HEMANGIOMAS

 

Epidemiology

 

Infantile hemangiomas (IH) are the most common benign tumors of childhood, occurring in up to 10 percent of children by 1 year of age. In contrast to other types of hemangiomas and vascular malformations, IH have a characteristic proliferative phase followed by a slower involution phase. They are more common in females (2-3:1 ratio) and in premature infants, especially those weighing less than 1500 grams. Other risk factors are Caucasian race and multiple gestation pregnancy.

Etiology and Pathogenesis

IH are primarily composed of endothelial cells but also contain fibroblasts, pericytes, interstitial cells, and mast cells. Although the precise pathophysiologic mechanisms of the growth and involution of endothelial cells remains unknown, several recent discoveries have advanced the understanding of IH. Glucose-transporter-1 (GLUT-1) has been identified as an immunohistochemical marker expressed in IH, regardless of stage, and in the microvasculature of the placenta. GLUT-1 is not expressed in other vascular tumors and malformations, thus making it a specific and useful marker for IH. IH and the placenta share other vascular antigens such as FcγRII, Lewis Y antigen, and Merosin; the two also have similar gene expression profiles based on DNA-based microarrays. Both “intrinsic” and “extrinsic” hypotheses exist to explain these findings: A somatic mutation may cause fetal vascular precursor cells (angioblasts) to improperly differentiate toward a placental microvascular phenotype or, alternatively, hemangiomas may originate from the placental vasculature. IH lack placental trophoblastic markers, suggesting that embolization of the placenta itself (as distinct from placental microvasculature) is not the source of IH.

Proliferating IH express CD31 and CD34, known markers for endothelial cells, in addition to CD133, expressed in primitive cell populations. This co-expression suggests that endothelial progenitor cells are involved in the pathogenesis of IH. However, IH also express myeloid markers CD14, CD15, CD32, and CD83 suggesting that these endothelial cells are distinct from those of normal vasculature. While most IH are negative for lymphatic markers such as Prox-1, podoplanin, and D2-40, some IH express the lymphatic marker LYVE-1. This immunophenotype is similar to the immature endothelial cells in the cardinal vein, which can differentiate into either lymphatic or blood vessels. Expression of CD31, CD34, CD133, and LYVE-1 is markedly reduced or absent in other vascular tumors and malformations and during the involuting phase of IH. The concept of hemangioma cells being immature and incompletely differentiated could help explain their rapid growth during the first few months of life, followed by their eventual self-destruction via apoptosis.

Clinical Findings

 HISTORY

 The clinical history is one of the most important keys to diagnosing an IH (Table 126-1).²¹ Absence at birth or presence as a premonitory mark, usually an area of pallor, telangiectasias, or duskiness is characteristic, whereas a fully formed soft-tissue mass at the time of birth is most likely not an IH, but another vascular anomaly or other disease process.

 INFANTILE HEMANGIOMAS AT

AGLANCE

• Infantile hemangiomas are the most common tumor of infancy.
• Hemangiomas in high-risk anatomic sites are likely to require further work-up and, often, intervention.
• Segmental hemangiomas have a greater risk for morbidity than localized hemangiomas.
• Kasabach-Merritt syndrome is not due to infantile hemangioma.

CUTANEOUS LESIONS

 Growth Characteristics.

 Though IH are not present at birth as fully formed tumors, they almost always

become apparent within the first month of life. The exception is deep hemangiomas, which are noted on average 1 month later than more superficial ones. The period of most rapid growth typically occurs within the first 5 months of life but can continue up to 1 year of age and in very large hemangiomas up to 18 months. This is followed by a slower involution phase which is more variable in length, lasting for months to years  Smaller hemangiomas typically involute sooner than very large ones, but there are exceptions. Most IH complete their course by the age of 7 to 10 years. Some children have normal skin after involution whereas the remainder has telangiectasias, atrophy, fibrofatty residuum, or scarring.

