Propranolol therapy for infantile haemangiomas: Review of the literature

Abstract

Objectives

Haemangiomas are the most common tumors of infancy affecting approximately 1 in 10 children. Unlike other tumors, haemangiomas enter an involution phase, during which they usually regress over the next several months to years. Sometimes intervention is required due to proliferative growth which is complicated by ulceration, bleeding, persistent aesthetic deformity or infection.

Methods

Review of the literature.

Results

Propranolol, a nonselective beta-blocker, has recently been introduced as a novel modality for the treatment of proliferating haemangiomas. The exact mechanism of action of propranolol in the treatment of haemangiomas remains unclear, but vasoconstriction, down-regulation of angiogenic factors such as VEGF and bFGF and up-regulation of apoptosis of capillary endothelial cells may be responsible for the reduction of haemangiomas. Besides, an inhibition of MMP-9 and HBMEC expression by propanolol is discussed as possible mechanism influencing the growth of haemangiomas. However, there are different case reports of successfully treated infants in the current literature.

Conclusion

There is the obtain that propranolol will detach steroids in the therapy for infantile haemangiomas.

Introduction

Haemangiomas are the most common tumors of infancy affecting approximately 1 in 10 children [1]. Haemangiomas are more common in Caucasians, being evident in up to 12% of all children and occurring more frequently in females than in males, in a ratio of 3:1. Sixty per cent of haemangiomas are located in the head and neck area, whereas 25% occur on the trunk and 15% on the extremities [2]. Usually 80% of all haemangiomas are single lesions, but 20% of affected infants develop multiple tumors. Infantile haemangiomas are characterized by an inconspicuous appearance at birth, but undergo rapid and intermittent growth throughout the first year of life. By the age of 5 years usually 50% of the lesions have involuted. This increases to nearly 70% by the age of 7 years and about 90% by the age of 9 years. Nevertheless, in 40–50% of all affected children teleangiectatic cutaneous vessels, fibrous-fatty tissue or scar formations can be observed as a residue of the lesions [3], [4].

Although general outlines of haemangioma growth characteristics have long been recognized, specific details about haemangima growth and information regarding differences in growth patterns between haemangioma subtypes are lacking. There are different theories on the origin of infantile haemangiomas. These include suggestions of placental origin, intrinsic defect or somatic endothelial mutation, and extrinsic factors creating a conductive milieu for growth. However, no current hypothesis explains all the characteristics of infantile haemangiomas. In the last several years, much has been learned about molecular features of haemangioma and haemangioma-derived endothelial cells cultured in vitro. Haemangioma endothelial cells exhibit constitutive vascular endothelial growth factor signalling the endothelial cells comprising infantile haemangiomas show intense and persistent immunoreactivity for a number of tissue-specific markers that is highly characteristic of placental microvasculature like GLUT-1. Therefore there is the hypothesis that haemangiomas possibly stem from placental tissue or resemble it [3], [4]. Infantile haemangiomas vary tremendously from small, benign growth to large, function-threatening tumors. Most require no treatment, but treatment is needed if dramatic aesthetic, and/or functional impairment as visual or airway obstruction or ulceration arises [5]. Until now oral corticosteroids are considered as first-line therapy for such troublesome and severe haemangiomas. Systemic steroids have proven effectiveness, but the risks of long-term and high dose use include growth disturbances and immune system dysfunction as well as ulcerations up to severe tissue loss. Moreover, there are cases of fast growing infantile haemangiomas which show no response to steroid therapy. Other therapeutic options as interferon alpha and vincristine are used less often because of side effects and toxicity [6]. In cases of life-threatening haemangiomas and haemangiomatosis cyclophosphamide was also reported to offer promising results [7]. However, the serious side effects of cyclophosphamide like avascular necrosis, cardiomyopathy, pulmonary fibrosis, gonadal damage, and subsequent malignancies [8] have to be kept in mind and therefore the application of cyclophosphamide in the therapy of infantile haemangiomas needs to be carefully considered. Reported successful invasive treatments, especially for airway haemangiomas, include intralesional steroid injection, endoscopic and open excision, laser therapy, and tracheotomy. The treatment plan depends on many factors, including the size and extent of the lesion, social situations, and surgeon's comfort or experience with any given treatment modality.

The use of propranolol in the treatment of haemangiomas was serendipitously discovered last year in 2 children who showed rapid regression of disease when treated for cardiopulmonary conditions [9]. The treatment course occurred during the proliferative phase of growth, but the impact of propranolol on persistent disease remains unknown. After this notification [9] several groups worldwide initiated propranolol therapy in children with haemangiomas and gained experiences with this treatment. Therefore it was necessary to summarize the results. This review presents the current knowledge on propranolol therapy in infantile haemangiomas and the assumptions regarding the possible mechanism of propanolol in haemangioma therapy.