Pediatric Vascular Tumors

Infantile Hemangioma

Most infantile hemangiomas (IH) are sporadic, however rare cases are associated with an abnormality of chromosome 5 and 34% of patients had a family history of infantile hemangioma, most commonly in a first-degree relative. The pathogenesis of IH is development from progenitor cells which normally would evolve into blood vessels. The precursor cell seems to be a multipotent hemangioma-derived stem cell, which produces an erythrocyte-type glucose transporter (GLUT1). ^, These stem cells are similar to placental endothelium but genetically derived from the child. Hypoxia is widely accepted as the primary stimulus for growth of IH. Endothelial proliferation likely occurs from complex interactions between activated T cells, alterations in vascular endothelial growth factor receptor (VEGFR) expression, and the binding of endothelial growth factor A to VEGFR-2 receptors. Sometime between early infancy and 4 years of age, these tumors involute, the mechanism of which is unclear. Endothelial proliferation slows and apoptosis increases during this time, with potential triggers related to a decrease in proangiogenic maternal estrogens or an increase in angiogenesis inhibitors in the epidermis. The tumor is replaced by fat cells, which also derive from the aforementioned stem cells.

IH is the most common benign vascular neoplasm of infancy with an incidence of 4%–5%. IH affects non-Hispanic white infants more often than those with darker skin. Premature infants with low birth weight, particularly girls, also have a higher risk of developing these tumors. For every 500-g decrease below a 2500-g baby, the risk of IH increases 40%. Additional risk factors include: advanced maternal age, placenta previa, pre-eclampsia and other placental anomalies. Lesions tend to be solitary (80%) and involve the head and neck, trunk, or extremity in decreasing order of frequency. The tumors appear most often at 3–6 weeks of age, but may be evident as small pale, telangiectatic, or ecchymotic spots in nearly one-half of infants at birth. ^,

IH has a proliferative growth phase during the first 9 months of life, with most rapid growth in the first 8 weeks of life. Eighty percent of volumetric growth is achieved by age 5 months. ^, Tumor appearance during this stage varies based on whether it involves the superficial or deep dermis. If the tumor is in the superficial dermis, it appears bright red, but when deeper, the lesion either has a bluish or normal color. Many IH are mixed with both superficial and deep components ( Fig. 187.1A –C). Proliferation often slows by 5 to 6 months of age; however, in those with a primarily deep component, proliferation can be prolonged, sometimes up to 18 months of age. Subsequent growth coincides with growth of the child. The involution phase begins by 1 year of age, at which point the tumor shrinks, the color fades, the center of the lesion pales, and the tumor softens. Involution is complete by 4 years of age in most children. Some patients with a large deep component are left with fibro-fatty tissue and redundant skin. Scarring is most often associated with ulcerative lesions. Telangiectasias and discoloration are other sequelae after lesion regression is complete. ^,

IH may be multiple and involve the skin or liver. The cutaneous lesions are often less than 5 mm in diameter and domelike ( Fig. 187.1D ). If more than five hemangiomas are present, the child has a 16% chance of harboring visceral lesions, with the most common extracutaneous location being the liver. The brain, gut, and lung are rarely involved. Most hepatic IH are small, discovered incidentally, and are classified as multifocal or diffuse. Multifocal hepatic hemangiomas are usually asymptomatic, although high-output cardiac failure by arteriovenous or portovenous shunting occurs rarely. Similar to cutaneous IH, involution begins by 1 year of age and often earlier in most children. ^,

Diffuse IH can be seen in the liver and often do not need active treatment and rather simply close observation. At times, large, diffuse IH may replace much of the liver parenchyma and cause massive hepatomegaly. Compression of the inferior vena cava or upward pressure on the diaphragm with reduction of the pleural space causes respiratory symptoms or abdominal pain and pressure in select patients. High-output cardiac failure is rarely seen. Almost all infants with profound liver involvement develop hypothyroidism because this hemangioma expresses a deiodinase that inactivates thyroid hormone, necessitating thyroid-stimulating hormone monitoring. As the hemangioma regresses, the need for replacement therapy ebbs. Differential diagnosis includes hepatic arteriovenous malformation (AVM) and malignant neoplasm. Hemangiomas and AVMs exhibit fast-flow characteristics, with 90% of fast-flow lesions being hemangiomas and the remaining ones AVMs. Hepatoblastoma and metastatic neuroblastoma do not have the shunting characteristics of hemangioma.

IH may be associated with specific syndromes in which there are anomalies of the cardiovascular, gastrointestinal, and urogenital systems; brain or spinal cord; eye; and/or bone. A child with a large, segmental midline lumbosacral region IH carries a 33% chance of having a spinal anomaly, such as a tethered cord, lipoma, or intraspinal hemangioma ( Fig. 187.2A ). Magnetic resonance imaging (MRI) between 3 and 6 months of age is important to exclude spinal abnormality in these cases. Lower body IH may be associated with urogenital anomalies or ulceration, myelopathy, bone deformities, anorectal malformations, arterial, and/or renal anomalies. This association is termed LUMBAR, and disproportionately affects females. The IH is usually large, segmental, and superficial; has minimal postnatal growth, and often ulcerates. The hemangioma may be seen in the sacral or lumbar regions, the perineum and genitalia, or lower extremity.

