google Scholar 

  22. Hase T, Kodama M, Kishida A, Matsushita M, Kurumi Y, Mizukuro T, Okabe H, Uno M, Ohta S, Shimada M (1995) Successful management of infantile hepatic hilar hemangioendothelioma with obstructive jaundice and consumption coagulopathy. J Pediatr Surg 30:1485–1487

    CAS  PubMed  Google Scholar 

  23. Hsi Dickie B, Fishman SJ, Azizkhan RG (2014) Hepatic vascular tumors. Semin Pediatr Surg 23:168–172

    PubMed  Google Scholar 

  24. Huang SA, Tu HM, Harney JW, Venihaki M, Butte AJ, Kozakewich HP et al (2000) Severe hypothyroidism caused by type 3 iodothyronine deidonase in infants with hemangiomas. N Engl J Med 343:185–189

    CAS  PubMed  Google Scholar 

  25. Iacobas I, Phung TL, Adams DM, Trenor CC 3rd, Blei F, Fishman DS et al (2018) Guidance document for hepatic hemangioma (infantile and congenital) evaluation and monitoring. J Pediatr 203:294–300

    PubMed  Google Scholar 

  26. Ingram JD, Yerushalmi B, Connell J, Karrer FM, Tyson RW, Sokol RJ (2000) Hepatoblastoma in a neonate: a hypervascular presentation mimicking hemangioendothelioma. Pediatr Radiol 30:794–797

    CAS  PubMed  Google Scholar 

  27. Ito H, Yamasaki T, Okamoto O, Tashara E (1989) Infantile hemangioendothelioma of the liver in patient with interstitial deletion of chromosome 6q: report of an autopsy case. Am J Med Genet 34:325–329

    CAS  PubMed  Google Scholar 

  28. Ji Y, Chen S, Xianng B, Xu Z, Jiang X, Liu X et al (2016) Clinical features and management of multifocal hepatic hemangiomas in children: a retrospective study. Sci Rep 6:31744

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kalpatthi R, Germak J, Mizelle K, Yeager N (2007) Thyroid abnormalities in infantile hepatic hemangioendotheliomas. Pediatr Blood Cancer 49:1021–1024

    PubMed  Google Scholar 

  30. Kamath SM, Mysorekar VV, Kadamba P (2015) Hepatic angiosarcoma developing in an infantile hemangioendothelioma: a rare case report. J Cancer Res Ther 11:1022

    PubMed  Google Scholar 

  31. Kassarjian A, Zurakowski D, Dubois J (2004) Infantile hepatic hemangiomas: clinical and imaging findings and their correlations with therapy. Am J Roentgenol 182:785–795

    Google Scholar 

  32. Keslar PJ, Buck JL, Selby DM (1993) Infantile hemangioendothelioma of the liver revisited. RadioGraphics 13:657–670

    CAS  PubMed  Google Scholar 

  33. Kim TJ, Lee YS, Song YS, Park CK, Shim SI, Kang CS, Lee KY (2010) Infantile hemangioendothelioma with elevated serum α-fetoprotein. Hum Pathol 41:763–767

    CAS  PubMed  Google Scholar 

  34. Krowchuk DP, Frieden IJ, Mancini AJ, Darrow DH, Blei F, Greene AK et al (2019) Clinical practice guideline for the management of infantile hemangiomas. Pediatrics 143:e20183475

    PubMed  Google Scholar 

  35. Kuroda T, Hoshino K, Nosaka S, Shiota Y, Nakazawa A, Takimoto T (2014) Critical hepatic hmenagioma in infants: recent nationwide survey in Japan. Pediatr Int 56:304–308

    PubMed  Google Scholar 

  36. Léauté-Labrèze C, Harper JI, Hoeger PH (2017) Infantile haemangioma. Lancet 390:85–94

    PubMed  Google Scholar 

  37. Lee BB (2013) Venus malformation and haemangioma: differential diagnosis, diagnosis, natural history and consequences. Phlebology 28:176–187

