Infantile hemangiomas are the most common benign tumor of childhood. Lymphangiomas are benign hamartomatous vascular tumors. Both lesions can be problematic when located in the periocular region. Pediatricians must be familiar with the characteristics of each which would necessitate referral to an ophthalmologist or other subspecialist for evaluation, including obstruction of the visual axis which can lead to amblyopia of the affected eye. Additional potential complications include proptosis, ocular motility limitation, optic nerve injury, and poor eyelid closure with or without corneal surface disease. All children with periocular hemangiomas or lymphangiomas should be referred to an ophthalmologist for further evaluation.
Key points
- •
Hemangiomas are the most common benign tumor of childhood.
- •
Most hemangiomas do not require treatment, but periocular hemangiomas should be followed closely.
- •
Ocular sequelae of unchecked vascular malformation growth can include amblyopia, strabismus, proptosis, corneal exposure, or optic nerve injury/atrophy.
- •
Recent shifts in hemangioma treatment paradigm have occurred: from systemic and intralesional steroids to systemic propranolol and topical timolol.
- •
Amblyogenic vascular anomalies (those involving the eyelids, those affecting eyelid closure, or those with suspected proptosis) should prompt referral to ophthalmology.
Introduction
Pediatric vascular anomalies include a diverse spectrum of tumors and malformations that can be found anywhere on the body, but elicit a unique set of sequelae when found near the eye. The most common of these are capillary hemangiomas, followed closely in incidence by cavernous hemangiomas. Additional vascular anomalies that are less frequent, but no less clinically significant, include arteriovenous malformations, lymphangiomas, angiosarcomas, and hemangiopericytomas.
Each of the above listed lesions, when found near the eye, has the potential to affect ocular health and vision. Potential sequelae include amblyopia (deprivational or refractive), strabismus, ocular motility restriction, globe proptosis, corneal exposure, and optic nerve injury/atrophy. Consequently, it is crucial for pediatricians to be familiar with these lesions, their potential ocular sequelae, and clinical signs which should precipitate referral to an ophthalmologist.
Introduction
Pediatric vascular anomalies include a diverse spectrum of tumors and malformations that can be found anywhere on the body, but elicit a unique set of sequelae when found near the eye. The most common of these are capillary hemangiomas, followed closely in incidence by cavernous hemangiomas. Additional vascular anomalies that are less frequent, but no less clinically significant, include arteriovenous malformations, lymphangiomas, angiosarcomas, and hemangiopericytomas.
Each of the above listed lesions, when found near the eye, has the potential to affect ocular health and vision. Potential sequelae include amblyopia (deprivational or refractive), strabismus, ocular motility restriction, globe proptosis, corneal exposure, and optic nerve injury/atrophy. Consequently, it is crucial for pediatricians to be familiar with these lesions, their potential ocular sequelae, and clinical signs which should precipitate referral to an ophthalmologist.
Hemangioma
Extent of Problem
Infantile hemangiomas are the most common benign tumor of childhood, being found in anywhere from 2.6% to 10% of the pediatric population up to 1 year of age. They can be found on any part of the body, but 38% to 60% are found in the head and neck. Although one-third of these lesions are present at birth, most develop over the first year of life and progress through proliferative and involutional phases. Typically, hemangiomas reach 80% of their final size by the time a child is 5 months old.
Superficial lesions can present with a bright red, lobulated, placoid appearance (hence the term “strawberry nevus”), or deeper lesions can present as a more bluish-purple, subcutaneous mass. Hemangiomas involving the orbit may present with displacement of the globe, proptosis (axial displacement of the globe), or ocular motility limitations. Lesions can sometimes display both superficial and deep components ( Fig. 1 ). They are usually solitary, but up to 20% of affected infants have multiple lesions. Hemangiomas can also be found in either a localized or a segmental (territorial) distribution. They tend to grow more in depth than radially or territorially.
Hemangiomas generally proceed through 3 phases of growth. The initial proliferative phase is characterized by a period of rapid growth, usually in the first 3 to 6 months. This period of rapid growth is followed by a period of quiescence and then by involution. The involutional phase typically begins in the lesion’s center and progresses throughout the first decade of life, mostly occurring by age 5.
A small subset of hemangiomas presents at birth. These congenital hemangiomas often display marked growth during the proliferative phase and tend to involute much faster than those lesions that present in the weeks to months after birth.
It is worth noting that there is some question as to whether the quiescent period is truly a distinct phase. Recent advances in understanding of the molecular basis of hemangioma growth and involution suggest that the proliferative and involution phases are mediated, in effect, by a “balance of power” between growth factors and factors driving apoptosis. It would stand to reason, then, that an apparent quiescent phase could simply be the junction between proliferative and involutional phases, and not itself a distinct phase.
