Infantile Hemangioma

Back

Practice Essentials

Infantile hemangiomas are benign vascular neoplasms that have a characteristic clinical course marked by early proliferation and followed by spontaneous involution. Hemangiomas are the most common tumors of infancy and usually are medically insignificant.

Essential update: FDA approves propranolol formulation for treatment of infantile hemangioma

The FDA has approved an oral pediatric formulation of propranolol hydrochloride (Hemangeol) for the treatment of proliferating infantile hemangioma requiring systemic therapy. Approval was based on a randomized, placebo-controlled study in infants aged 5 weeks to 5 months. Treatment with 3 mg/kg/day of propranolol resulted in a 60.4% success rate in complete or nearly complete resolution of the target hemangioma, as compared with a 3.6% success rate with placebo (P < .0001). Re-treatment after discontinuation of treatment was necessary in 11.4% of patients.[1]

Signs and symptoms

Infantile hemangiomas may be cutaneous or extracutaneous. Frequency of cutaneous hemangiomas at particular sites is as follows:

Sites of extracutaneous hemangiomas include the following:

Cutaneous hemangiomas progress sequentially through the following stages:

Features are as follows:

Infantile hemangiomas characteristically exhibit early rapid growth followed by slow involution, as follows[2, 3, 4, 5] Rapid growth during the neonatal period (birth to 4 wk)

See Clinical Presentation for more detail.

Diagnosis

Skin biopsy can be performed if the diagnosis is in question after a thorough history and physical examination. Infantile hemangiomas uniformly stain positively for glucose transporter 1 (GLUT-1) during both the proliferation and the involution phases.

The following laboratory studies have been investigated as possible markers of hemangioma proliferation and differentiation[6, 7] :

Magnetic resonance imaging (MRI) has the following uses:

Features of ultrasonography:

See Workup for more detail.

Management

The vast majority of infantile hemangiomas do not require any medical or surgical intervention.[9] Treatment options for clinically significant hemangiomas include the following:

Features of laser surgery:

Features of surgical excision:

Features of pharmacologic treatment:

See Treatment and Medication for more details.

Image library


View Image

This proliferating superficial infantile hemangioma on the trunk required no therapy.

Background

Infantile hemangiomas are benign vascular neoplasms that have a characteristic clinical course marked by early proliferation and followed by spontaneous involution. During the proliferative phase in the neonatal period or early infancy, a rapidly dividing endothelial cell proliferation is responsible for the enlargement of infantile hemangiomas. Finally, an involutional phase occurs, whereby most infantile hemangiomas are clinically resolved by age 9 years.

Hemangiomas are the most common tumors of infancy, and most infantile hemangiomas are medically insignificant. Occasionally infantile hemangiomas may impinge on vital structures, ulcerate, bleed, cause high-output cardiac failure or significant structural abnormalities or disfigurement. Rarely, a cutaneous infantile hemangioma may be associated with one or more underlying congenital anomalies.

Pathophysiology

Infantile hemangiomas are composed of proliferating, plump endothelial cells. Early in proliferation, the cells are in disarray, but, with time, they form vascular spaces and channels replete with blood cells (see image below).


View Image

Histopathology of a proliferating infantile hemangioma with plump endothelial cells in the dermis.

These benign-appearing endothelial cells produce limited basement membrane structures. Hemangiomas assume a lobular architecture as proliferation slows and ends. Mast cells appear to affect this process and are implicated in the promotion of feeding arterioles and veins that supply each lobule. They also have been found in high concentrations during involution.

Takahashi hypothesized that during the third trimester of fetal development, immature endothelial cells coexist with immature pericytes, which maintain their proliferative capacity for a limited period during postnatal life.[13] Angiogenic peptides, such as beta-fibroblast growth factor, vascular endothelial growth factor (VEGF), and proliferating cell nuclear antigen, induce proliferation of these immature cells, resulting in the development of the hemangioma. As the endothelial cells differentiate, an influx of mast cells, various myeloid cells, and tissue inhibitors of metalloproteinases (TIMPs) occurs.[16] TIMPs, along with interferon and transforming growth factor produced by the mast cells, terminate the endothelial cell proliferation and passively induce involution by senescence of endothelial cells.

United States

Infantile hemangiomas occur in approximately 1-2% and 10% of white infants at birth and at age 1 year, respectively.[4, 5] African American and Japanese infants have a similar incidence of 1-2% at birth; however, there are no studies regarding the incidence at age 1 year (the actual incidence since the majority are not present at birth) in other nonwhite populations.[5, 17] The incidence of infantile hemangiomas is approximately 22-30% of preterm infants with birthweight less than 1 kg; for preterm infants with birthweight greater than 1.5 kg,[18] the incidence is the same as for term infants. An increased incidence is recognized in infants from multiple gestations.

The incidence is increased with older maternal age, maternal placenta previa, and preeclampsia.[19] Some, but not all, surveys have demonstrated increased incidence in infants born to mothers who have undergone prenatal chorionic villus sampling.

Mortality/Morbidity

Most infantile hemangiomas are benign and do not cause any morbidity or mortality. Occasionally, they may impinge on vital structures and interfere with breathing, vision, eating, or hearing. Ulceration of certain areas (eg, diaper area, neck, mucosal surfaces) is not uncommon. Excessive bleeding is infrequent and rarely, if ever, life threatening. In the past, infantile hemangiomas were confused with other vascular neoplasms, particularly kaposiform hemangioendothelioma and tufted angiomas, which can incite a consumptive coagulopathy that may be life threatening. This is referred to as Kasabach-Merritt phenomenon (KMP). It is now generally accepted that infantile hemangiomas are rarely, if ever, responsible for KMP.[20, 21]

Large cutaneous or visceral hemangiomas (particularly liver) can result in high-output cardiac failure resulting from increased vascular flow. Permanent significant structural abnormalities may result, particularly when facial structures are involved. The highest risk appears to be with involvement of the nasal tip, lips, and ears.[22] Segmental hemangiomas, which cover a particular section or area of skin, may be markers for underlying malformations or developmental anomalies of the heart, blood vessels, or nervous system (PHACE and PELVIS syndromes [see below] and lumbosacral hemangiomas) and, depending on the severity of the associated anomaly, can result in increased morbidity or mortality.[23, 24]

PHACE syndrome (see image below) is posterior fossa structural brain abnormalities (Dandy-Walker malformation and various forms of hypoplasia); hemangiomas of the face, head, and neck (segmental, >5 cm in diameter); arterial lesions (especially carotid, cerebral, and vertebral); cardiac anomalies (coarctation of the aorta in addition to many other structural anomalies); eye abnormalities; and, rarely, associated midline ventral defects such as sternal cleft or supraumbilical raphe). A consensus statement with detailed diagnostic criteria for both PHACE and possible PHACE syndromes was published in 2009.[25]


View Image

Segmental infantile hemangioma in a female infant with PHACE syndrome involving the posterior neck and right forehead associated with an absent right ....

PELVIS syndrome (see image below) is perineal hemangioma with any of the following: external genital malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and/or skin tags.


View Image

Segmental infantile hemangioma with minimal or arrested growth of the bilateral buttocks and posterior thigh in this male infant with PELVIS syndrome ....

Race

Hemangiomas occur most commonly in white infants, with an incidence rate 10-12 times that of black and Asian infants.

Sex

Females are affected more often than males by a ratio of 3:1. This disparity is higher (9:1) in those infants with large cervicofacial segmental hemangiomas associated with PHACE syndrome.

Age

Thirty percent of infantile hemangiomas are present at birth, and 70% of them initially appear in the first several weeks of life.

History

Infantile hemangiomas exhibit a characteristic evolution, with early rapid growth (proliferation) followed by slow involution.[2] The earliest sign of an infantile hemangioma is blanching of the involved skin. This may be followed by fine telangiectasias and then a red or crimson macule. Rarely, a shallow ulceration may be the first sign of an incipient infantile hemangioma.

