Imaging of infantile hemangiomas is used to assess the extent of disease during lesion proliferation and planning of palliative interventions intended to limit complications. The lesions typically demonstrate T2-weighted signal hyperintensity relative to muscle and avidly enhance following contrast administration; T1-weighted signal hyperintensity and T2*-weighted MR signal loss likely represents hemorrhage within the lesion, a common feature of hemangiomas. During involution, whether spontaneous or therapeutically induced, dramatic reductions in the extent and enhancement of the lesion are typical. The aggressive osseous reaction of the petrous bone in the early imaging studies in this case is atypical for hemangiomas, which usually produce smoothly marginated erosions. The findings on subsequent imaging studies was more typical for involution. Computed tomography scans 19 months after presentation demonstrated replacement of the osseous reaction with mature, dense bone, as is expected with hemangioma involution. Complete resolution is common, but it may take years for the imaging appearance to fully normalize.
Understanding angiogenesis and its role in cellular proliferation has lead to the development of mechanism-specific therapies. Thalidomide, first approved as a sedative, became best known for its teratogenicity.16,17
Limb malformations resulting from in utero exposure to thalidomide are due to inhibition of new blood vessel formation through the VEGF/bFGF pathway.3
Thalidomide has been rediscovered as an antiangiogenic agent. Common therapeutic indications include multiple myeloma and pediatric brain tumors.13
The number of medications acting directly on the VEGF/bFGF pathway, whether by downregulation of production or by receptor blockade, is rapidly expanding, with thalidomide becoming the prototype. Animal experiments demonstrate the ability of thalidomide to inhibit VEGF-stimulated neovascularization of the cornea in both the mouse and the rabbit.3,12
The use of thalidomide, alone or in combination with other agents, has become routine in the treatment of hematological malignancies and solid tumors in children and adults. Multiple Phase I and II studies have been published regarding the efficacy of thalidomide in cancer and more are currently ongoing. The greatest safety concern is the risk of dysmelia or limb malformations due to in utero exposure.
The VEGF/bFGF pathway has been implicated in the pathogenesis of hemangiomas.6,10
Cutaneous hemangiomas consistently overexpress VEGF and HIF-2α.9
Proliferating hemangiomas are associated with serum VEGF levels that are significantly higher than those found in association with involuting hemangiomas and other vascular malformations.7,22
Levels of VEGF and bFGF have not been studied in association with intracranial hemangioma, but no evidence suggests that they would be different from the levels found in patients with other hemangiomas. This case report is the first to correlate intracranial hemangioma growth with measurements of VEGF and bFGF. More recently other antiangiogenic agents, such as interferon α-2a and -2b, have been investigated in the treatment of hemangiomas.8
Because interferon α has significant toxicities, the search for an effective and safe agent for use in children continues.
The evaluation of therapeutic effectiveness in patients with hemangiomas is difficult because it is well understood that these lesions will undergo regression on their own. Unlike the anticipated response to the administration of traditional cytotoxic chemotherapy, the response to thalidomide should not be expected to entail rapid regression. Treatment with antiangiogenesis agents is characterized by a delay in the onset of action as the tumor must outgrow its existing blood supply before diminishing in size. In the case presented in this paper, the tumor initially grew with significant velocity, slowing after 4 months of therapy with evidence of decreased growth before the patient reached 8 months of age. Regression does not usually begin until after a plateau phase, which was not seen in this patient. Once regression began, it was rapid and nearly complete before the child reached 2 years of age. The percentage increase in volume, a measure of growth velocity, of periorbital hemangiomas has been reported to range from 4 to 931% between imaging studies during the growth phase.21
A systematic evaluation of average growth velocities based on age for hemangiomas has not been described. This is probably due to the mostly benign nature of the lesions as well as the expense and inconvenience of serial MR imaging to assess tumor volume and continued variability in nomenclature. The lack of a plateau phase in growth and the early onset of tumor regression in our patient strongly suggest that thalidomide treatment had a positive effect on the course of her disease.
We have presented the case of a child diagnosed with a life-threatening intracranial hemangioma managed by VEGF/bFGF–targeted therapy using thalidomide. There was minimal toxicity with thalidomide therapy and the neurological outcome has been better than expected. The excellent clinical outcome and toxicity profile using the mechanism-specific therapy described in this case warrants further clinical investigation and offers a new therapeutic option in the management of other life-threatening hemangiomas.