Mulliken and Glowacki classified common pediatric vascular lesions on the basis of endothelial cell characteristics. They found that during the proliferative phase, hemangiomas were found to have endothelial cell hyperplasia with and without lumina, as well as thickening of the underlying basement membrane. During the involution phase, fibrosis and fat deposition dominate the histologic appearance of hemangiomas. In contrast, those lesions characterized as vascular malformations demonstrate large vascular channels with a unilamellar basement membrane lined by flat endothelium, without proliferation of endothelial cells.
Cause, Contributory Factors, Risk Factors
Infantile hemangiomas are vascular tumors composed of clusters of endothelial cells with increased mitosis surrounding small vascular spaces. Angiogenesis-related cellular markers (type IV collagenase, basic fibroblastic growth factor, vascular endothelial growth factor, urokinase, and E-selectin) have been identified in proliferative phase hemangiomas. As they involute, there is a progressive decrease in the cellular component of endothelial and mast cells, and the lesion becomes mostly composed of fibrous and fatty tissue. Finally, the vascular components atrophy completely.
Patients with infantile hemangioma are more likely to be female gender(by a ratio of 2 or 3 to 1), fair-skinned, premature, or a product of multiple gestation. Advanced maternal age, placenta previa, and pre-eclampsia also seem to be influencing factors, but this may be confounded by the fact that these prenatal risk factors are simultaneous risk factors for premature birth. There is no known inheritance pattern, and siblings of children with infantile hemangiomas do not seem to have higher risk for developing the lesions than does the general population.
Mast cells appear to play a pathophysiologic role in the proliferative phase of infantile hemangiomas. Glowacki and Mulliken demonstrated that mast cells were present in proliferative phase hemangiomas in concentrations more than 5-fold greater than normal skin and 10-fold greater than in involuting hemangiomas. In vitro studies have also suggested that estrogen and hypoxia synergistically stimulate endothelial cell proliferation.
Sequelae of the problem
Although most infantile hemangiomas, once involuted, display little sign of their earlier presence, some can become problematic, primarily because of location. If located in the airway or the mouth, these lesions can interfere with breathing or feeding. Visceral hemangiomas can create life-threatening sequelae by virtue of the fact that lesions with a high flow pattern can precipitate high-output cardiac failure and anemia. When lesions are found in the periocular region, several complications can occur.
Amblyopia is a condition whereby the vision of the affected eye is reduced because of refractive error, strabismus, or occlusion. It is one of the most common sequelae of periocular hemangiomas, occurring in 43% to 60% of affected patients. Amblyopia can occur as a result of obstruction of the visual axis, which is especially common for hemangiomas involving the eyelids ( Fig. 2 ). In addition, the lesion can exert pressure on the eye itself, creating a change in refractive error and often inducing astigmatism. Astigmatism alone can cause amblyopia of the affected eye if severe enough.
Deeper hemangiomas involving the orbit can create proptosis. If severe, this can hamper eyelid closure and cause exposure keratopathy, a potentially vision-threatening deterioration of the cornea. In addition, if the optic nerve is stretched or compressed by the lesion, injury and subsequent optic atrophy with vision loss can occur. Ocular motility may be affected as well, which can lead to strabismus and possible strabismic amblyopia. Ulceration is the most common complication of infantile hemangiomas and can occur on periocular lesions as well as those located elsewhere.
Clinical Assessment
Most infantile hemangiomas can be diagnosed purely based on their characteristic appearance. Superficial hemangiomas appear as bright red, lobulated lesions, as their name “strawberry hemangioma” describes. Deeper hemangiomas present as bluish-purple-hued masses. Orbital hemangiomas may display few signs aside from proptosis of the globe, but their differential diagnosis includes other mass lesions, such as rhabdomyosarcoma, neuroblastoma, and lymphatic malformations. Thus, it is crucial to arrive at a correct diagnosis quickly.
In general, lesions at greater risk for complications include airway-threatening or sight-threatening lesions, lesions with a segmental distribution, larger lesion size, and facial location. Location of the lesion is a key factor in determining whether to refer a patient to an ophthalmologist or other subspecialist, and whether to obtain imaging tests. Lesions located on the eyelids or in the orbit, causing proptosis, can potentially threaten vision. These lesions should be monitored very closely by an ophthalmologist. Patients demonstrating more than 5 cutaneous hemangiomas anywhere on the body should be considered for imaging to evaluate for visceral hemangiomas. Any patient with proptosis of the eye should have imaging performed.