    PubMed  Google Scholar 

  38. Leon-Vilapalos J, Wolfe K, Kangesu L et al (2005) GLUT-1: an extra diagnostic tool to differentiate between hemangiomas and vascular malformations. Br J Plast Surg 8:348–352

    Google Scholar 

  39. Lerut J, Iesari S (2018) Vascular tumours of the liver: a particular story. Transl Gastroenterol Hepatol 3:62

    PubMed  PubMed Central  Google Scholar 

  40. Lou Y, Peng WJ, Cao Y, Cao DS, Xie J, Li HH (2014) The effectiveness of propranolol in treating infantile haemangiomas: a meta-analysis including 35 studies. Br J Clin Pharmacol 78:44–57

    CAS  PubMed  Google Scholar 

  41. Marsciani A, Pericoli R, Alaggio R, Brisigotti M, Vergine G (2010) Massive response of sever infantile hepatic hemangioma to propranolol. Pediatr Blood Cancer 54:176

    PubMed  Google Scholar 

  42. Maruiwa M, Nakamura Y, Motomura K, Murakami T, Kojiro M, Kato M et al (1988) Cornelia de Lange syndrome associated with Wilm’s tumour and infantile hemangioendothelioma of the liver: report of two autopsy cases. Virchows Arch A Pathol Anat Histopathol 413:463–468

    CAS  PubMed  Google Scholar 

  43. Mazereeuw-Hautier J, Hoeger PH, Benlahrech S, Ammour A, Broue P, Vial J, Ohanessian G, Léauté-Labrèze C, Labenne M, Vabres P, Rössler J, Bodemer C (2010) Efficacy of propranolol in hepatic infantile hemangioma with diffuse neonatal hemangiomatosis. J Pediatr 157:340–342

    PubMed  Google Scholar 

  44. Mo JQ, Dimashkich HH, Bove KE (2004) GLUT1 endothelial reactivity distinguishes hepatic infantile hemangiomas from congenital hepatic vascular malformation with associated capillary proliferation. Hum Pathol 35:200–209

    CAS  PubMed  Google Scholar 

  45. Mulliken JB, Glowacki J (1982) Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 69:412–422

    CAS  PubMed  Google Scholar 

  46. North PE, Waner M, Mizeracki A, Mihm MC Jr (2000) GLUT-1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 31:11–22

    CAS  PubMed  Google Scholar 

  47. North PE, Waner M, Mizeracki A, Mrak RE, Nickolas R, Kincannon J et al (2001) A unique microvascular phenotype shared by juvenile hemangiomas and placenta. Acta Dermatol 137:559–570

    CAS  Google Scholar 

  48. Ozmen E, Adaletli I, Kayabibi Y, Emre Ş, Kiliç F, Dervişoğlu S et al (2014) The impact of share wave elastography in differentiation of hepatic hemangioma from malignant liver tumors in pediatric population. Eur J Radiol 83:1691–1697

    PubMed  Google Scholar 

  49. Razon MJ, Kräling BM, Mulliken JB, Bischoff J (1998) Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation 5:189–195

    CAS  PubMed  Google Scholar 

  50. Riley MR, Garcia MG, Cox KL, Berquist WE, Kerner JE Jr (2006) Hepatic infantile hemangioendothelioma with unusual manifestations. J Pediatr Gastroenterol Nutr 42:109–113

    PubMed  Google Scholar 

  51. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD (2009) American Association for the Study of Liver Diseases. Liver biopsy. Hepatology 49:1017–1044

    PubMed  Google Scholar 

  52. Sari N, Yalçin B, Akyüz C, Haliloglu M, Büyükpamukçu M (2006) Infantile hepatic hemangioendothelioma with elevated serum alpha-fetoprotein. Pediatr Hematol Oncol 23:639–647

    PubMed  Google Scholar 

  53. Sarıalioğlu F, Yazıcı N, Erbay A, Boyvat F, Demir Ş, Özçay F, Uslu N (2017) A new perspective for infantile hepatic hemangioma in the age of propranolol: experience at Baskent University. Exp Clin Transplant 15:74–78