Rapid growth during the neonatal period (birth to 4 wk) is the historical hallmark of infantile hemangiomas. This rate is characteristically beyond the growth rate of the infant, thereby differentiating this neoplasm from vascular malformations that grow commensurate with the infant. As proliferation ensues, the infantile hemangioma becomes elevated and may be dome shaped, lobulated, plaquelike, tumoral, or any combination of these morphologies.[4, 5] The proliferation phase occurs during the first year, with the most growth occurring during the first 4-6 months of life. Proliferation slows considerably between the middle and end of the first year of life; however, most hemangiomas have completed this phase by age 4 months. During this time, the hemangioma may remain quiescent or may begin to involute.[26]

The involutional phase of an infantile hemangioma may be rapid or prolonged. No specific characteristics appear to influence the rate or completeness of involution of infantile hemangiomas. The exception is a separate type of hemangioma referred to as a rapidly involuting congenital hemangioma (RICH), which proliferates in utero and is fully developed at birth.[27] RICHs tend to completely involute during the second year of life. Congenital hemangiomas are not considered to be a variant of the infantile hemangioma.

Fifty percent of infantile hemangiomas complete involution by age 5 years and 70% by age 7 years; the remainder may take an additional 3-5 years to complete the process.[3] Of lesions that have involuted by age 6 years, 38% have residual evidence with scar formation, telangiectasia, or redundant or anetodermic skin. Infantile hemangiomas that take longer to involute have a higher incidence of permanent cutaneous residua. Eighty percent of infantile hemangiomas that complete involution after age 6 years may exhibit cutaneous residua.[28]

Physical

Eighty percent of infantile hemangiomas are focal and solitary. Sixty percent of cutaneous hemangiomas occur on the head and neck, 25% on the trunk, and 15% on the extremities (see image below). Hemangiomas also can occur in extracutaneous sites, including the liver, gastrointestinal tract, larynx, CNS, pancreas, gall bladder, thymus, spleen, lymph nodes, lung, urinary bladder, and adrenal glands.


View Image

This proliferating superficial infantile hemangioma on the trunk required no therapy.

Features of early proliferating infantile hemangiomas (birth to age 6 wk) include blanching of the involved skin, followed by fine telangiectasias, and then a red or crimson macule or papule that often is surrounded by a faint halo of vascular blanching. Occasionally, an infantile hemangioma is heralded by a shallow ulceration, especially lip and buttock lesions (see image below).[17]


View Image

Exquisitely painful ulcerated mixed hemangioma (superficial and deep) of the left deltoid in a 6-month-old female infant. This lesion was treated succ....

As infantile hemangiomas proliferate (birth to age 12 mo), depending on their size and depth, their morphology and texture may be dome shaped, bosselated, plaquelike, tumoral, or any combination of these morphologies.

If the infantile hemangioma is located in the subcutaneous tissue, the overlying skin may be completely normal. Color varies with the depth from the surface and can be bright red or crimson (superficial dermis), purple, blue, or flesh colored with predominant involvement of the deeper tissues. Telangiectases and large superficial veins radiating from the infantile hemangioma often are associated. The consistency is firm, rubbery, and tense and expands with increased intravascular pressure (eg, with crying when on the head and neck). Tenderness to palpation is a variable generally uncommon feature of infantile hemangiomas.

Most infantile hemangiomas reach a maximum size of 0.5-5 cm, but they can range from the size of a pinhead to greater than 20 cm in diameter. Most infantile hemangiomas remain well circumscribed and focal. A minority may be segmental in nature, covering a larger portion of the cutaneous surface. This variant has more superficial than deep involvement, as is seen with extensive facial lesions (see image below).


View Image

This superficial and deep infantile hemangioma resulted in astigmatism of the left eye, requiring spectacles to correct the refractive error and to pr....

Another variant is the infantile hemangioma with minimal or arrested growth (IH-MAG). These have been previously referred to as abortive, reticular, or telangiectatic infantile hemangiomas. By definition these IHs have a proliferative component equaling less than 25% of their total surface area. They are mostly flat and may simply present with an erythematous blush of the affected skin.

As its prior name suggests, an abortive or reticular infantile hemangioma often has telangiectasia coursing through it. This variant may be confused with a capillary malformation; however, the growth characteristics and presence of visible telangiectases assist in differentiation. This variant has been seen in association with underlying vascular and other extracutaneous congenital anomalies (PHACE and PELVIS syndromes and with underlying vascular anomalies on an extremity) as well as demonstrating a predilection for the lower body, in contradistinction to classic IHs.[29, 30]

During involution, which may begin as early as a few months from birth or as late as 2-3 years, the infantile hemangioma shrinks centrifugally from the center of the lesion. This is less notable with deeper lesions. The superficial lesions become less red, taking on a duskier maroon-to-purple color, and finally regaining normal flesh tones (often referred to as "graying"). With involution, the infantile hemangiomas become softer and more compressible with decreased tenderness, and they exhibit less expansion during increased intravascular pressure (eg, crying).

During the late involution phase (quiescent residual lesions), the skin may return to normal with no evidence of a previous pathologic process. Approximately 50-60% of all hemangiomas resolve incompletely, leaving permanent changes in the skin. These changes include telangiectases, superficial dilated veins, stippled scarring, anetoderma or epidermal atrophy (particularly with superficial lesions), hypopigmentation, and/or redundant skin with fibrofatty residua (especially with subcutaneous lesions).[28]

Causes

Neither the cause nor the cell of origin of infantile hemangiomas has been definitively elucidated. Theories abound and several lines of evidence support several divergent theories of the cell of origin, including placental tissue, endothelial progenitor cells (EPCs), and mesenchymal stem cells.[31]

A distinct group of tissue-specific markers, including Lewis Y, merosin, and FcγRII, but most notably glucose transporter 1 (GLUT-1), are uniquely coexpressed by hemangiomas and placental microvessels, suggesting a unique relationship between hemangiomas and placental microvessels. Two theories postulated to explain this observation include (1) colonization of receptive mesenchyme by potentially abnormal angioblasts switched toward a placental endothelial phenotype and (2) embolic placental endothelial cells that have reached fetal tissues from chorionic villi through right-to-left shunts.

The placenta and hemangioma share a similar life cycle of robust vascular growth. The placenta produces very high levels of the proangiogenic cytokine, vascular endothelial growth factor (VEGF). As a protective mechanism against uncontrolled angiogenesis in the fetus and mother, a soluble form of the VEGF receptor, sFlt-1, found in both amniotic fluid and maternal serum, is also produced by the placenta. sFlt-1 binds circulating VEGF, preventing excessive angiogenesis in nonplacental tissues. Postpartum, the connection to the placenta and sFlt-1 is removed, abrogating this negative feedback and allowing proliferation of cells, such as those in hemangiomas, responsive to VEGF.[32, 33]

Hemangiomas fail to stain for numerous trophoblastic markers, somewhat discounting the placental embolism theory.[34] Some reports suggest that infants born to mothers who have undergone chorionic villus sampling may be at an increased risk of developing hemangiomas, but this has not been uniformly observed.[35] See Pathophysiology.

An in utero local tissue environment of either hypoxia or acidity appears to influence the subsequent vasculature. Both of these microenvironmental conditions are potent inducers of angiogenesis, leading to increased production of hypoxia-inducible factor (HIF), which, in turn, causes VEGF gene transcription in association with cytokine-stromal cell-derived factor 1 (SDF-1). This appears to stimulate endothelial progenitor cells to proliferate and differentiate into endothelial cells.[36]

Several VEGF receptors (VEGFRs) may play a role in the development of hemangiomas. VEGFR1 on endothelial cells acts as a decoy receptor such that the binding of VEGF to this receptor does not effect a change in the endothelial cell. However, the binding of VEGF to VEGFR2 elicits robust endothelial cell proliferation and migration. Hemangioma endothelial cells exhibit low levels of VEGFR1, with marked constitutive activation of VEGFR2. Gene transcription for VEGFR1 in hemangioma cells is dependent on nuclear factor of activated T cells (NFAT). This, in turn, is dependent on a pathway involving beta1 integrin, VEGFR2, and integrinlike receptor tumor endothelial marker-8 (TEM8).