The optimal imaging study for hemangiomas is magnetic resonance imaging (MRI). The characteristic morphology and architecture are captured particularly well by high-resolution thin-section T2-weighted images with fat suppression, or T1-weighted images with gadolinium. The former modality highlights the internal lobular structure of the hemangioma. The latter modality displays hemangiomas at a signal intensity equal to or slightly higher than that of muscle, with signal voids within and around the periphery of the lesion. Gadolinium injection displays marked contrast enhancement. Rhabdomyosarcoma lesions, if highly vascularized, can mimic hemangioma characteristics on MRI.
Computed tomographic (CT) scanning demonstrates hemangiomas as lobulated enhancing masses with irregular margins, but does not demonstrate internal structure as well as does MRI. Ultrasonography is a cost-effective modality that does display characteristic variable internal reflectivity, and its highest value lies in monitoring lesions for changes over the course of time.
Kasabach-Merritt Syndrome
Initially described in 1940, Kasabach-Merritt syndrome is characterized by consumptive coagulopathy, with resulting thrombocytopenia, in the context of hemangiomata. Occasionally, the hemangiomas can be occult, but rapidly enlarging cutaneous hemangiomas can also be related to this syndrome. Patients demonstrate severe thrombocytopenia and usually have some degree of microangiopathic hemolysis. MRI findings in Kasabach-Merritt syndrome are similar to those of typical hemangiomas, but hemosiderin deposits can help identify sites of red cell destruction. Angiography can sometimes be useful for determining the extent of vasculature before embolization therapy. Management of this syndrome includes supportive treatment, surgical or compression therapy, vascular embolization, and in rare cases, radiotherapy, corticosteroids, interferon-α, and chemotherapy.
PHACE Syndrome
Large segmental facial or scalp hemangiomas should prompt consideration of other congenital anomalies, such as in the PHACE syndrome. This syndrome’s acronym name refers to posterior fossa abnormalities, hemangioma, arterial lesions, cardiac abnormalities (including aortic coarctation), and eye abnormalities. Major diagnostic criteria for this syndrome include anomalies of the major cerebral arteries, posterior fossa anomalies such as Dandy-Walker complex or cerebellar hypoplasia/dysplasia, aortic arch anomalies, sternal defects, and ocular abnormalities of the posterior segment. Minor criteria include persistent cerebral embryonic arteries (other than the trigeminal artery), extra-axial brain lesion with features consistent with hemangioma, ventricular septal defect, hypopituitarism or ectopic thyroid, and ocular abnormalities of the anterior segment. In patients with lesions that elicit suspicion for PHACE syndrome, brain imaging, echocardiogram, and formal ophthalmologic evaluation should be performed.
Management
There have been several major paradigm shifts in the management of hemangiomas. In the 1940s and 1950s, irradiation was a common intervention (although some decried such aggressive treatment in lesions that are typically self-limited). Radiotherapy can still be effective in select cases, although it should be reserved for those situations in which there are no viable alternatives.
In the 1960s, corticosteroid therapy was the mainstay of treatment of problematic hemangiomas. Multiple subsequent reports in the literature have indicated regression of hemangiomas in response to systemic administration of corticosteroids. The most commonly recommended oral corticosteroid is prednisone, dosed at either 1 to 2 mg/kg daily or 2 to 4 mg/kg every other day. Mechanisms by which corticosteroids induce hemangioma regression are not well understood. Systemic complications are a potential pitfall, and clinicians must be on the lookout for adrenal suppression, growth delay, gastrointestinal upset, hypertension, and increased susceptibility to infection.
Intralesional steroid injection has also been an option for hemangioma treatment. Local administration of corticosteroids further decreases the risks of systemic complications, although reports of central retinal artery occlusion (a condition that causes severe vision loss) can be found in the literature. In addition, localized atrophy (of fat and subcutaneous tissues), hypopigmentation, subcutaneous deposits of corticosteroid material, and local eyelid necrosis have all been reported. Nevertheless, the overall complication rate is considered to be low. Injections may need to be repeated more than once, typically at intervals as often as every 4 to 6 weeks. Vaccinations with live-attenuated virus should be avoided for 4 weeks before or after intralesional steroid injection.
Surgical excision remains an option for lesions unresponsive to medical management. However, the logistics of surgery can be problematic because of the unencapsulated nature of these lesions and the potential for uncontrolled bleeding. Although surgery is a less attractive option than medical management, it is certainly a viable one for refractory lesions.
