European Journal of Pediatrics

, Volume 174, Issue 12, pp 1579–1584 | Cite as

Sirolimus for the treatment of children with various complicated vascular anomalies

  • Herwig Lackner
  • Anna Karastaneva
  • Wolfgang Schwinger
  • Martin Benesch
  • Petra Sovinz
  • Markus Seidel
  • Daniela SperlEmail author
  • Sofia Lanz
  • Emir Haxhija
  • Friedrich Reiterer
  • Erich Sorantin
  • Christian E. Urban
Original Article


Vascular anomalies include a heterogeneous group of disorders that are categorized as vascular tumors or vascular malformations. Treatment options include resection, embolization, laser therapy, and sclerotherapy or medical treatment such as propranolol, steroids, interferon, and cytostatic chemotherapy. Mammalian target of rapamycin seems to play a key role in the signal pathway of angiogenesis and subsequently in the development of vascular anomalies. Recently, the successful use of sirolimus has been reported in children with lymphatic malformations and kaposiform hemangioendotheliomas. We report on six patients with different vascular anomalies (kaposiform hemangioendothelioma n = 2, combined lymphatico-venous malformation n = 2, pulmonary lymphangiectasia n = 1, and orbital lymphatic malformation n = 1) who were treated with peroral sirolimus. Three of the children initially presented with a Kasabach-Merrit phenomenon. Median duration of treatment was 10 months; two children are still on treatment. Three children each achieved complete and partial remission. Kasabach-Merrit phenomenon resolved within 1 month in all patients. Treatment with sirolimus was tolerated well; only mild reversible leukopenia was observed.

Conclusion: Sirolimus proved to be effective in children with complicated lymphatic or lymphatico-venous malformations and kaposiform hemangioendotheliomas. Treatment was tolerated well with acceptable side effects. The optimum length of treatment and possible long-term side effects have to be evaluated.

What is Known:

Vascular anomalies including vascular tumors and vascular malformations may lead to life-threatening conditions.

Some patients are refractory to established treatment and/or are not available for local invasive procedures.

What is New:

We reviewed the literature focusing treatment of vascular anomalies in children and adolescents.

Our data support recent studies that sirolimus is an effective treatment option in patients with complicated vascular tumors and malformations.


Sirolimus Vascular anomalies Children Treatment 



Computed tomography


Food and Drug Administration


Infantile hemangioma


International Society for the Study of Vascular Anomalies


Kaposiform hemangioendothelioma


Kasabach-Merrit phenomenon


Magnetic resonance imaging


Mammalian target of rapamycin


Vascular endothelial growth factor


Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All procedures performed in our retrospective report were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Author’s contributions

HL and AK prepared the manuscript and searched the literature. DS, WS, MB, PS, MS, DFR, ES, EH and CU revised the manuscript. All authors contributed in the clinical management of the patients and reviewed the manuscript.