    PubMed  Google Scholar 

  54. Shah KD, Beck AR, Jhaveri MK, Keohane M, Weinberg M, Gerber M (1987) Infantile hemangioendothelioma of heterotopic intrathoracic liver with diaphragmatic hernia. Hum Pathol 18:754–756

    CAS  PubMed  Google Scholar 

  55. Sigamani E, Iyer VK, Agarwala S (2010) Fine needle aspiration cytology of infantile haemangioendothelioma of the liver: a report of two cases. Cytopathology 21:398–302

    CAS  PubMed  Google Scholar 

  56. Spiegel AH (1929) Penduculated angioendothelioma of the liver. Arch Pediatr 46:188

    Google Scholar 

  57. Tsai MC, Liu HC, Yeung CY (2019) Efficacy of infantile hepatic hemangioma with propranolol treatment: a case report. Medicine (Baltimore) 98:e14078

    Google Scholar 

  58. Varrasso G, Schiavetti A, Lanciotti S, Sapio M, Ferrara E, Grazia D et al (2017) Propranolol as first-line treatment for life-threatening diffuse infantile hepatic hemangioma: a case report. Hepatology 2017(66):283–285

    Google Scholar 

  59. Von Schweintz D (2006) Management of liver tumors in childhood. Semin Pediatr Surg 15:17–24

    Google Scholar 

  60. Walter JW, North PE, Waner M, Mizeracki A, Bier F, Walker JW et al (2002) Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosom Cancer 33:296–303

    Google Scholar 

  61. Warmann S, Bertram H, Kardorff R, Sasse M, Hausdort G, Fuchs J (2003) Interventional treatment of infantile hepatic hemangioenthothelioma. J Pediatr Surg 38:1177–1181

    CAS  PubMed  Google Scholar 

  62. Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, et al (2015) Vascular anomalies classification: recommendations from the International Society for the Study of Vascular Anomalies. 136: 203-14

  63. Wood PB, Putnam TC, Chacko AK (1977) Infantile hepatic hemangioendotheliomas associated with hemihypertrophy. Pediatr Radiol 5:242–245

    CAS  PubMed  Google Scholar 

  64. Yeh I, Bruckner AL, Sanchez R, Jeng MB, Newll BD, Frieden IJ (2011) Diffuse infantile hepatic hemangioma: a report of four cases managed with medical therapy. Pediatr Dermatol 28:267–275

    PubMed  Google Scholar 

  65. Zhang Z, Chen HJ, Yang WJ, Bu H, Wei B, Long XY et al (2010) Infantile hepatic hemangioendothelioma: a clinicopathologic study in a Chinese population. W J Gastroenterology 16:4549–4547

    Google Scholar 

Download references

Funding

There is no funding source.

Author information

Authors and Affiliations

  1. Department of Paediatric Surgery, “ATTIKON” General University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Nikolaos Zavras, Anastasia Dimopoulou & George Vaos

  2. Third Department of Surgery, “ATTIKON” General University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Nikolaos Machairas & Anna Paspala

Authors
  1. Nikolaos Zavras
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anastasia Dimopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nikolaos Machairas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Paspala
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. George Vaos
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Nikolaos Zavras selected the item, supervised the selection of articles and drafted the manuscript. Anastasia Dimopoulou contributed to the design of the study and drafted the manuscript. Nikolaos Machairas performed the literature search and selection of articles. Anna Paspala contributed to the conception and design of the study. George Vaos critically revised the manuscript and gave the final approval.

Corresponding author

Correspondence to Anastasia Dimopoulou.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Communicated by Piet Leroy

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zavras, N., Dimopoulou, A., Machairas, N. et al. Infantile hepatic hemangioma: current state of the art, controversies, and perspectives. Eur J Pediatr 179, 1–8 (2020). https://doi.org/10.1007/s00431-019-03504-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-019-03504-7

Keywords

Search

Navigation