Missense mutations in genes encoding for VEGFR2 and TEM8 have been identified in a subset of infantile hemangiomas. These mutations are likely responsible for the constitutive activation of VEGFR2 and resultant hemangioma endothelial cell proliferation. Soluble VEGFR1 or anti-VEGF antibodies normalize the constitutive VEGFR2 signaling. Consequently, these or other similar molecules may be exploited in future hemangioma therapy.[37]

It is believed that infantile hemangiomas may be derived from endothelial progenitor cells (EPCs). EPCs are bone marrow-derived CD133 (or AC133) – positive, CD34-positive, and KDR (VEGFR-2)-positive pluripotent cells that demonstrate the ability to develop into Glut-1–positive endothelial cells.[38] A hemangioma model using these cells exhibits growth characteristics typical of an infantile hemangioma, with both proliferating and involuting phases and the development of fibrofatty residua during involution. The endothelial cells in an infantile hemangioma are thought to be primitive endothelial clonal cells that exhibit abnormal behavior.[39]

Two possibly interrelated theories exist regarding the pathogenesis of hemangiomas with regard to the EPCs, intrinsic and extrinsic. The intrinsic theory proposes that EPCs are monoclonal and behave differently from normal endothelial progenitor cells. The extrinsic theory postulates that the EPCs are polyclonal and behave normally and proliferate in response to the surrounding tissue angiogenic and angiostatic factors.[40]

Mesenchymal stem cells may also play a role in the formation of infantile hemangiomas. These cells have been identified in hemangioma tissue.[41] Mesenchymal stem cells retain the capacity to differentiate into numerous mesodermal cells, including adipocytes, suggesting that these cells may be the source of the resultant adipose tissue found in involuted hemangiomas.

Evidence to support a hereditary/genetic component in the development of most infantile hemangiomas is minimal; most appear to be sporadic. However, at least one report described a kindred in which infantile hemangiomas may be the result of an autosomal dominant trait.[42] These infantile hemangiomas were seen in association with an increased incidence of vascular malformations (mostly capillary malformations) in various members of the same family.

Laboratory Studies

No laboratory studies have been universally accepted for the diagnosis and treatment of infantile hemangiomas; however, reports in the literature have investigated the use of serum vascular endothelial growth factor (VEGF) as well as urinary beta-fibroblast growth factor, VEGF, and matrix metalloproteinases (MMPs) as markers of hemangioma proliferation and differentiation.[6, 7]

Use of glucose transporter 1 (GLUT-1) stain is helpful for evaluating tissue removed during biopsy or excision.[43] Both proliferating and involuting infantile hemangiomas uniformly stain positively for GLUT-1, while other cutaneous vascular neoplasms, malformations, and normal cutaneous vasculature do not, making this stain very sensitive and specific for histologic confirmation of infantile hemangiomas. In addition, red blood cell membranes stain positively for GLUT-1, creating an effective internal control.

Imaging Studies

MRI with and without intravenous gadolinium is the imaging modality of choice to delineate the location and extent of both cutaneous and extracutaneous hemangiomas. MRI also helps in differentiating other high-flow vascular lesions (eg, arteriovenous malformations vs proliferating hemangiomas). Involuting hemangiomas have features that resemble low-flow lesions (eg, venous malformations).

Ultrasonography is useful in differentiating hemangiomas from other deep dermal or subcutaneous structures, such as cysts or lymph nodes. Ultrasonography is generally limited by its inability to fully evaluate the magnitude and extent of the hemangioma. Dubois et al found that an evaluation exhibiting high vessel density (>5 vessels/cm2) and high peak arterial Doppler shift (exceeding 2 kHz) was both sensitive and specific for infantile hemangiomas compared with other soft tissue masses.[8]

Plain radiography is fairly limited but may be useful for evaluating hemangiomas that impinge on the airway.

Procedures

If the diagnosis is in question after a thorough history and physical examination, a skin biopsy can be helpful in distinguishing unusual or atypical hemangiomas from other vascular lesions. Specimens may be evaluated by routine histological examination and special stains as outlined in Histologic Findings.

Histologic Findings

Routine histopathology varies according to the stage of the hemangioma. In early proliferation, hemangiomas are characterized by nonencapsulated masses and dense cords of mitotically active, plump endothelial cells in close association with pericytes. Few, small caliber lumina are present. Special stains reveal well-developed basement membranes around primitive vessels. Mast cells are present in varying numbers in all stages. As the hemangioma proliferates, the vascular lumina enlarge. An increase of apoptotic endothelial cells and a decrease in plump, mitotically active endothelial cells herald the involution phase.

As involution progresses, the endothelial cells continue to mature and assume a flatter appearance. The vascular lumina continue to enlarge until few, mature ectatic vessels remain.[44] The proliferating endothelial cell mass may be replaced with fibrofatty tissue. Varying degrees of epidermal atrophy, scar tissue, and loss of elastic tissue can be seen in late involuting lesions.[45]

Specimens may be evaluated for tissue-specific immunohistochemical markers such as GLUT-1, merosin, Fc-gamma-RII, and Lewis Y antigens. These markers may aid in differentiating infantile hemangiomas (positive staining for all) from other vascular neoplasms or malformations, such as the congenital hemangiomas (eg, rapidly involuting congenital hemangioma, noninvoluting congenital hemangioma), kaposiform hemangioendothelioma, tufted angioma, or pyogenic granuloma, none of which stains positively for these antigens. These markers are coexpressed by infantile hemangiomas, erythrocyte cell membranes, and placental microvessels.[43]

Medical Care

The vast majority of infantile hemangiomas do not require any medical or surgical intervention.[9] Medical care of clinically significant hemangiomas has been limited to a few medications, including glucocorticosteroids (topical, intralesional, and oral), interferon alfa, and, rarely, vincristine and topical imiquimod.[46] Beta-blockers, most specifically propranolol,[47] have serendipitously been shown to induce involution of infantile hemangiomas.[48, 49, 50, 51]

An expert panel has developed provisional recommendations for the use of propranolol, including in patients with PHACE syndrome (posterior fossa abnormalities, hemangioma, arterial lesions, cardiac abnormalities/aortic coarctation, and eye abnormalities).[14, 15] PHACE syndrome is associated with a higher risk of neurologic and cognitive impairment.

The provisional recommendations cover the following[14, 15] :

The individual therapies are discussed in detail under Medication. Also see Further Reading for a partial listing of clinical trials that are currently recruiting.

Surgical Care

Laser surgery

Laser surgery is beneficial in treating both proliferating and residual vessels from hemangiomas. The flashlamp-pumped pulsed-dye laser has become the most widely used laser for selective ablation of vascular tissue in childhood.

Pulsed-dye laser surgery is effective for treating ulcerated hemangiomas and thin superficial hemangiomas, especially those on areas likely to result in significant functional or psychological impact (eg, fingers, eyes, lips, nasal tip, ears, face).[10, 11] Many ulcerated hemangiomas respond with decreased pain (sometimes as early as a few days after the initial treatment), rapid reepithelialization, and hastened involution.

Treatments generally are performed every 2-4 weeks until complete healing results. Occasionally, particularly with deep or combined superficial and deep lesions, ulceration may worsen with pulsed-dye laser treatment.[52]

The risk of scarring or residual skin changes associated with pulsed-dye laser surgery of hemangiomas may be greater than without early laser treatment or with the treatment of capillary malformations (port wine stains), but the benefits of early involution should be weighed against the risks of a passive approach or alternative therapies.[53, 54]

Other lasers that appear to be efficacious in treating hemangiomas include the pulsed Nd:YAG, frequency-doubled Nd:YAG, and KTP lasers. Carbon dioxide lasers are occasionally used for airway hemangiomas.[55] Each of these lasers has specific benefits and limitations regarding depth of penetration, absorption of skin chromophores, and caliber of the vessel treated. Complications also vary depending on the laser, settings, and site treated.[56]

The use of nonablative fractional photothermolysis (nFP) for the treatment of the anetodermic fibrofatty residua in involuted infantile hemangiomas may be an alternative to surgical excision.[57]

See Laser Treatment of Acquired and Congenital Vascular Lesions for a detailed discussion.