 

 Classification

 Hemangiomas which involve the upper dermis (so-called superficial hemangiomas) have a bright red color; whereas those with deep dermal and subcutaneous location are skin color to blue in color. Those involving both superficial and deeper skin structures, so-called mixed hemangiomas, have both features. In addition to this clinical appearance, infantile hemangiomas can be classified as localized, segmental, or indeterminate. Localized hemangiomas exhibit clear spatial containment as if arising from one central focus . Segmental hemangiomas (similar to other segmental dermatologic disease such as vitiligo and neurofibromatosis) correspond to a portion of a developmental segment or broad anatomic territory . They are often plaque-like in nature with a linear or geographic configuration. Those hemangiomas not clearly identifiable as localized or segmental are termed indeterminate . The patterns of facial segmental IH have been found to correspond to neural-crest derived facial prominences, and a new map for them has recently been proposed. Multifocal hemangiomas are usually multiple localized hemangiomas. Though the exact number is somewhat arbitrary, more than five hemangiomas confers a risk of extra-cutaneous hemangiomas.

Classification of hemangiomas by subtype not only facilitates communication but also helps predict risk of complications and need for treatment. A prospective study of 1058 children with IH showed that segmental hemangiomas are 11 times more likely to experience complications and eight times more likely to receive treatment than localized hemangiomas even when controlled for size.

 Atypical Presentations.

 Atypical presentations of IH include deep hemangiomas and telangiectatic hemangiomas. Deep IH proliferate in the lower dermis and subcutaneous tissue without penetration of the papillary dermis . They present as a localized, firm, rubbery subcutaneous mass that can be slightly raised with a bluish color or with telangiectasias involving the overlying skin, or they may be deep enough that the overlying skin is completely flat and of normal hue. If there is involvement of the papillary dermis, the cutaneous surface is often bright red and thus classified as a superficial and deep IH. Telangiectatic hemangiomas are flat or slightly elevated and deep red with an array of superficial dilated capillaries radiating over the surface . These are virtually identical to premonitory marks, but for unknown reasons, have not proliferated.
 

 Medical and Extracutaneous Risks.

 Certain hemangiomas have known associated risks. Anatomic location is one of the most important clues to these risks. Sites such as the periocular, lumbosacral, or mandibular areas should lead to closer scrutiny. In addition, the presence of multiple or segmental hemangiomas is associated with greater risk of extracutaneous disease.

PHACES.

Facial segmental IH are associated with PHACES , a neurocutaneous syndrome that consists of the following features: posterior fossa brain malformations, segmental cervicofacial hemangioma, arterial anomalies, cardiac defects or coarctation of the aorta, eye anomalies, and sternal defects, such as sternal clefting or supraumbilical raphe. Only one extracutaneous anomaly is required for diagnosis, thus the clinical spectrum varies considerably. Posterior fossa malformations, particularly the Dandy-Walker malformation, are the most commonly reported feature of PHACE syndrome, and intracranial arterial defects can lead to a Moyamoya phenomenon, ischemia, and stroke. Thus, brain imaging [magnetic resonance imaging (MRI) and magnetic resonance angiography] should be considered in all infants with a large segmental hemangioma of the face. In addition, formal ophthalmologic examination and echocardiogram may be performed, given the relative frequency of anomalies in these sites.

 Periocular Hemangiomas.

 Infants with periocular hemangiomas are at risk for anisometropia and amblyopia, which if untreated, can lead to permanent visual loss  Direct pressure on the cornea can produce astigmatism or myopia, and the mass effect of the tumor itself can cause ptosis, proptosis, visual axis occlusion, or strabismus. Any patient with a hemangioma in the periocular area should have a prompt formal ophthalmologic evaluation with repeat visits during the proliferative phase (typically the first 3 to 4 months of life). Imaging studies may be needed to assess whether retrobulbar involvement is present.

“Beard Area” Hemangiomas.

Segmental hemangiomas involving the preauricular, mandibular, chin, and neck skin (or so-called beard area) have a 60 percent risk of having symptomatic airway disease. They usually present with the insidious onset of biphasic stridor between weeks 4 and 12 of life and are often mistakenly diagnosed as tracheomalacia, upper respiratory infection, or croup. If the hemangioma continues to enlarge, respiratory distress can ensue and become life-threatening. Prompt evaluation by a pediatric otolaryngologist and treatment is essential.³⁴ Hemangiomas can also involve the parotid gland, and often require treatment due to deformity of adjacent structures, and, in rare cases, high-output congestive heart failure.

