Capillary hemangiomas are one of the most common benign orbital tumors of infancy. They are benign endothelial cell neoplasms that are typically absent at birth and characteristically have rapid growth in infancy with spontaneous involution later in life. This is in contrast to another known group of childhood vascular anomalies, vascular malformations. Vascular malformations, such as lymphangiomas and arteriovenous malformations, are present at birth and are characterized by very slow growth with persistence into adult life.[1, 2]
Capillary hemangiomas are believed to be hamartomatous proliferations of vascular endothelial cells. They are now thought to be of placental origin due to a unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Periorbital capillary hemangiomas follow a similar course to hemangiomas on other parts of the body. They generally exhibit 2 phases of growth, a proliferative phase and an involutional phase. The proliferative phase of rapid growth typically occurs from 8-18 months. Pathologically, it is characterized by an increased number of endothelial and mast cells, the latter being a stimulus for vessel growth. Endothelial cell proliferation returns to normal following the proliferation phase.
The involutional phase is characterized by slow regression of the hemangiomas. One half of all lesions will involute by age 5 years, and 75% will involute by age 7 years. During this phase, mast cell numbers decrease to normal and there is a decrease in endothelial and mast cell activity. These vascular spaces become lined with endothelial cells without muscular support.[3]
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As many as 50% of systemic capillary hemangiomas can occur in the head and neck region. Of all the patients who eventually develop capillary hemangiomas, 30% of them have evidence of their presence at birth, while 100% have manifest them by age 6 months.
Systemic involvement with hemangiomas can be a significant source of morbidity and mortality.
The Kasabach-Merritt syndrome is associated with mortality rates from 30-50%. These patients characteristically present with a consumption coagulopathy and thrombocytopenia secondary to platelet sequestration in large visceral hemangiomas. Disseminated intravascular coagulation may occur. These patients also experience high-output congestive heart failure. Nasopharyngeal hemangiomas can be associated with respiratory obstruction. Surgical intervention often is required in these cases.
PHACES syndrome is associated with large segmental hemangiomas of the head and neck. The acronym refers to Posterior fossa abnormalities (Dandy-Walker malformation), Hemangiomas, Arterial lesions, Cardiac abnormalities (coarctation), Eye abnormalities, and Sternal clefting. As a spectrum of severity exists in these patients, they must be closely monitored for progressive cardiovascular and neurovascular deterioration.
The ophthalmic morbidity of hemangiomas is largely related to their space-occupying effects. The most devastating ophthalmic complication of hemangiomas relates to their ability to cause deprivation amblyopia in the affected eye if the lesion is large enough to directly occlude the visual axis. If the lesion is large enough to cause corneal distortion and astigmatism, anisometropic amblyopia will result.
Female patients outnumber male patients with hemangiomas by a ratio of 3:1.
Capillary hemangiomas are present in approximately 1-2% of neonates. All patients who eventually develop hemangiomas have them by age 6 months.
The prognosis for cosmetic and visual recovery is excellent if treatment is instituted at an appropriate time and careful attention is paid to the visual development. Most lesions involute by age 5 years.
The history can be quite variable in this group of patients. Typically, parents may notice a red spot growing in size and thickness in the periorbital area.
The parents may be acutely aware of a gradual inability of the child to open an affected eye due to progressive involvement of the eyelid.
Patients usually present with a unilateral, superonasal eyelid or brow lesion. It typically blanches with pressure, unlike the lesions seen with port-wine stains. The mass lesion may be sufficient to cause a ptosis of the involved eyelid.[4] Alternatively, if the lesion extends posteriorly in the orbit, proptosis and visual loss may be present.
Examination of the visual system may reveal decreased visual acuity on the ipsilateral side.
Unfortunately, amblyopia is seen in 43-60% of patients with eyelid hemangiomas.
Anisometropia also can be found on examination as a result of the mass effect on the cornea. The axis of plus cylinder is usually toward the hemangioma.
Capillary hemangiomas are believed to be hamartomatous proliferations of vascular endothelial cells.
Neuroimaging studies can be of great assistance in establishing the diagnosis.