Surgical excision

Surgical excision of involuted hemangiomas is not uncommon because of the cutaneous defects resulting from them.[12] Atrophic and hypertrophic scars, as well as anetodermic and tumoral fibrofatty skin, may result in significant cosmetic or functional impairment. The benefits of excision during late involution include a reduced risk of hemorrhage and a potentially smaller lesion because of the natural course. In addition, because involuted hemangiomas are composed primarily of fibrofatty tissue, complete removal of all tissue is unnecessary, while removing too much tissue could detract from proper contours.

Surgical excision of proliferating hemangiomas is potentially hazardous because of the risk of hemorrhage and damage to vital structures associated with them (ie, head, neck); therefore, only specially trained surgeons should perform this procedure. Certain benefits to early excision include saving a life or preserving vision and decreasing the negative psychosocial effects associated with a cosmetically disfiguring lesion during early childhood. Other benefits of early excision include the use of naturally expanded skin to aid in primary closure and the ability to use a relatively avascular tissue plane surrounding actively growing hemangiomas. New advancements in surgical instruments that cauterize while cutting lessen the risk of hemorrhage.

Consultations

An ophthalmologist or a pediatric ophthalmologist should evaluate children with periorbital hemangiomas, particularly with involvement of the upper eyelid. Refraction with retinoscopy is performed to evaluate for visual disturbances, particularly astigmatism, and to prevent visual deprivation amblyopia. Also see Capillary Hemangioma in the Medscape Reference Ophthalmology section.

Infants with rapidly growing hemangiomas that are impinging on vital structures of the head and neck, particularly the airway or auditory canals, should be referred to an otolaryngologist or a pediatric otolaryngologist for evaluation and treatment. Infants with large V3 dermatomal hemangiomas (beard area hemangiomas) have a higher incidence of upper airway hemangiomas, and early consultation for mild signs or symptoms (noisy breathing or stridor) may prevent possible future complications.

Consultation with a plastic surgeon is indicated for symptomatic involuting or proliferating lesions that are unresponsive to medical therapy and for which surgical excision is being contemplated.

The presence of an infantile hemangioma over the midline lumbar back may be a cutaneous sign of an underlying occult spinal dysraphism, such as a tethered cord. MRI or ultrasonography if the infant is younger than 5 months is indicated for midline hemangiomas, especially if any other signs of spinal dysraphism (eg, deviated gluteal cleft, atypical sacral dimple, tuft of hair, tail) are present. MRI is the more sensitive study, even in infancy, and should be considered when clinical suspicion is high. Consultation with a pediatric neurosurgeon should be sought for any questionable or worrisome lesions.

Medication Summary

The goals of pharmacotherapy for infantile hemangiomas are to reduce morbidity and mortality and to prevent complications. Note that only propranolol oral solution (Hemangeol) is approved for treatment of infantile hemangiomas by the FDA, and all other therapies should be considered off-label usage.

Prednisolone (Prelone Syrup, Pediapred Oral Solution, Delta-Cortef, OraPred)

Clinical Context:  Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.

Class Summary

Oral and intralesional corticosteroids are effective at slowing the growth and decreasing the size of proliferating infantile hemangiomas. The mechanism of action has not been elucidated completely; however, corticosteroids have been shown to inhibit VEGF-A expression and subsequent proliferation in hemangioma stem cells in a murine hemangioma model.[58] Evidence indicates that corticosteroids block estradiol receptors in hemangiomas in vitro. Response vary widely, from less than 40% to greater than 90%, depending on dose, duration of treatment, and age at which corticosteroid therapy is initiated.[59] Corticosteroid therapy should be administered during the proliferative phase because it has a negligible effect on involuting and otherwise stable infantile hemangiomas. The oral route generally is preferred over intralesional therapy; however, the location, size, patient age, and physician experience factor into the decision-making process.

Propranolol (Hemangeol)

Clinical Context:  The mechanism of propranolol's effects on infantile hemangiomas is not well understood. Propranolol is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It is indicated for treatment of proliferating hemangioma requiring systemic therapy. Available as an oral solution (4.28 mg/mL).

Class Summary

Propranolol oral solution (Hemangeol) was approved by the FDA in March 2014. Approval was based on the results from a dose-ranging study of 460 infants aged 35 days to 5 months with proliferating hemangiomas (excluding life-threatening, ulcerated, or function-threatening IH). Overall, 2 of 55 patients (4%) in the placebo arm and 61 of 101 patients (60%) taking propranolol 3.4 mg/kg/day for 6 months had complete or nearly complete resolution of their hemangioma at week 24 (p < 0.0001).[60] Beta-blockers, most specifically propranolol and more recently topical timolol, have been in use since mid 2008 for infants with severe or disfiguring hemangiomas.[61, 62] Several reports in the literature describe efficacy for life- and sight-threatening airway and retro-orbital hemangiomas, respectively.[48, 63, 64] Some have been treated with the beta-1 selective blocker, acebutolol. However, most infants reported have been treated with the nonselective blocker, propranolol, at a dose of 2-3 mg/kg/d in 2-3 divided doses. Duration of therapy varies from 2-10 months. As early as 24 hours after the initiation of therapy, many infantile hemangiomas have begun to change from intense red to purple, with evidence of softening. Most continue to improve until nearly flat and with significantly diminished color.

A retrospective study of 39 children in France with infantile hemangiomas of the head and neck concluded that propranolol treatment effectively lightened and reduced hemangiomas, especially as first-line treatment started during proliferative growth (mean age, 4.1 m; mean duration, 8.5 m).[65] Of 37 hemangiomas successfully treated with propranolol, 26 were in locations (parotid area, lips, or nose) where the authors would not have initiated corticosteroid therapy.

Treatment of nasal infantile hemangioma with propranolol reduced the need for invasive treatment in a retrospective cohort study of 58 children (mean age, 5 months). The researchers divided the study participants into a pre-propranolol group, a propranolol group, and a non-propranolol group. Infants treated with propranolol for a mean of 7.6 months at a total dosage of 2 mg/kg/day were 56% less likely than infants in the pre-propranolol group to undergo any invasive treatment, 61% less likely to undergo surgical treatment, and 25% less likely to receive laser treatment.[66, 67]

The mechanism of action of propranolol in these patients is unknown; however, some hypothesize that local vasoconstriction may be a factor, which is based on the early color change and softening of the lesion. One study has demonstrated that nonspecific and beta2-selective blockers (eg, propranolol) triggered apoptosis of capillary endothelial cells in adult rat lung tissue, suggesting a similar mechanism may be plausible for hemangioma endothelial cells.[68]

No protocol for initiating propranolol therapy in infants with hemangiomas is universally accepted.[69] Therapy should be approached with extreme caution in neonates and infants who generally do not have preexisting venous hypertension or any other hemodynamic disorder. Of particular note, infants with hemangiomas associated with PHACE syndrome with cerebrovascular anomalies are at higher risk for cerebral vascular accidents and therefore should not receive beta-blockers.

Provisional guidelines for initiation

Pretreatment

Exclude infants with evidence of the following:

Baseline laboratory tests and evaluation include the following:

Dosing - See below

Monitoring

Initially in the hospital (whether in or out of intensive care unit, cardiac care unit, or monitored bed), monitor for 24-72 hours; practices vary considerably.

Monitoring 1 hour after administration (dosing) includes the following:

At home, parents should observe for signs of lethargy, poor feeding, and/or bronchospasm.

Blood pressure and heart rate should be evaluated intermittently at the pediatrician's office.

Discontinuation

Consider gradual taper over 2 weeks, rather than abrupt discontinuation. Cardiac hypersensitivity may occur 24-48 hours after propranolol is discontinued (peaks at 4-8 d).

Interferon alfa 2a (Roferon-A)

Clinical Context:  Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. May be given topically, systemically, and intralesionally.