Lumbosacral and Perineal Hemangiomas.

Segmental hemangiomas overlying the lumbosacral area can have associated spinal, bony, and genitourinary anomalies. Most frequently, posterior midline IH have a particularly high risk of spinal dysraphism and tethered cord, and MRI is strongly recommended. Segmental perineal hemangiomas may be associated with urogenital and anorectal anomalies such as anterior or vestibular anus, hemiclitoris, atrophy or absence of the labia minora, and hypospadias.

Multifocal Hemangiomas.

Multifocal IH are multiple, small (1 to 20 mm), non-contiguous lesions that can be confined to the skin but can also involve the viscera, termed diffuse neonatal hemangiomatosis . Visceral hemangiomas are most commonly found in the liver  but have been reported in the lymph nodes, spleen, brain/meninges, iris, retina, salivary glands, thymus, gastrointestinal tract, lung, bladder, kidney, gallbladder, pancreas, and adrenal gland. Although most often described with multiple cutaneous hemangiomas, visceral hemangiomas have also been reported with solitary segmental

hemangiomas. The associated IH is most often located on the face but can be seen anywhere on the body. A combined prospective and retrospective study of 750 infants revealed 45 percent of infants with numerous small “miliary” hemangiomas have hepatic hemangiomas whereas 12 percent to 14 percent of those with three to five small lesions, six or more cutaneous hemangiomas, or one large (> 5 cm) lesion have involvement.

 Hepatic Hemangiomas.

 The liver is the second most common site for IH and can be associated with hypothyroidism (see the section Laboratory Tests). Many hepatic hemangiomas are small, focal, low-flow lesions which are asymptomatic and unlikely to need treatment. However, those with high-flow or shunting (either arteriovenous or portovenous) are more likely to present with high-output cardiac failure, liver dysfunction, or abdominal compartment syndrome often requiring embolization or surgical intervention. Infants with multiple hepatic tumors or left-to-right shunting typically present within the first 16 weeks of life with a clinical triad of hepatomegaly, congestive heart failure, and anemia. GLUT-1 immunohistochemical staining has revealed two distinct groups: GLUT-1-positive tumors, which are small, multifocal, histologically similar to IH, more common in females, and only symptomatic when numerous lesions were present; and GLUT-1-negative tumors, which have no gender predilection, are symptomatic at birth or shortly thereafter, and require aggressive medical and surgical intervention.⁴² In most instances, ultrasound may be initially used as a screening technique followed by computed tomography or MRI if multiple, unusually large, or symptomatic hepatic hemangiomas are found.

 LABORATORY TESTS

 Thyroid Function Tests.

 Hypothyroidism is a rare complication in infants with massive hemangiomas of the liver. First reported by Huang et al., hemangioma tissue demonstrates high levels of type 3 iodothyronine deiodinase activity, which accelerates the degradation of thyroid hormone. Infants with significant hepatic hemangiomas should have thyroid function evaluated, including T3 (the hormone consumed) and thyroid-stimulating hormone, because T4 levels may initially remain normal. Conversely, screening liver ultrasound looking for hemangiomas should be performed in infants with hypothyroidism of unknown etiology even in the absence of cutaneous hemangiomas.

 Platelet Studies.

 Platelet studies are not indicated as the Kasabach-Merritt phenomenon (KMP) is not associated with IH but rather with kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) (see the section Pharmacologic Therapy).

Recommended tests and imaging studies are included in the section Cutaneous Lesions with discussion of specific IH and their related physical findings.

 Complications

 Ulceration is the most common complication of IH, occurring in approximately 15 percent of patients usually during the proliferative phase. It occurs most frequently with segmental IH and at sites that are constantly exposed to moisture and friction such as the perioral, perianal, and other intertriginous sites.^47,48 Secondary infection can occur but its frequency is debatable. Cultures usually show polymicrobial growth and are

likely the result of colonization. However, if infection is suspected, systemic antibiotics should be prescribed.