Ultrasonography shows a lesion with irregular contour and low-to-medium internal reflectivity.
CT scan reveals a poorly circumscribed mass with no bony erosion. The lesion usually enhances with intravenous contrast.
Magnetic resonance imaging (MRI) reveals a lesion that is hypointense to fat on T1-weighted scans and hyperintense to fat on T2-weighted scans.
A well-circumscribed lobular pattern with prolonged parenchymal staining is seen with angiography. Involuting lesions tend to have less tissue staining.
Cardiac echocardiography and imaging of the great vessels are useful in the diagnosis of PHACES syndrome.
Pathological findings include proliferation of a single layer of endothelial cells and pericytes. Endothelial cells of the basement membrane characteristically have large amounts of endoplasmic reticulum. The small vascular spaces lead to the formation of a high-flow lesion.
The indications for treatment can be divided into systemic, ophthalmic, and dermatologic reasons. Systemic reasons for intervention include congestive heart failure, thrombocytopenia, hemolytic anemia, and nasopharyngeal obstruction.[5] Ophthalmic indications for intervention include occlusion of the visual axis, optic nerve compression, severe proptosis, and anisometropia.[6, 7] Dermatologic indications for intervention include maceration and erosion of the epidermis, infection, and cosmetic disfigurement.
The first-line treatment of capillary hemangiomas is simple observation. Since most of these lesions regress on their own, there is no need to intervene unless one of the above criteria is met.[8]
Corticosteroids, in various formulations, also have been used in the treatment of capillary hemangiomas.[9, 10, 11, 12, 13, 14, 15, 16, 17]
Topical steroid therapy
Topical steroid formulations, such as clobetasol propionate cream, can be applied topically to the lesion. The response to these treatments, even with the strongest corticosteroid formulations, is slower than other methods because several weeks are required to obtain a response.
Complications include dermal atrophy, pigmentary changes in the skin, and dermatitis, as well as less common ophthalmic complications, such as elevated intraocular pressure and cataract formation. Systemic absorption also can occur.
Overall, this modality is not appropriate for vision-threatening lesions.
Injectable steroid therapy
Injectable steroid formulations also are used in the treatment of these lesions.
Endothelial cell sensitization to catecholamines is the mechanism by which intralesional corticosteroids exert their effects. Although there may be a period of temporary enlargement, blanching usually is noted within 2-3 days and involution is seen by 2-4 weeks. Their effectiveness is most pronounced 2 weeks after injection but can be seen up to 2 months later. The overall success rate for this intervention is 75%.
Risks of injection include lid necrosis, depigmentation, and fat necrosis. The most disconcerting adverse effect concerns reports of central retinal artery occlusion following the intralesional injection of corticosteroids. Although the precise pathogenesis is uncertain, some suggest it may be related to anomalous vessels. A technically slower injection of corticosteroid or a smaller volume of solution may lessen the risk.[18, 19, 20]
Steroid injections can be repeated, but, ideally, they should be separated in time by 2-3 months to allow for maximum benefit to be seen. Adrenal suppression after cutaneous steroid injections has been reported.
Systemic corticosteroid therapy
Systemic corticosteroids are used for amblyogenic life-threatening lesions.
An excellent response rate can be expected in 30% of patients, a questionable response in 40%, and no response in 30% when systemic corticosteroids are used under close observation. The response may be quite dramatic within the first 2 weeks, and the effect may last from 1-4 months. Doses of 2-3 mg/kg may be necessary for up to several months.
Complications of systemic therapy with corticosteroids include Cushingoid changes, personality changes, gastrointestinal irritation, oral candidiasis, delayed growth, diabetes, hypertension, and rebound growth of hemangiomas on cessation.
Interferon alfa-2a has emerged as a new modality to combat the life-threatening and vision-threatening hemangiomas of infancy that are resistant to steroid treatment.[21] While it has potent effects on these lesions, it is commonly associated with adverse effects of varying severity.
Interferon alfa-2a exerts its effect by preventing endothelial cell migration in capillary hemangiomas. Authors have shown significant tumor regression after treatment with interferon.