Interferon alfa-2b (Intron A)

Clinical Context:  Protein product manufactured by recombinant DNA technology. Indications to treat adult hairy cell leukemia, malignant melanoma, condyloma acuminata, AIDS-related Kaposi sarcoma, and certain forms of chronic viral hepatitis. Has also used to treat children with these conditions and, most recently, infants with life-threatening hemangiomas.

Class Summary

Initially used as an antiviral agent in HIV-infected patients, interferon alfa-2a was found to induce regression of Kaposi sarcoma. This led to its use in treating other vascular lesions (eg, hemangiomas). Interferon alfa inhibits endothelial cell migration and proliferation and specific growth factors (eg, endothelial growth factor, fibroblast growth factor). Numerous studies have demonstrated the efficacy of interferon alfa-2a and interferon alfa-2b in treating infantile hemangiomas.[70, 71]

Because interferon alfa-2a works by a different mechanism, it can be used in lesions that are unresponsive to steroids.[72] In fact, unlike steroids, it does not require that administration occur during the proliferation phase to be effective. The onset of action is slower than that of corticosteroids, usually requiring several weeks; this makes it less attractive for use in acute life- or sight-threatening situations. Interferon alfa-2a should be used only if steroid, beta-blocker, and other potentially toxic therapies fail.

The most significant adverse event limiting its use in hemangiomas is potentially irreversible spastic diplegia; while most infants have displayed significant recovery of spasticity of lower extremities, it appeared permanent in other infants.[73, 74] A meta-analysis of interferon use in children revealed all cases of neurological dysfunction occurred when interferon was used prior to the patient’s first birthday.[75]

Imiquimod (Aldara cream)

Clinical Context:  Immune response modifier indicated for treatment of condyloma acuminata, actinic keratoses, and superficial basal cell carcinoma in adults. Not approved by FDA for use in children.

Becaplermin 0.01% gel (Regranex Gel)

Clinical Context:  A few reports in the literature (Metz, 2004) suggest this is helpful for ulcerated infantile hemangiomas, especially those in the diaper area. Data limited and no placebo-controlled trial published to date. Seven infants with refractory ulcerated infantile hemangiomas experienced healing 3-21 d after initiating therapy.

Class Summary

Only a few case reports and two small open-label uncontrolled trials suggest some minimal efficacy for the treatment of infantile hemangiomas.[76, 77, 78] This treatment should be considered experimental until placebo-controlled trials are performed and therapy is determined safe for infants. Imiquimod cream is the only medication in this new class. It purportedly works by stimulation of toll-like receptor 7 (TLR-7) and increases local interferon alpha and gamma, through which it may exert antiangiogenic effects. In a mouse model, imiquimod-treated vascular tumors showed decreased tumor cell proliferation, increased tumor apoptosis, and increased expression of tissue inhibitor of matrix metalloproteinase-1, with decreased activity of matrix metalloproteinase-9, both of which are observed in the natural involution of infantile hemangiomas.

Complications

No demographic, prenatal, and perinatal factors have been shown to be associated with higher rates of complications.[19]

Ulceration

Ulceration occurs in 10-15% of infantile hemangiomas, especially combined superficial and deep lesions. The cause of ulceration is not clear but may be a result of outstripped blood supply to the overlying skin or secondary to the action of certain cytokines.

Ulceration usually occurs in tense, rapidly proliferating hemangiomas and occurs more commonly in the anogenital region, lip, and chest, although any site may develop an ulcer. The ulcerations are extremely painful and result in scar formation upon healing, which may take months. A white discoloration seen early in the course (usually within the first 3 months of life), mimicking that seen in early involution, may herald an impending ulceration, particularly in segmental infantile hemangiomas.[79]

Secondary infection can occur, but cellulitis, abscess, and bacteremia are rare.

While intermittent bleeding is common, serious hemorrhage appears to be rare. Life-threatening arterial hemorrhage has been reported in at least 7 infants, mostly complicating segmental hemangiomas of the head and neck. Closer observation and imaging studies to assess underlying vasculature may be helpful in very high-risk cases.[80]

Treatment for ulcerated hemangiomas includes topical or oral antibiotics, bio-occlusive dressings (especially hydrocolloid dressings), pulsed-dye laser surgery, becaplermin gel (human recombinant platelet-derived growth factor),[81] and external compression therapy (especially helpful for limb lesions).[82] Pulsed-dye laser surgery has been reported to be effective for ulcerated superficial hemangiomas and often decreases pain, even before the ulcer has reepithelialized.[53] Medical therapy to hasten hemangioma involution with glucocorticosteroids or beta-blockers can also be helpful for recalcitrant ulcers.

Airway obstruction

Airway obstruction is a rare complication of hemangiomas; upper lip lesions very seldom obstruct both nasal passages. This can be a problem for young infants who are obligate nose breathers. Cervical parapharyngeal or palatal hemangiomas can cause acute or subacute obstruction.

Insidious signs and symptoms, such as sleep apnea, cor pulmonale, or even failure to thrive, can be associated with hemangiomas in the upper aerodigestive tract. Laryngeal (often referred to as subglottic) hemangiomas present early (6-8 wk) with symptoms of inspiratory or biphasic stridor, especially with feeding or crying. Cough, cyanosis, or hoarseness may be associated findings. The diagnosis is confirmed by direct laryngoscopy, MRI, soft tissue anteroposterior neck radiographs, or esophagography.

Prompt consultation with a pediatric otolaryngologist should be sought for all suspected cases. Treatment includes systemic corticosteroids or interferon alfa, as well as excisional or laser surgery. Tracheostomy is sometimes necessary until the hemangioma involutes.

Upper airway hemangiomas appear to be associated more commonly with superficial cutaneous hemangiomas involving the mandibular branch of the trigeminal nerve (beard area hemangiomas).[83] They can occur without cutaneous involvement.

Visual obstruction

Visual obstruction should be considered whenever a hemangioma involves the eyelids or periorbital tissues.

Hemangiomas can lead to visual deprivation amblyopia by 3 separate mechanisms: physical obstruction of the visual axis, astigmatism from direct pressure on the anterior segment from eyelid involvement (upper eyelid is more common than lower eyelid), and unilateral myopia. Strabismus can result either secondary to amblyopia or from paralysis of the extraocular muscles infiltrated by an orbital hemangioma.

A pediatric ophthalmologist should evaluate all children with periorbital hemangiomas using refraction with retinoscopy, with upper eyelid lesions requiring the most frequent observation. A thorough discussion of periocular hemangiomas is beyond the scope of this chapter; however, a review by Ceisler and colleagues describes the appropriate evaluation and potential treatments.[84]

Also see Capillary Hemangioma in the Medscape Reference Ophthalmology section.

Other complications

Diffuse neonatal hemangiomatosis is a potentially life-threatening condition characterized by numerous cutaneous hemangiomas accompanied by visceral hemangiomas. When more than 10 cutaneous hemangiomas are present, the risk of visceral lesions rises. The liver and gastrointestinal tract are affected most often, although any organ can be involved. Congestive heart failure is a cause of early mortality because of increased vascular volume. Evaluation should include an imaging study of the liver (eg, liver scanning, MRI, ultrasonography) and stool guaiac tests to rule out intestinal bleeding from gut hemangiomas. Systemic corticosteroids and/or interferon alfa and conventional surgery are possible treatments.

Kasabach-Merritt phenomenon (KMP) is marked by platelet sequestration and severe thrombocytopenia associated with a rapidly proliferating vascular neoplasm. This often is accompanied by a potentially fatal, generalized bleeding disorder. KMP is heralded by rapid enlargement, edema of the surrounding tissues, and accompanying purpura.[85] Evidence suggests that most cases of KMP are associated with kaposiform hemangioendothelioma or tufted angioma and not infantile hemangiomas, as previously believed.[20] The early reports of KMP were described in lesions in which a clinical, not histological, diagnosis was made. Systemic corticosteroids are not usually effective, but vincristine has been effective in several cases of KMP caused by kaposiform hemangioendotheliomas and tufted angiomas.