Local wound care, barrier protection, and pain control are essential for treatment. Bio-occlusive dressings may be helpful but those intended to stick to the skin may be limited by location because they do not adhere well near orifices. In these areas, thick applications of petrolatum-based ointments can be helpful. Pain can be a major issue in management. It can be minimized with an occlusive dressing, oral acetaminophen with or without codeine, and the use of very small amounts of topical lidocaine ointment no more than a few times a day. Ulcerations generally heal with scarring within 2 to 3 weeks with topical care. For refractory cases, other treatment modalities including pulsed dye laser or Becaplermin 0.01% gel, a synthetic platelet-derived growth factor, have anecdotally been reported to be effective.Therapies aimed at halting hemangioma growth, such as intralesional and systemic steroids or excision, may be useful in some cases.

Other serious complications such as hypothyroidism, internal organ involvement, or vital structure compromise due to the location of IH in certain anatomic sites have been discussed in the section Cutaneous Lesions.

Prognosis and Clinical Course

The prognosis of most IH is excellent, with spontaneous involution and little to no sequelae, but a significant minority can result in permanent disfigurement or medical sequelae. Certain characteristics are associated with an increased risk of complications and need for treatment  Consideration of early treatment should be given to hemangiomas with these characteristics, depending on the specific clinical setting.

 

Treatment

 The decision to initiate treatment is based on many factors, including size and location, psychosocial implications, and risks and benefits of the proposed therapy. For the majority of small hemangiomas, “active nonintervention” is the most appropriate approach. This does not mean doing nothing. The infant should be seen frequently, especially during the first few months (corresponding to the proliferative phase). During these visits, education about the natural course of IH and discussions about the psychosocial impact on the child and/or the family should occur. Photographs of the likely outcome for a similar lesion are often helpful. Many parents experience anxiety and may find themselves subject to comments from complete strangers about their child's hemangioma. Most parents of young children do not think their child is deeply affected by these reactions, but facial hemangiomas in particular can cause psychological suffering once the child reaches school age. Potential treatment options should be discussed well ahead of entrance to elementary school.

 

 

If it is decided that treatment is necessary, options include pharmacologic, laser, or surgical interventions. However, management remains controversial with few double-blind controlled studies and no Food and Drug Administration-approved labeled indications for medical treatments.

 PHARMACOLOGIC THERAPY

 Corticosteroids.

 Systemic corticosteroids are the first-line treatment for deforming, endangering, or life-threatening IH  They work best during the growth phase, causing slowing or cessation of growth in up to 90 percent of cases, with actual shrinkage in approximately one-third. Although the mechanism of action is not well understood, recent studies suggest the upregulation of mitochondrial cytochrome b, clusterin/ApoJ (possible apoptotic markers), and/or interleukin-6 as markers of corticosteroid-induced cessation of hemangioma growth. Prednisone or prednisolone is given at a dose of 2 to 3 mg/kg/day, typically for 4 to 8 weeks followed by a tapering of varying length, depending on the age of the child and indication for treatment. A recent large meta-analysis showed an 84 percent response rate with an average dose of 2.9 mg/kg for a mean of 1.8 months before tapering. Although 3 mg/kg/day is more effective (94 percent response) than 2 mg/kg/day (75 percent response), greater adverse events are found with the higher dose.

Short-term complications of systemic corticosteroids include: cushingoid facies (71 percent), personality changes (29 percent), gastric irritation (21 percent), fungal infection (oral or perineal, 6 percent), and diminished gain of height (35 percent) and weight (42 percent) during treatment. More than 90 percent of children with diminished gain of height return to their pre-treatment growth curve by 24 months of age (Table 126-3). Other complications include hypertension, steroid-induced myopathy, and immunosuppression. Blood pressure should be monitored with each visit to the dermatologist or pediatrician.⁶⁴ Children taking more than 2 mg/kg/day of prednisone for longer than 14 days are considered to have a deficit in cell-mediated immunity. Liveviral vaccinations should be deferred in infants receiving high-dose corticosteroids. Rare cases of Pneumocystis carinii pneumonia have been reported in this setting, leading some physicians to use trimethoprim-sulfamethoxazole prophylaxis during treatment.