  1. 1.
    Adams DM, Wentzel MS (2008) The role of the hematologist/oncologist in the care of patients with vascular anomalies. Pediatr Clin N Am 55:339–355CrossRefGoogle Scholar
  2. 2.
    Blatt J, Stavas J, Moats-Staats B et al (2010) Treatment of childhood kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer 55:1396–1398CrossRefPubMedGoogle Scholar
  3. 3.
    Blei F (2015) Kaposiform hemangioendothelioma: therapeutic efficacy for an enigmatic diagnosis. Pediatr Blood Cancer 62:551–552CrossRefPubMedGoogle Scholar
  4. 4.
    Blei F (2012) Medical management of vascular anomalies. Facial Plast Surg 28:575–583CrossRefPubMedGoogle Scholar
  5. 5.
    Ezekowitz RA, Mulliken JB, Folkman J (1992) Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 326:1456–1463CrossRefPubMedGoogle Scholar
  6. 6.
    Fahrtash F, McCahon E, Arbuckle S (2010) Successful treatment of kaposiform hemangioendothelioma and tufted angioma with vincristine. J Pediatr Hematol Oncol 32:506–510CrossRefPubMedGoogle Scholar
  7. 7.
    Falger JC, Mueller T, Arbeiter K et al (2006) Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy. Pediatr Transplant 10:565–569CrossRefPubMedGoogle Scholar
  8. 8.
    Fost NC, Esterly NB (1968) Successful treatment of juvenile hemangiomas with prednisone. J Pediatr 72:351–357CrossRefPubMedGoogle Scholar
  9. 9.
    Garzon MC, Huang JT, Enjolras O et al (2007) Vascular malformations: part I. J Am Acad Dermatol 56:353–370CrossRefPubMedGoogle Scholar
  10. 10.
    Hammill AM, Wentzel MS, Gupta A et al (2011) Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 57:1018–1024CrossRefPubMedGoogle Scholar
  11. 11.
    Holmes WJ, Mishra A, Gorst C et al (2011) Propranolol as first-line treatment for rapidly proliferating infantile haemangiomas. J Plast Reconstr Aesthet Surg 64:445–451CrossRefPubMedGoogle Scholar
  12. 12.
    ISSVA Classification of Vascular Anomalies ©(2014) International Society for the Study of Vascular Anomalies. Available at “”. Accessed April 2014Google Scholar
  13. 13.
    Jahnel J, Lackner H, Reiterer F et al (2012) Kaposiform hemangioendothelioma with Kasabach. Merritt phenomenon: from vincristine to sirolimus. Klin Padiatr 224:395–397CrossRefPubMedGoogle Scholar
  14. 14.
    Kai L, Wang Z, Yao W et al (2014) Sirolimus, a promising treatment for refractory Kaposiform hemangioendothelioma. J Cancer Res Clin Oncol 140:471–476CrossRefPubMedGoogle Scholar
  15. 15.
    Kim D, Benjamin L, Wysong A et al (2015) Treatment of complex periorbital venolymphatic malformation in a neonate with a combination therapy of sirolimus and prednisolone. Dermatol Ther Mar 5 (Epub ahead of print)Google Scholar
  16. 16.
    Lackner H, Urban C, Schwinger W et al (1995) Cyclophosphamide therapy in life-threatening inoperable cystic hygromas. Pediatr Surg Int 10:199–201CrossRefGoogle Scholar
  17. 17.
    Leaute-Labreze C, Dumas de la Roque E, Hubiche T et al (2008) Propranolol for severe hemangiomas of infancy. N Engl J Med 358:2649–2651CrossRefPubMedGoogle Scholar
  18. 18.
    Margolin JF, Soni HM, Pimpalwar S (2014) Medical therapy for pediatric vascular anomalies. Semin Plast Surg 28:79–86PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Pan WK, Li P, Huang Q (2015) Propranolol induces regression of hemangioma cells via the down-regulation of the PI3K/Akt/eNOS/VEGF pathway. Pediatr Blood Cancer. doi: 10.1002/pbc.25453 Google Scholar
  20. 20.
    Reinglas J, Ramphal R, Bromwich M (2011) The successful management of diffuse lymphangiomatosis using sirolimus: a case report. Laryngoscope 121:1851–1854PubMedGoogle Scholar
  21. 21.
    Sadan N, Wolach B (1996) Treatment of hemangiomas of infants with high doses of prednisone. J Pediatr 128:141–146CrossRefPubMedGoogle Scholar
  22. 22.
    Sans V, de la Roque ED, Berge J et al (2009) Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics 124:423–431CrossRefGoogle Scholar
  23. 23.
    Schroeder U, Lauten M, Stichtenoth G et al (2014) Laryngomalacia and complicated, life-threatening mTOR-positive Kaposiform hemangioendothelioma cured by Supraglottoplasty and sirolimus. Klin Padiatr 226:362–368CrossRefPubMedGoogle Scholar
  24. 24.
    Timke C, Krause MF, Oppermann HC et al (2007) Interferon alpha 2b treatment in an eleven-year-old boy with disseminated lymphangiomatosis. Pediatr Blood Cancer 48:108–111CrossRefPubMedGoogle Scholar
  25. 25.
    Trenor CC (2011) Sirolimus for refractory vascular anomalies. Pediatr Blood Cancer 57:904–905CrossRefPubMedGoogle Scholar
  26. 26.
    Uno T, Ito S, Nakazawa A et al (2015) Successful treatment of Kaposiform hemangioendothelioma with everolimus. Pediatr Blood Cancer 62:536–538CrossRefPubMedGoogle Scholar
  27. 27.
    Vesikari T, Nuutila A, Cantell K (1988) Neurologic sequelae following interferon therapy of juvenile laryngeal papilloma. Acta Paediatr Scand 77:619–622CrossRefPubMedGoogle Scholar
  28. 28.
    Wang Z, Li K, Dong K et al (2013) Successful treatment of Kasabach-Merritt phenomenon arising from Kaposiform hemangioendothelioma by sirolimus. J Pediatr Hematol Oncol 37:72–73CrossRefGoogle Scholar
  29. 29.
    White CW, Wolf SJ, Korones DN et al (1991) Treatment of childhood angiomatous diseases with recombinant interferon alfa-2a. J Pediatr 118:59–66CrossRefPubMedGoogle Scholar
  30. 30.
    Zarem HA, Edgerton MT (1967) Induced resolution of cavernous hemangiomas following prednisolone therapy. Plast Reconstr Surg 39:76–83CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Herwig Lackner
    • 1
  • Anna Karastaneva
    • 1
  • Wolfgang Schwinger
    • 1
  • Martin Benesch
    • 1
  • Petra Sovinz
    • 1
  • Markus Seidel
    • 1
  • Daniela Sperl
    • 1
    Email author
  • Sofia Lanz
    • 1
  • Emir Haxhija
    • 2
  • Friedrich Reiterer
    • 3
  • Erich Sorantin
    • 4
  • Christian E. Urban
    • 1
  1. 1.Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology/OncologyMedical University of GrazGrazAustria
  2. 2.Department of Pediatric and Adolescence SurgeryMedical University of GrazGrazAustria
  3. 3.Division of NeonatologyMedical University of GrazGrazAustria
  4. 4.Division of Pediatric RadiologyMedical University of GrazGrazAustria

Personalised recommendations