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• W2142709253 abstract "Reviews of vascular tumors of the liver in infants have established hemangioendothelioma as the most common vascular tumor of the liver in the infant age group (1,2). Hepatic hemangioendothelioma in infancy is a rare congenital syndrome characterized by multifocal benign vascular dilatation involving the liver. The clinical course depends on tumor size, its growth characteristics, the localization, and complications. The most feared complications are cardiac failure and consumptive coagulopathy with thrombocytopenia (Kassabach-Merrit syndrome), which may occur in up to 50% of affected children (3). Spontaneous regression of the lesion can be expected, but radiation therapy (4,5), corticosteroids (6), antineoplastic therapy (7,8), or surgery (6,9,10) may be needed to initiate the process. Interferon α2a has been used in the treatment of a number of hemangiomas of infancy (11-13). Successful use in one other hemangioendothelioma of the liver has been reported before (13). Here we describe our experience in the use of interferon α2a in a 5-month-old child with multiple hemangioendotheliomas of the liver resistant to high-dose corticosteroids. CASE REPORT A 3-month-old girl with a large, distended abdomen was admitted to the Sophia Children's Hospital in Rotterdam. After a pregnancy of 42 weeks, she was born by cesarean section and weighted 4,810 g. Soon after the girl's birth, the mother had noticed distension of the girl's abdomen. The stools were “pencil shaped” and hard with normal color. On examination, she was pink, but pale infant with a large, nontender but firm liver that filled and distended the upper abdomen and extended to the pelvic rim. Her skin was normal. On laboratory evaluation, she proved to have a microcytic hypochromic anemia with low serum iron. At that time, the results of coagulation studies and liver function tests were all normal. Excretion of catecholamines or metabolites in the urine were within the normal range. An abdominal sonogram of the patient showed hepatomegaly caused by multiple hypoechoic nodules replacing most of the normal liver parenchyma (Fig. 1). Color Doppler sonography did not reveal significant hyperperfusion and the hepatic artery was only slightly dilated. A normal [131I]metaiodobenzylguanidine ([131I]MIBG) scan in addition to the normal urinary catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) excretion made the diagnosis of neuroblastoma stage 4S doubtful (14). Arteriographic imaging revealed that the truncus coeliacus and the hepatic artery were not impressively enlarged. There were multiple smaller or larger afferent vessels with connections to the diffuse enlarged liver. An open liver biopsy was performed to establish a definitive diagnosis. Pathologic examination showed a hepatic hemangioendothelioma involving the whole liver. In view of the multiple afferent vessels, no single vessel was available for embolization or ligation. Prednisone 3 mg/kg/day over 14 days followed by 2 mg/kg/day was initiated. Instead of improvement, the clinical condition deteriorated with signs of congestive heart failure, coagulopathy, and persistent anemia despite transfusions. Furthermore, due to the high position of the diaphragm, there were respiratory and feeding problems. Several small skin hemangiomas developed and increased in size. Instead of regression of the liver, the whole abdomen as well as the pelvis became filled with the enlarged liver (Fig. 2). Supportive treatments consisted of diuretics daily, blood transfusions when necessary, intranasal oxygen, and tube feeding. Despite 6 weeks of corticosteroid therapy, she continued to deteriorate. Subsequently therapy was changed to interferon α2a. One million units of recombinant human interferon α2a subcutaneously once a day (3 million E/m2/day) was started while the dose of prednisone was tapered and stopped 2 weeks later. Apart from a short period of low temperature elevation (38°C) with some general malaise, no major side effects, like renal or liver dysfunction, were encountered. Ultrasound examinations showed a slight decrease in the size of the liver, starting 6 weeks after initiating interferon α2a, followed by continued shrinkage of the lesions. The skin hemangiomas decreased in size as well. Nearly 6 months after admission, she was discharged from the hospital with the above-mentioned maintenance therapy. Subsequently, respiratory and circulatory support could be stopped and, after 7 months of interferon, it could be tapered and stopped. The patient is now 2 years old and is flourishing with only a mildly enlarged liver, palpable 2 cm below the right costal margin. DISCUSSION Hemangiomas and hemangioendotheliomas are in fact proliferations of capillaries rather than vascular malformations. The vessels are dilated as a consequence of the high flow. Hemangiomas are the most common vascular disorders of infancy. They are small, harmless birthmarks that appear soon after birth, enlarge in the first 8-18 months, and then involute slowly in 5-8 years. They sometimes can be