Med Pediatr Oncol 2002;38:118±119

Hemangioendothelioma: Successful Therapy With Interferon-aA Study in Association With the Italian Pediatric

Haematology/Oncology Society (AIEOP)

Giovanni Deb, MD,1* Alberto Donfrancesco, MD,1 Ilaria Ilari, MD,1 Luigi De Sio, MD,1

Giuseppe M. Milano, MD,1 Cesare Ghitti, MD,2 Giovanna Fontana, MD,3 Alessandro Sandri, MD,3

and Lawrence Helson, MD4

INTRODUCTION

Infantile hemangioendothelioma (HE) is a rare inter-mediate to aggressive grade vascular neoplasm, mostcommonly presenting before the age of 6 months. Thereis a 1.8:1 female predominance [1,2]. HEs may beassociated with vascular malformations involving thebrain, skin, gut and other organs [3].

In contrast to asymptomatic hemangiomas, whichgenerally undergo spontaneous regression within a year,HEs may be symptomatic and rapidly fatal.

They can act as arterio±venous ®stulas, produce life-threatening high output congestive heart failure withrespiratory compromise and a mortality rate as high as90% [4].

HE can also be associated with hemolytic anemia,thrombocytopenia, and coagulopathy (Kasabach±Merrittsyndrome) that are usually unresponsive to standardtherapy. Despite treatment, mortality is in the 30±40%range for infants bleeding from profound thrombocyto-penia in this setting. Aggressive management is clearlywarranted in such patients [5].

Traditional therapeutic approaches to angiomatousdisease include surgery, systemic steroids, radiationtherapy, arterial embolization, or ligation of the afferentartery. These are not always successful in the treatment ofHEs displaying locally aggressive behaviour or imping-ing on vital structures.

In vitro studies with interferon (IFN) have suggestedthat IFN might interfere with angiogenesis by blockingendothelial cell motility, proliferation, and by directlyinhibiting angiogenesis [6]. Furthermore, IFN exertsdirect cytostatic effects slowing down cellular pro-liferation by increasing the length of the cell cycle[7].

IFN-� treatment has produced regressions of infantileangiomatous disease including HE [8,9,10], although notall reports have been favorable [11].

After successfully treating a case of Kaposiform HE[12] we tried to con®rm these encouraging results in alarger series. A multi institutional study of this raredisease was accordingly started.

From February 1994 until April 1999, 6 patients(3 males/3 females), median age 3 months (range 2 days±9 months) with HE had entered the study.1

The HE was measured by ultrasound scan (US),computed tomography (CT), or magnetic resonanceimaging (MRI) and proven histologically in all patients.Four exhibited the Kasabach±Merritt (K±M) syndrome.

After informed consent had been obtained fromparents or guardians according to institutional guidelines,the patients were treated with IFN� for a median periodof 12 weeks (range 6±24 weeks) (Table I).

The agent was administred subcutaneously once daily,starting at 1� 106 U/m2/day, increasing the dose after oneweek to 2� 106 U/m2/day and then after a second weekto the full dosage of 3� 106 U/m2/day. Complete bloodcounts, coagulation panels, liver function tests and bloodchemistries were performed daily during the ®rst week oftreatment, weekly thereafter and monthly after dischargefrom the hospital. Treatment was administered in theevening, as this appears to increase the tolerance to theside effects of interferon therapy.

All six patients had a tumor regression > 50%measured by US, CT, or MRI, including the four casescharacterized by the K±M phenomenon. The intervalbetween the administration of IFN and the response totreatment ranged from 6 weeks to 6 months with amedian period of 3 months.

ÐÐÐÐÐÐ1Divisione di Oncologia, Ospedale Pediatrico Bambino GesuÁ-Roma,Italy

2Ospedale S. Gerardo-Monza, Italy

3UniverstiaÁ di Torino, Italy

4Clinical Consultant, Ouakerrown, Pennsylvania

*Correspondence to: Dr. Giovanni Deb, Ospedale Bambino GesuÁ,Divisione di Oncologia, Piazza S. Onofrio, 4, 00165-Roma, Italy.E-mail: deb@opbg.net

Received 17 November 2000; Accepted 23 May 2001

1These six children are separate and distinct from the 18 patients withinfantile hemangiomas successfully treated with interferon-a by us andreported by G. Deb et al. in the Int J Pediatr Hematol/Oncol1996;3:109±113.

ß 2002 Wiley-Liss, Inc.DOI 10.1002/mpo.1284

The ®rst two patients were treated with IFN a-2a. Thiswas changed to IFN a-2b because IFNa-2a treatment-related neurologic sequelae (spastic diplegia) werereported by others as most likely related to the for-mulation of the drug.