Patients with PHACE syndrome present with hemangiomas and one or more extracutaneous congenital anomalies. Reports have also described intracranial invasion of associated infantile hemangiomas.[86] PHACE syndrome is an acronym denoting posterior fossa abnormalities (most characteristically Dandy-Walker malformation and other forms of brain hypoplasia), hemangiomas (cervicofacial, segmental/> 5 cm in diameter), arterial anomalies (especially carotid, cerebral, and vertebral), cardiac anomalies (especially coarctation of the aorta), eye abnormalities, and, rarely, midline ventral abnormalities (sternal clefting or supraumbilical raphe). See Mortality/Morbidity.

Segmental infantile hemangiomas involving the perineal area may be associated with other underlying congenital anomalies as delineated in the PELVIS or SACRAL syndromes.[24] The acronymic PELVIS syndrome describes the association of a perineal hemangioma with any of the following: external genital malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, or skin tag. SACRAL syndrome is spinal dysraphism with anogenital, cutaneous, renal, and urologic anomalies, associated with an angioma of lumbosacral localization.

An isolated midline lumbosacral hemangioma may be a cutaneous marker for underlying occult spinal dysraphism, the most common being an intraspinal lipoma with resultant tethered cord. Spinal imaging should be performed in these cases. Symptoms may not occur for several years and which infants require corrective surgery has been debated, because as many as 10% of the population have asymptomatic tethering of the spinal cord. The decision should be left to a neurosurgeon with experience with this condition.

Rarely, infantile hemangiomas have been implicated in cases of consumptive hypothyroidism.[87] This was initially reported with hepatic hemangiomas; however, this has also been reported with bulky cutaneous infantile hemangiomas.[88] This phenomenon appears be secondary to high activity of the type 3 iodothyronine deiodinase enzyme in hemangioma tissue, which is responsible for degradation of T4 to reverse T3 (rT3). One case reported also demonstrated increased production of a thyrotropinlike hormone from a hepatic hemangioma.[89] Thyroid function tests should be ordered in the appropriate clinical setting.

Psychosocial problems associated with disfiguring facial hemangiomas can be significant.[90] During infancy and early childhood, parents often have reactions of loss and grief. Parental feelings of disbelief, panic, or fear often are associated with the rapid growth of these lesions. The variability in the natural course, in regard to timing and completeness of resolution, adds to parental anxiety. Parental stress is heightened by strangers who stare, startle, or raise questions about causality, such as trauma (especially implied or suspected child abuse), infection, or cancer. Psychosocial stigmatization can be problematic for both parents and patients with disfiguring facial hemangiomas. Lesions that result in significant facial or obvious disfigurement should be addressed before the child starts school.

Prognosis

The prognosis for most uncomplicated infantile hemangiomas is very good, with complete involution of 50% by age 5 years, 70% by age 7 years, and 90% by age 9 years. Despite resolution of the vascular component, residual skin changes are observed in roughly 50% of cases. Of hemangiomas that have involuted by age 6 years, 38% still have residual evidence with scar formation, telangiectasia, or redundant or anetodermic skin. Hemangiomas that take longer to involute have a higher incidence of permanent cutaneous residua. Eighty percent of lesions that complete involution after age 6 years may exhibit significant cosmetic deformities. An increased incidence of permanent residua exists when the lip, nasal tip, eyelid, and ear are involved.

Author

Richard J Antaya, MD, Director of Pediatric Dermatology, Professor, Departments of Dermatology and Pediatrics, Yale University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Jean Paul Ortonne, MD, Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France

Disclosure: Nothing to disclose.

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Disclosure: Nothing to disclose.

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Disclosure: Nothing to disclose.