life-threatening, especially when they involve the larynx, paratracheal regions, or vital structures such as the heart, mediastinum, and liver (15). By contrast, the hepatic hemangioendothelioma of infancy is a different pathologic entity, characterized by multifocal benign vascular lesions, typically involving both the liver and skin (16). The hepatic hemangioendothelioma of infancy becomes symptomatic by 2 months of age in 85% of the patients (17). Girls seem to be affected more than boys (F:M = 1.5-2:1) (8,18). Congestive heart failure and consumptive coagulopathy with thrombocytopenia (Kassabach-Merrit syndrome) are the most important complications and are often fatal (2,3,17). If the patient survives the complications, the lesions appear to resolve over time (18). Definitive diagnosis is made by open liver biopsy and arterial angiography, but cases have been described in which noninvasive imaging techniques have been used to establish the diagnosis (8,19). Initial management can be conservative because spontaneous regression can occur. Importantly, however, life-threatening complications can develop rapidly, caused by direct compression of vital structures that has in the past resulted in a 60% mortality. In general, there is consensus that symptomatic patients require supportive management. Digitalis and diuretics are used to treat congestive heart failure, and corrective replacement therapy is used for anemia or coagulopathy (4,6-8). Consensus ends there. If the lesion is solitary or easily approachable from a surgical standpoint, some would advocate simple excision (6), selective embolization of afferent vessels (10), or ligation of the afferent vessel (9). An alternative approach is steroid therapy at doses of 2 mg/kg/day (6). A steroid response can be observed within 1-3 weeks. Radiation therapy in doses from 200 to 2,000 cGy has been widely used (4,5) and may be beneficial in reducing the activity of the vascular bed. A third nonsurgical treatment involves the use of antineoplastic agents (7,8). More recently, interferon α has been proposed as an alternative therapy for hemangiomas (11-13). In the extensive study by Ezekowitz et al. (13), one patient with a hemangioma in the liver was successfully treated in this manner after a 1-month treatment with prednisone and embolization of hepatic arteries. Originally, interferon α2a was developed as an antiviral agent and it was found in 1980 to inhibit capillary endothelial cell locomotion (20). Some years later, it became known that interferons inhibited endothelial cell proliferation in vitro and angiogenesis in animals (21). Until now, little is known about the role of interferon in the treatment of patients with hepatic hemangioendothelioma of infancy. Described side effects are signs and symptoms as in viral disease (fever, muscle pain), bone marrow depression and, in the long term, a possible reversible regression in psychomotor development (Dr. A. Ezekowitz, personal communication). In the adult population, thyroid autoimmunity and, consecutively, hypothyroidism can be expected in certain patients treated with interferon α, especially if administered in a chronic fashion (22). The key determinant for the manifestation of this interferonrelated autoimmune phenomenon seems to be a predisposition for autoimmunity, since patients with initially detectable thyroid antibodies are prone to exacerbations of thyroid autoimmunity (23). Until now, this phenomenon has not been described in pediatric patients. Assessing the efficacy of any drug in hepatic hemangioendotheliomas is made difficult by the fact that spontaneous regression of the hepatic vascular process may play a role in any apparent clinical improvement. The option of arterial ligation or embolization should always be considered. The rate of response after high-dose corticosteroids in hemangiomas varies from 30% to 60% (17), and we believe it correct to use prednisone first. In most responders, a steady state or shrinkage will be visible within 3 weeks. Relapse is highly improbable. It is our opinion that either chemotherapy or radiation therapy is reserved for last in the sequence of therapeutic attempts, because of late sequelae of those modalities; for example, there are documented cases of malignant lesions eventually developing in irradiated hemangioma sites (8). In our patient with a corticosteroid-resistant hemangioendothelioma of the liver, interferon α proved to be a good next step and is therefore proposed for patients who follow a similar clinical course. Acknowledgment: We are extremely grateful to Dr. Giulio D'Angio and Dr. Alan Ezekowitz for their critical and valuable comments on the manuscript.FIG. 1: . Ultrasonographic of sagittal image of the liver shows hepatomegaly caused by multiple hypoechoic nodules.FIG. 2: . At the age of 5 months, the abdomen was very distended with a girth of 58 cm (measurement on the line)." @default.
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• W2142709253 title "Hepatic Hemangioendothelioma of Infancy: Treatment with Interferon α" @default.
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