Other less common treatment options have included cryotherapy, interferon-α, bleomycin, vincristine, embolization, and laser therapy. These treatments have generally been reserved for lesions refractory to more common treatments.
The currently preferred treatment modality was discovered serendipitously by Léauté-Labrèze and colleagues and reported in 2008. Two infants with hemangiomas developed cardiac issues and were subsequently placed on systemic propranolol. Their hemangiomas regressed within the first week of systemic β-blocker initiation. In light of this, 9 other infants with severe or disfiguring hemangiomas were also placed on systemic propranolol, achieving similar results. Initial changes in the lesions including softening and diminished intensity in color were seen within the first 24 hours of therapy. This discovery sparked the most recent paradigm shift in hemangioma management, culminating in a consensus statement on systemic propranolol for hemangiomas in 2013. Indeed, β-blockers now seem to have replaced corticosteroids as the first-line therapy for problematic infantile hemangiomas. Hypotension is the most commonly reported serious complication thus far. Other potentially serious complications include bradycardia, hypoglycemia or hypoglycemic seizure, hyperkalemia, and bronchial hyperreactivity. Less serious complications commonly reported include sleep disturbances, somnolence, gastrointestinal upset, and cold/mottled extremities.
Current recommendations for systemic propranolol were made in a consensus statement in 2013. Although the authors stress that evidence-based recommendations are not yet available, a comprehensive review of the literature to date was performed, and conservative recommendations based on that large body of work were made.
Pretreatment considerations
Contraindications to propranolol therapy include cardiogenic shock, sinus bradycardia, hypotension, greater than first-degree heart block, heart failure, bronchial asthma, and hypersensitivity to propranolol. Pretreatment assessment should include a careful history, evaluating for key elements of these conditions, and a careful examination including cardiac and pulmonary systems. Electrocardiogram screening is recommended for patients in whom the heart rate is less than normal for age, patients with a history of arrhythmia, and patients with a family history of congenital cardiac issues, arrhythmias, or connective tissue disorders. Infants with PHACE syndrome theoretically have an increased risk of stroke with propranolol therapy. However, these infants often are at high risk for medical morbidities and permanent facial scarring, and as such, can also be prime candidates for propranolol therapy. There are some cautiously positive reports of successful propranolol therapy in PHACE syndrome, but these patients should be evaluated carefully for induction, using head and neck MRI/magnetic resonance angiography as well as cardiac imaging with special attention to the aortic arch. Comanagement with neurology may be indicated if a patient with PHACE syndrome would be at higher risk of stroke while on systemic propranolol.
Induction of systemic propranolol
The consensus recommendation for target dose of propranolol is 1 to 3 mg/kg/d divided into 3 times daily dosing with a minimum of 6 hours between doses. The median dose reported in the literature is 2 mg/kg/d. The final dose should be titrated up from a low starting point, with special attention paid to dose response. Initiation in an inpatient setting is recommended for infants of a corrected gestational age of 8 weeks or less, as well as those with comorbidities such as those described above, regardless of age.
Monitoring
Baseline heart rate and blood pressure should be measured before initiation, and these measurements should be repeated at 1 and 2 hours after administration of the first dose (peak effect of propranolol being achieved 1–3 hours after administration). Dose response is most drastic after the first dose, so there is no further need to monitor vital signs after subsequent doses in patients more than 8 weeks of age with no comorbidities. A set of measurements should be repeated after the target dose is achieved. Holter monitoring is not thought to be routinely necessary at this time. Serum glucose measurements are not recommended as part of routine monitoring, but parents should be educated on regular feeding and avoidance of prolonged fasting. Propranolol should be discontinued during illness, especially if the child is not inclined to eat. Care should be taken in patients undergoing sedation for procedures or imaging studies as well.
Hypotension is the most commonly reported serious complication thus far. Other potentially serious complications include bradycardia, hypoglycemia or hypoglycemic seizure, hyperkalemia, and bronchial hyperreactivity. Less serious complications commonly reported included sleep disturbances, somnolence, gastrointestinal upset, and cold/mottled extremities.
In addition to systemic β-blocker therapy, topical timolol has also been found efficacious in the treatment of superficial hemangiomas ( Fig. 3 ). Typically, 0.5% timolol maleate drops, or 0.25% timolol maleate gel, is applied to lesions 2 to 3 times daily. This therapy was first described by Guo and Ni in 2010, and subsequent literature supports the finding that it is effective for more superficial lesions, even in cases of infants with PHACE syndrome. Further work is needed to provide stronger evidence-based support for this therapy, but it seems to have similarly promising prospects to those of systemic propranolol.