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

References

  1. Brooks M. FDA OKs Propranolol Hydrochloride for Infantile Hemangioma. Medscape Medical News. Available at http://www.medscape.com/viewarticle/822115. Accessed March 24, 2014.
  2. Lister WA. The natural history of strawberry naevi. Lancet. 1938;1:1429.
  3. Bowers RE, Graham EA, Tomlinson KM. The natural history of the strawberry nevus. Arch Dermatol. 1960;82:667.
  4. Jacobs AH. Strawberry hemangiomas; the natural history of the untreated lesion. Calif Med. Jan 1957;86(1):8-10. [View Abstract]
  5. Pratt AG. Birthmarks in infants. AMA Arch Derm Syphilol. Mar 1953;67(3):302-5. [View Abstract]
  6. Zhang L, Lin X, Wang W, et al. Circulating level of vascular endothelial growth factor in differentiating hemangioma from vascular malformation patients. Plast Reconstr Surg. Jul 2005;116(1):200-4. [View Abstract]
  7. Zhang L, Lin XX, Qi ZL, et al. [Role of urinary basic fibroblast growth factor in differentiating hemangiomas from vascular malformation]. Zhonghua Wai Ke Za Zhi. Feb 1 2006;44(3):186-8. [View Abstract]
  8. Dubois J, Patriquin HB, Garel L, et al. Soft-tissue hemangiomas in infants and children: diagnosis using Doppler sonography. AJR Am J Roentgenol. Jul 1998;171(1):247-52. [View Abstract]
  9. Margileth AM, Museles M. Cutaneous hemangiomas in children. Diagnosis and conservative management. JAMA. Nov 1 1965;194(5):523-6. [View Abstract]
  10. Kim HJ, Colombo M, Frieden IJ. Ulcerated hemangiomas: clinical characteristics and response to therapy. J Am Acad Dermatol. Jun 2001;44(6):962-72. [View Abstract]
  11. Garden JM, Bakus AD, Paller AS. Treatment of cutaneous hemangiomas by the flashlamp-pumped pulsed dye laser: prospective analysis. J Pediatr. Apr 1992;120(4 Pt 1):555-60. [View Abstract]
  12. Achauer BM, Chang CJ, Vander Kam VM. Management of hemangioma of infancy: review of 245 patients. Plast Reconstr Surg. Apr 1997;99(5):1301-8. [View Abstract]
  13. Takahashi K, Mulliken JB, Kozakewich HP, Rogers RA, Folkman J, Ezekowitz RA. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest. Jun 1994;93(6):2357-64. [View Abstract]
  14. Brooks M. For Propranolol in Infantile Hemangioma, Only 'Provisional' Guidelines Available. Medscape Medical News. Dec 24, 2012. Available at http://www.medscape.com/viewarticle/776692. Accessed January 8, 2013.
  15. Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. Jan 2013;131(1):128-40. [View Abstract]
  16. Ritter MR, Reinisch J, Friedlander SF, Friedlander M. Myeloid cells in infantile hemangioma. Am J Pathol. Feb 2006;168(2):621-8. [View Abstract]
  17. Hidano A, Nakajima S. Earliest features of the strawberry mark in the newborn. Br J Dermatol. Aug 1972;87(2):138-44. [View Abstract]
  18. Amir J, Metzker A, Krikler R, Reisner SH. Strawberry hemangioma in preterm infants. Pediatr Dermatol. Sep 1986;3(4):331-2. [View Abstract]
  19. Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. J Pediatr. Mar 2007;150(3):291-4. [View Abstract]
  20. Enjolras O, Wassef M, Mazoyer E, et al. Infants with Kasabach-Merritt syndrome do not have "true" hemangiomas. J Pediatr. Apr 1997;130(4):631-40. [View Abstract]
  21. Sarkar M, Mulliken JB, Kozakewich HP, Robertson RL, Burrows PE. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg. Nov 1997;100(6):1377-86. [View Abstract]
  22. Thomson HG, Lanigan M. The Cyrano nose: a clinical review of hemangiomas of the nasal tip. Plast Reconstr Surg. Feb 1979;63(2):155-60. [View Abstract]
  23. Frieden IJ, Reese V, Cohen D. PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol. Mar 1996;132(3):307-11. [View Abstract]
  24. Girard C, Bigorre M, Guillot B, Bessis D. PELVIS Syndrome. Arch Dermatol. Jul 2006;142(7):884-8. [View Abstract]
  25. [Best Evidence] [Guideline] Metry D, Heyer G, Hess C, Garzon M, Haggstrom A, Frommelt P, et al. Consensus Statement on Diagnostic Criteria for PHACE Syndrome. Pediatrics. Nov 2009;124(5):1447-56. [View Abstract]
  26. Waner M, Suen JY. The natural history of hemangiomas. In: Hemangiomas and Vascular Malformations of the Head and Neck. 1999:13-45.
  27. Boon LM, Enjolras O, Mulliken JB. Congenital hemangioma: evidence of accelerated involution. J Pediatr. Mar 1996;128(3):329-35. [View Abstract]
  28. Finn MC, Glowacki J, Mulliken JB. Congenital vascular lesions: clinical application of a new classification. J Pediatr Surg. Dec 1983;18(6):894-900. [View Abstract]
  29. Mulliken JB, Marler JJ, Burrows PE, Kozakewich HP. Reticular infantile hemangioma of the limb can be associated with ventral-caudal anomalies, refractory ulceration, and cardiac overload. Pediatr Dermatol. Jul-Aug 2007;24(4):356-62. [View Abstract]
  30. Suh KY, Frieden IJ. Infantile hemangiomas with minimal or arrested growth: a retrospective case series. Arch Dermatol. Sep 2010;146(9):971-6. [View Abstract]
  31. Bischoff J. Progenitor cells in infantile hemangioma. J Craniofac Surg. Mar 2009;20 Suppl 1:695-7. [View Abstract]
  32. Banks RE, Forbes MA, Searles J, et al. Evidence for the existence of a novel pregnancy-associated soluble variant of the vascular endothelial growth factor receptor, Flt-1. Mol Hum Reprod. Apr 1998;4(4):377-86. [View Abstract]
  33. Hornig C, Barleon B, Ahmad S, Vuorela P, Ahmed A, Weich HA. Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids. Lab Invest. Apr 2000;80(4):443-54. [View Abstract]
  34. Bree AF, Siegfried E, Sotelo-Avila C, Nahass G. Infantile hemangiomas: speculation on placental trophoblastic origin. Arch Dermatol. May 2001;137(5):573-7. [View Abstract]
  35. Burton BK, Schulz CJ, Angle B, Burd LI. An increased incidence of haemangiomas in infants born following chorionic villus sampling (CVS). Prenat Diagn. Mar 1995;15(3):209-14. [View Abstract]
  36. Kleinman ME, Greives MR, Churgin SS, et al. Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma. Arterioscler Thromb Vasc Biol. Dec 2007;27(12):2664-70. [View Abstract]
  37. Jinnin M, Medici D, Park L, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. Nov 2008;14(11):1236-46. [View Abstract]
  38. Khan ZA, Boscolo E, Picard A, et al. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest. Jul 2008;118(7):2592-9. [View Abstract]
  39. Yu Y, Flint AF, Mulliken JB, Wu JK, Bischoff J. Endothelial progenitor cells in infantile hemangioma. Blood. Feb 15 2004;103(4):1373-5. [View Abstract]
  40. Mulliken JB. Update on vascular anomalies. In: Proceedings of the international workshop on vascular anomalies. Boston, Mass: June 21-24, 2008.
  41. Yu Y, Fuhr J, Boye E, et al. Mesenchymal stem cells and adipogenesis in hemangioma involution. Stem Cells. Jun 2006;24(6):1605-12. [View Abstract]
  42. Blei F, Walter J, Orlow SJ, Marchuk DA. Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. Arch Dermatol. Jun 1998;134(6):718-22. [View Abstract]
  43. North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. May 2001;137(5):559-70. [View Abstract]
  44. Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. Mar 1982;69(3):412-22. [View Abstract]
  45. Nakayama H. Clinical and histological studies of the classification and the natural course of the strawberry mark. J Dermatol. Aug 1981;8(4):277-91. [View Abstract]
  46. Frieden IJ, Eichenfield LF, Esterly NB, Geronemus R, Mallory SB. Guidelines of care for hemangiomas of infancy. American Academy of Dermatology Guidelines/Outcomes Committee. J Am Acad Dermatol. Oct 1997;37(4):631-7. [View Abstract]
  47. Price CJ, Lattouf C, Baum B, McLeod M, Schachner LA, Duarte AM, et al. Propranolol vs Corticosteroids for Infantile Hemangiomas: A Multicenter Retrospective Analysis. Arch Dermatol. Dec 2011;147(12):1371-6. [View Abstract]
  48. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. Jun 12 2008;358(24):2649-51. [View Abstract]
  49. Siegfried EC, Keenan WJ, Al-Jureidini S. More on propranolol for hemangiomas of infancy. N Engl J Med. Dec 25 2008;359(26):2846; author reply 2846-7. [View Abstract]
  50. Saint-Jean M, Léauté-Labrèze C, Mazereeuw-Hautier J, et al. Propranolol for treatment of ulcerated infantile hemangiomas. J Am Acad Dermatol. May 2011;64(5):827-32. [View Abstract]
  51. Hermans DJ, van Beynum IM, Schultze Kool LJ, van de Kerkhof PC, Wijnen MH, van der Vleuten CJ. Propranolol, a very promising treatment for ulceration in infantile hemangiomas: A study of 20 cases with matched historical controls. J Am Acad Dermatol. May 2011;64(5):833-8. [View Abstract]
  52. Poetke M, Philipp C, Berlien HP. Flashlamp-pumped pulsed dye laser for hemangiomas in infancy: treatment of superficial vs mixed hemangiomas. Arch Dermatol. May 2000;136(5):628-32. [View Abstract]
  53. Morelli JG, Tan OT, Yohn JJ, Weston WL. Treatment of ulcerated hemangiomas infancy. Arch Pediatr Adolesc Med. Oct 1994;148(10):1104-5. [View Abstract]
  54. David LR, Malek MM, Argenta LC. Efficacy of pulse dye laser therapy for the treatment of ulcerated haemangiomas: a review of 78 patients. Br J Plast Surg. Jun 2003;56(4):317-27. [View Abstract]
  55. Sie KC, McGill T, Healy GB. Subglottic hemangioma: ten years' experience with the carbon dioxide laser. Ann Otol Rhinol Laryngol. Mar 1994;103(3):167-72. [View Abstract]
  56. Burstein FD, Simms C, Cohen SR, Williams JK, Paschal M. Intralesional laser therapy of extensive hemangiomas in 100 consecutive pediatric patients. Ann Plast Surg. Feb 2000;44(2):188-94. [View Abstract]
  57. Laubach HJ, Anderson RR, Luger T, Manstein D. Fractional photothermolysis for involuted infantile hemangioma. Arch Dermatol. Jul 2009;145(7):748-50. [View Abstract]
  58. Greenberger S, Boscolo E, Adini I, Mulliken JB, Bischoff J. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med. Mar 18 2010;362(11):1005-13. [View Abstract]
  59. Sadan N, Wolach B. Treatment of hemangiomas of infants with high doses of prednisone. J Pediatr. Jan 1996;128(1):141-6. [View Abstract]
  60. Hemangeol [package insert]. Parsippany, NJ.: Pierre Fabre Pharmaceuticals, Inc.; 2014.
  61. Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol. May 2010;146(5):564-5. [View Abstract]
  62. Khunger N, Pahwa M. Dramatic response to topical timolol lotion of a large hemifacial infantile haemangioma associated with PHACE syndrome. Br J Dermatol. Apr 2011;164(4):886-8. [View Abstract]
  63. Bigorre M, Van Kien AK, Valette H. Beta-blocking agent for treatment of infantile hemangioma. Plast Reconstr Surg. Jun 2009;123(6):195e-6e. [View Abstract]
  64. Truong MT, Chang KW, Berk DR, Heerema-McKenney A, Bruckner AL. Propranolol for the treatment of a life-threatening subglottic and mediastinal infantile hemangioma. J Pediatr. Feb 2010;156(2):335-8. [View Abstract]
  65. Fuchsmann C, Quintal MC, Giguere C, et al. Propranolol as first-line treatment of head and neck hemangiomas. Arch Otolaryngol Head Neck Surg. May 2011;137(5):471-8. [View Abstract]
  66. Perkins JA, Chen BS, Saltzman B, Manning SC, Parikh SR. Propranolol Therapy for Reducing the Number of Nasal Infantile Hemangioma Invasive Procedures. JAMA Otolaryngol Head Neck Surg. Feb 20 2014;[View Abstract]
  67. Harding A. Propranolol Associated With Reduced Need for Invasive Hemangioma Treatment. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/821133. Accessed March 3, 2014.
  68. Sommers Smith SK, Smith DM. Beta blockade induces apoptosis in cultured capillary endothelial cells. In Vitro Cell Dev Biol Anim. May 2002;38(5):298-304. [View Abstract]
  69. [Guideline] Lawley LP, Siegfried E, Todd JL. Propranolol treatment for hemangioma of infancy: risks and recommendations. Pediatr Dermatol. Sep-Oct 2009;26(5):610-4. [View Abstract]
  70. Tamayo L, Ortiz DM, Orozco-Covarrubias L, et al. Therapeutic efficacy of interferon alfa-2b in infants with life-threatening giant hemangiomas. Arch Dermatol. Dec 1997;133(12):1567-71. [View Abstract]
  71. Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med. May 28 1992;326(22):1456-63. [View Abstract]
  72. Ricketts RR, Hatley RM, Corden BJ, Sabio H, Howell CG. Interferon-alpha-2a for the treatment of complex hemangiomas of infancy and childhood. Ann Surg. Jun 1994;219(6):605-12; discussion 612-4. [View Abstract]
  73. Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy. J Pediatr. Mar 1998;132(3 Pt 1):527-30. [View Abstract]
  74. Dubois J, Hershon L, Carmant L, Belanger S, Leclerc JM, David M. Toxicity profile of interferon alfa-2b in children: A prospective evaluation. J Pediatr. Dec 1999;135(6):782-5. [View Abstract]
  75. Michaud AP, Bauman NM, Burke DK, Manaligod JM, Smith RJ. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope. Jul 2004;114(7):1231-6. [View Abstract]
  76. Welsh O, Olazaran Z, Gomez M, Salas J, Berman B. Treatment of infantile hemangiomas with short-term application of imiquimod 5% cream. J Am Acad Dermatol. Oct 2004;51(4):639-42. [View Abstract]
  77. Hazen PG, Carney JF, Engstrom CW, Turgeon KL, Reep MD, Tanphaichitr A. Proliferating hemangioma of infancy: successful treatment with topical 5% imiquimod cream. Pediatr Dermatol. May-Jun 2005;22(3):254-6. [View Abstract]
  78. [Best Evidence] McCuaig CC, Dubois J, Powell J, Belleville C, David M, Rousseau E. A phase II, open-label study of the efficacy and safety of imiquimod in the treatment of superficial and mixed infantile hemangioma. Pediatr Dermatol. Mar-Apr 2009;26(2):203-12. [View Abstract]
  79. Maguiness SM, Hoffman WY, McCalmont TH, Frieden IJ. Early white discoloration of infantile hemangioma: a sign of impending ulceration. Arch Dermatol. Nov 2010;146(11):1235-9. [View Abstract]
  80. Connelly EA, Viera M, Price C, Waner M. Segmental hemangioma of infancy complicated by life-threatening arterial bleed. Pediatr Dermatol. Jul-Aug 2009;26(4):469-72. [View Abstract]
  81. Metz BJ, Rubenstein MC, Levy ML, Metry DW. Response of ulcerated perineal hemangiomas of infancy to becaplermin gel, a recombinant human platelet-derived growth factor. Arch Dermatol. Jul 2004;140(7):867-70. [View Abstract]
  82. Kaplan M, Paller AS. Clinical pearl: use of self-adhesive, compressive wraps in the treatment of limb hemangiomas. J Am Acad Dermatol. Jan 1995;32(1):117-8. [View Abstract]
  83. Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a "beard" distribution. J Pediatr. Oct 1997;131(4):643-6. [View Abstract]
  84. Ceisler EJ, Santos L, Blei F. Periocular hemangiomas: what every physician should know. Pediatr Dermatol. Jan-Feb 2004;21(1):1-9. [View Abstract]
  85. Esterly NB. Kasabach-Merritt syndrome in infants. J Am Acad Dermatol. Apr 1983;8(4):504-13. [View Abstract]
  86. Ersoy S, Mancini AJ. Hemifacial infantile hemangioma with intracranial extension: a rare entity. Pediatr Dermatol. Jul-Aug 2005;22(4):309-13. [View Abstract]
  87. Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med. Jul 20 2000;343(3):185-9. [View Abstract]
  88. Konrad D, Ellis G, Perlman K. Spontaneous regression of severe acquired infantile hypothyroidism associated with multiple liver hemangiomas. Pediatrics. Dec 2003;112(6 Pt 1):1424-6. [View Abstract]
  89. Ho J, Kendrick V, Dewey D, Pacaud D. New insight into the pathophysiology of severe hypothyroidism in an infant with multiple hepatic hemangiomas. J Pediatr Endocrinol Metab. May 2005;18(5):511-4. [View Abstract]
  90. Tanner JL, Dechert MP, Frieden IJ. Growing up with a facial hemangioma: parent and child coping and adaptation. Pediatrics. Mar 1998;101(3 Pt 1):446-52. [View Abstract]
  91. Chan H, McKay C, Adams S, et al. RCT of timolol maleate gel for superficial infantile hemangiomas in 5- to 24-week-olds. Pediatrics. May 6 2013;[View Abstract]
  92. Henderson D. Infantile Hemangiomas: Daily Timolol Maleate Slows Growth. Medscape Medical News [serial online]. May 6 2013;Accessed May 15 2013. Available at http://www.medscape.com/viewarticle/803637