Toxicity was mild in our patients. There were a fewfebrile episodes secondary to IFN and a slowly prog-ressive increase in transaminases in one child, returningto normal within two weeks from discontinuation oftherapy. No neurologic toxicities were observed.

No regrowth of the tumor was observed after dis-continuation of treatment. All patients are alive and wellafter a median follow up of 21 months (range 12±29months) after withdrawal of IFN.

The four patients with K±M syndrome experiencedstriking resolution of the thrombocytopenia. The im-provement observed in patients with consumptivecoagulopathy might have been the result of decreasedplatelet adherence and trapping secondary to increasedendothelial cell prostacyclin production and release, inaddition to the antiangiogenic effects of IFN.

Most hemangiomas of infancy respond to high dosesof prednisone, but only 30% of the alarming hemangio-mas regress after high-dose corticosteroid treatment andeven lower response rates have been reported for patientswith the K±M syndrome. The remaining 70% are eitherunresponsive with a high mortality rate or require long-term steroid maintenance treatment. The rapid andimpressive responses observed in our patients, as wellas in others series reported in the literature, prompt us tosuggest that IFN-a should be adopted as initial therapyfor HE, particularly in high-risk infants.

REFERENCES

1. Mueller BU, Mulliken JB. The infant with a vascular tumor.Semin Perinatol 1999;23:332±340.

2. Selby DM, Stocker JT, Waclawiw MA. Infantile hemangioen-dothelioma of the liver. Hepatology 1994;20:39±45.

3. Bar-Server Z, Horev G, Lubin E, et al. A rare coexistence of amulticentric hepatic hemangioendothelioma with a large brainhemangioma in a preterm infant. Pediatr Radiol 1994;24:141±142.

4. Enjolras O, Riche MC, Merland JJ, et al. Management of alarminghemangiomas in infancy: a review of 25 cases. Pediatrics 1990;85:491±498.

5. Zukeberg LR, Nickoloff BJ, Weiss SW. Kaposiform hemangioen-dothelioma of infancy and childhood. An aggressive neoplasmassociated with Kasabach-Merritt syndrome and lymphangioma-tosis. Am J Surg Pathol 1993;17:321±328.

6. Folkman J. Successful treatment of an angiogenic disease. N EnglJ Med 1989;320:1211±1212.

7. Baron S, Tyring SK, Fleischmann WR, et al. The Interferons.Mechanisms of action and clinical applications. JAMA 1991;266:1375±1383.

8. White CW, Wolf SJ, Korones DN, et al. Treatment of childhoodangiomatous disease with recombinant interferon alfa-2a. JPediatr 1991;118:59±66.

9. Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2atherapy for life-threatening hemangiomas of infancy. N Engl JMed 1992;326:1456±1463 [ibid. corrections 1994; 330:300. Ibid.additional corrections 1995;333:595±596].

10. Chang E, Boyd A, Nelson CC, et al. Successful treatment ofinfantile hemangiomas with interferon alpha-2b. J PediatrHematol Oncol 1997;19:237±244.

11. Teillac-Hamel D, Prost Y, Bodemer C, et al. Serious childhoodangiomas: unsuccessful alpha-2b interferon treatment: a report offour cases. Br J Dermatol 1993;129:473±476.

12. Deb G, Jenkner A, De Sio L, et al. Spindle cell (Kaposiform)hemangioendothelioma with Kasabach-Merritt syndrome in aninfant: successful treatment with a-2A interferon. Med PediatrOncol 1997;28:358±361.

TABLE I. Patients' Characteristics and Response to Treatment

Patientsex Age Diagnosis Treatment Responses

F* 2 months HE of the right ¯ank K±M syndrome Interferon-a2a for 6 months Resolution of K-M syndrome after6 weeks 100% regression after 24 weeks

F 9 months HE of the supraclavicular fossa Interferon-a2a for 3 months 100% regression after 12 weeksM 3 months HE of the back of the neck K±M syndrome Interferon-a2b for 3 months Resolution of K-M syndrome after

3 weeks 55% regression after 12 weeksM 2 days HE of the leg K±M syndrome Interferon-a2b for 3 months Resolution of K-M syndrome after

3 weeks 55% regression after 6 weeksM 3 months HE of the right ¯ank K±M syndrome Interferon-a2b for 6 months Resolution of K-M syndrome after

8 weeks 90% regression after 20 weeksF 3 months HE of the liver Interferon-a2b for 3 months 50% regression after 4 weeks

*This patient, with the spindle cell form of HE, was reported previously [12].

Successful Therapy With Interferon-� 119