Unfortunately, adverse effects from treatment may have somewhat dampened the initial excitement with this treatment. Adverse effects include fever, chills, arthralgias, and retinal vasculopathy. Of more significance, the incidence of spastic diplegia has been as high as 20% in some reports, leading some to reevaluate the benefits of its use. The long-term effects of interferon on the developing brain are unknown.
Systemic propranolol has been added to the scope of treatment modalities available to patients with hemangiomas.
The literature surrounding this management option largely consists of anecdotal case reports, but an article by Al Dhaybi et al describes great success with oral propranolol, discontinued in only 1 of 18 patients due to side effects.[22] A reduction occurred in both radiographic volume and amblyogenic astigmatism.
A study by Missoi et al showed a 33% reduction in astigmatism and a 39% reduction in surface area in 17 children who were treated over a median duration of 6.8 months, suggesting that early intervention with propranolol is also effective for the treatment and prevention of visual acuity loss associated with periocular infantile hemangiomas.[23]
Propranolol has been suggested to be effective in reducing the size of juvenile hemangiomas, and, for patients who meet criteria for treatment of these lesions, it is worth consideration. The treatment does have potential complications, particularly cardiac, and patients need to be monitored closely.[24] It is highly recommended that the medication is administered and monitored for dose titration and systemic side effects by a pediatrician or pediatric cardiologist.
Combined oral and topical beta-blocker therapy (oral propranolol plus topical timolol maleate) has been reported as successful in the treatment of superficial periocular infantile hemangioma in the early proliferative stage.[25]
Topical timolol has been shown to be effective for localized and superficial hemangiomas.[26, 27, 28] Timolol may also be effective for larger, deeper lesions.[29]
Laser surgery has been attempted to ameliorate capillary hemangiomas but is still controversial. The hemostatic effects of the carbon dioxide laser have been used with success to surgically remove these lesions. Other lasers used include the argon laser and the Nd:YAG laser. The pulsed dye laser is only effective for very superficial lesions; its mechanism of action is too slow for sight-threatening hemangiomas. Overall, variable results have been seen with various laser modalities, and the risks of scarring and ulceration often deter its use.
Incisional surgical techniques also have had variable success. Surgical ligation of the hemangiomas produces equivocal results. Vascular embolization of the lesions should be used for large extraorbital hemangiomas only. Primary excision also has been advocated for infantile hemangiomas. Early surgical intervention can be considered as a primary treatment option in selected, isolated capillary hemangiomas without a significant cutaneous component. Surgery can provide definitive early treatment and prevent astigmatism and occlusion-related amblyopia.[30, 31]
Consultations with a pediatrician may be necessary to monitor for the systemic adverse effects if prednisone is used or if there is suspicion of systemic involvement.
Pediatric dermatologists may have particular expertise in the various treatment options available.
Concerns must be reiterated about ensuring that children with potentially amblyogenic capillary hemangiomas obtain frequent assessments of their visual acuity and refraction. Treatment would be indicated if astigmatism is greater than 1.5-2 diopters or if there is occlusion of the visual axis.
Young patients may require inpatient admission and monitoring if high doses of systemic steroids are administered.
Patients started on systemic steroids may need to be monitored continually on an outpatient basis until either an adequate response is seen or complications preclude its continuation.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Clinical Context: Decreases inflammation by stabilizing lysosomal membranes, inhibiting PMN and mast cell degranulation, and decreasing capillary vasoconstriction.
Clinical Context: Decreases inflammation by stabilizing lysosomal membranes, inhibiting PMN and mast cell degranulation. Class I superpotent topical steroid; suppresses mitosis and increases synthesis of proteins that decrease inflammation and cause vasoconstriction.
Clinical Context: Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Clinical Context: Treats inflammatory dermatosis that is responsive to steroids. Decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.
Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Clinical Context: Nonselective beta-adrenergic blocker. Its mechanism of action in shrinking hemangiomas remains unknown. Beta-2 adrenergic receptors are present on endothelial cells of hemangiomas.
The adrenergic system is the major regulator of cardiac and vascular function.