This proliferating superficial infantile hemangioma on the trunk required no therapy.

Histopathology of a proliferating infantile hemangioma with plump endothelial cells in the dermis.

Segmental infantile hemangioma in a female infant with PHACE syndrome involving the posterior neck and right forehead associated with an absent right vertebral artery and a laryngeal hemangioma.

Segmental infantile hemangioma with minimal or arrested growth of the bilateral buttocks and posterior thigh in this male infant with PELVIS syndrome (complicated by cutaneous ulceration, hypospadias, anal stenosis, intraspinal lipoma with tethered cord). The white material is a barrier diaper cream.

This proliferating superficial infantile hemangioma on the trunk required no therapy.

Exquisitely painful ulcerated mixed hemangioma (superficial and deep) of the left deltoid in a 6-month-old female infant. This lesion was treated successfully with pulsed dye laser.

This superficial and deep infantile hemangioma resulted in astigmatism of the left eye, requiring spectacles to correct the refractive error and to prevent amblyopia. Further growth of this hemangioma necessitated a course of oral prednisolone. The hemangioma shrunk rapidly, and the patient's astigmatism decreased such that the spectacles were unnecessary 1 month after beginning steroids.

Histopathology of a proliferating infantile hemangioma with plump endothelial cells in the dermis.

This proliferating superficial infantile hemangioma on the trunk required no therapy.

Exquisitely painful ulcerated mixed hemangioma (superficial and deep) of the left deltoid in a 6-month-old female infant. This lesion was treated successfully with pulsed dye laser.

This superficial and deep infantile hemangioma resulted in astigmatism of the left eye, requiring spectacles to correct the refractive error and to prevent amblyopia. Further growth of this hemangioma necessitated a course of oral prednisolone. The hemangioma shrunk rapidly, and the patient's astigmatism decreased such that the spectacles were unnecessary 1 month after beginning steroids.

Segmental infantile hemangioma in a female infant with PHACE syndrome involving the posterior neck and right forehead associated with an absent right vertebral artery and a laryngeal hemangioma.

Segmental infantile hemangioma with minimal or arrested growth of the bilateral buttocks and posterior thigh in this male infant with PELVIS syndrome (complicated by cutaneous ulceration, hypospadias, anal stenosis, intraspinal lipoma with tethered cord). The white material is a barrier diaper cream.