Intralesional corticosteroids can be an effective treatment for relatively small localized hemangiomas located in high-risk sites such as the lip, nasal tip, cheek, and ear. Injections for periocular hemangiomas are usually performed by ophthalmologists,

but reports of retinal artery embolization and blindness have resulted in a reduced use of this modality.^66-68 The largest published case series of intralesional steroids found that the majority showed greater than 50 percent reduction in volume with the best results occurring in relatively superficial hemangiomas. Adverse events occurred in 6.4 percent of patients and included cushingoid appearance, cutaneous atrophy, and anaphylactic shock

A few case series have reported on the efficacy of class 1 topical corticosteroids, especially for small, superficial hemangiomas.

 Interferon-α.

 Interferon-α therapy is reserved for hemangiomas causing morbidity that are unresponsive to oral corticosteroids, or where such therapy is contraindicated. It is quite effective, but a severe neurotoxicity, spastic diplegia, has been reported in up to 20 percent of infants treated . A recent meta-analysis of 441 patients showed 11 developed irreversible spastic diplegia and 16 developed motor disturbances that were reversible on discontinuation of the drug. All affected patients were younger than 1 year of age at initiation of therapy, suggesting that the drug may be safer after 1 year of age. Neurologic evaluations should also be performed monthly in treated children.

 Chemotherapy.

 Vincristine is often used in the treatment of the KMP and its associated tumors, KHE and TA. Given the potential neurotoxicity of interferon (see the section Interfon-α), vincristine is considered by some to be a second-line treatment for aggressive, complicated IH that do not respond to corticosteroids. However, further evaluation through prospective clinical trials is needed .

Cyclophosphamide has been reported in the pediatric hematology-oncology literature to be effective in the treatment of life-threatening diffuse neonatal hemangiomatosis.

 Imiquimod.

 Imiquimod 5% cream has anecdotally been reported to be effective in treating small superficial hemangiomas, but crusting and ulceration are potential side effects.

 LASER THERAPY

 The pulsed dye laser (PDL), originally designed to treat port-wine stains, has been used to treat IH with varying results. Several reports have shown improvement in treating hemangioma ulceration, and its use in diminishing residual telangiectasias and erythema after involution is well accepted. Its use in the treatment of proliferating hemangiomas is controversial. Batta et al. performed the only prospective, randomized, controlled study to date regarding the treatment of IH in 121 patients aged 1 to 14 weeks, using 585-nm PDL without cooling compared to observation alone. Their results showed no difference between complete and nearly complete clearance with laser compared to observation alone at age 1 year, with a trend toward increased hypopigmentation and textural change in the laser-treated group. Other studies have shown good results with either the 585-nm PDL or 595-nm PDL, with varying fluences, but several have emphasized that treatments work best for more superficial hemangiomas and are unable to halt growth of deeper components. Severe ulceration and scarring, particularly in treating segmental hemangiomas during the proliferative phase, have been reported  A conservative approach is to reserve PDL primarily for treating ulceration and for hastening resolution of erythema in IH that have stopped proliferating or have already undergone involution.

 SURGICAL THERAPY

 Surgical excision may be indicated at any time during the life cycle of an IH  In most instances, it is best to wait until regression is well under way and a more accurate assessment can be made regarding whether scarring and textural changes have occurred. Decisions regarding this can often be made at age 3 to 5 years, even if involution is not complete. Certain anatomic locations such as the nasal tip and lip often require surgery. Even earlier excision may be indicated in cases where clinical characteristics, such as pedunculated, very ulcerated, or extremely thick dermal involvement dictate that scarring will inevitably occur. A standard elliptical excision is often performed; however, circular excision followed by a purse-string closure may leave a smaller scar.

 ▪ OTHER VASCULAR TUMORS

 Many other benign vascular neoplasms occur in both children and adults. This chapter highlights many of the important ones. More comprehensive reviews of this subject can be found elsewhere.