Segmental plaque-like IH of the face may be associated with one or more anomalies in the brain or cerebrovascular system, heart, eye, sternum, or supraumbilical region, categorized as PHACE syndrome (see Fig. 187.2B ). The acronym represents posterior fossa brain malformation, hemangioma, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities, and sternal clefting or supraumbilical raphe. Ninety percent of affected children are female. The most common anomaly is a cerebrovascular malformation in 72% of patients, and approximately 8% of infants sustain a stroke. PHACE syndrome is found in less than 3% of all patients with IH, and extracutaneous features in this group are seen in less than one-third of the children. Recognition of PHACE syndrome is critical because these patients have higher risk of complications and sequelae than those with isolated IH.

Diagnosis of IH is made by history and physical examination in nearly all patients. Ultrasound shows a well-circumscribed hypervascular mass. Low-resistance arterial waveforms are present, and venous drainage is seen. MRI can be used if ultrasound imaging is equivocal, but is rarely necessary. IH is seen as a parenchymal mass with dilated vessels and signal voids during the proliferative phase, unlike an arteriovenous malformation. The lesion is isointense on T1 sequences and hyperintense on T2 images and enhances homogeneously after the administration of contrast. An involuting IH is lobular and has adipose tissue and a reduced number of vessels, with signal void or enhancement. MRI or MR angiography is used to image the brain and neck for children with PHACE syndrome. Echocardiography and an eye examination are important adjuncts. Although ultrasound may be useful when LUMBAR associations are suspected, MRI often is needed to image the lumbosacral spine, abdomen, and pelvis. Choice of study is based on age of the infant or child and type of lesion.

Less than 1% of IH require histopathologic evaluation for diagnosis. Biopsy is indicated if malignant disease is suspected by atypical appearance or if the diagnosis remains unclear after the lesion is imaged. Microscopic evaluation of a proliferating lesion shows tightly packed capillaries with plump endothelial cells and minimal intervascular stroma. In contrast, an involuting lesion shows reduction in the number of capillaries that have enlarged channels, increased stroma, and fibrofatty tissue. A hallmark of IH is that it shows GLUT-1 positivity throughout all stages of proliferation and involution.

Observation is the mainstay of management as most tumors are small and localized and do not involve esthetically or functionally important areas. Parents can be reassured by showing them examples of proliferative, involuting, and regressed lesions that were managed in other infants. Close observation is needed during the proliferative phase to be certain the tumor does not ulcerate or pose risk of destruction of adjacent important structures.

An early therapeutic intervention at 1–3 months of age has been cited as critical for complicated infantile hemangiomas to prevent medical complications and permanent disfigurement. Photos have been used to triage low-risk versus high-risk infantile hemangiomas, and a scoring system has been used for primary care physicians to encourage early referral to multidisciplinary hemangioma specialists. ^,

Topical beta-blockers are used primarily for the treatment of small, localized, superficial hemangiomas as an alternative to observation. They have also been used in combination with systemic therapy in complicated hemangiomas or to prevent rebound in a hemangioma being tapered off of systemic treatment. ^, The same precautions as noted below for propranolol should be followed for topical beta-blockers as the systemic absorption of timolol is variable. Cautious administration is required for ulcerated and deep hemangiomas because higher plasma concentrations of timolol can be seen. Topical dosing requires the ophthalmic gel-forming 0.5% solution of timolol with one drop applied to the hemangioma twice daily until a treatment response is achieved. Data from a multicenter, retrospective, cohort study of 731 children with predominantly superficial IH treated with topical timolol 0.5% twice daily supported that 92% of patients showed significant improvement in color, and 77% of patients showed improvement in size, extent, and volume.

Approximately 16% of lesions develop skin ulceration during the proliferative phase, at an average of 4 months of age. Ulceration is more common on the lips, neck, anogenital, and other flexural regions; larger and segmental IH are also at risk of ulceration ( Fig. 187.3 ). Standard wound care is topical antibiotic and Vaseline, followed by gauze. These lesions may be very painful, so topical lidocaine may be needed. Topical pharmacotherapy may be appropriate treatment for small IH that do not require systemic therapy. Topical corticosteroid, such as clobetasol, may prove effective for small, superficial lesions, although hypopigmentation and skin atrophy can occur. Application of timolol, also has been proven effective for small, superficial lesions.

Systemic therapy is indicated for large hemangiomas that cannot be treated with local injections and is considered when topical therapy has been ineffective. Several drugs have been used, including beta-blockers, steroids, and anti-metabolic agents. Propranolol, a nonselective beta-blocker, is the first-line therapy for infantile hemangiomas. Potential mechanisms of action include vasoconstriction and/or decreased expression of VEGF and bFGF, leading to apoptosis. ^,

In a large industry-sponsored randomized trial, 456 infants aged 5 weeks to 5 months with a proliferating infantile hemangioma of at least 1.5 cm received either a placebo or propranolol (dose = 1 mg/kg per day or 3 mg/kg per day) for 3 or 6 months. After interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg/kg per day for 6 months was selected for the final efficacy analysis. Eighty-eight percent of infants treated with propranolol demonstrated improvement by week 5, compared with only 5% of patients who received placebo. In another study of 635 infants with IH, the overall response rate was 91% following propranolol treatment (dose = 2 mg/kg per day), with most patients showing regression and only 2% with side effects, none of which were severe. Finally, a recent meta-analysis evaluated 5130 patients from 61 studies and concluded that propranolol was more effective and safer than were other treatments for IH. Consensus treatment guidelines are presented in Table 187.2 . ^{, ,}

Rebound tumor growth occurs if the medication is abruptly discontinued during the proliferative phase. Rebound refers to the growth of IH after propranolol cessation. A multi-institutional, retrospective review of 997 patients with IH identified a rebound rate of 25.3% in 912 patients. Multivariate analysis revealed risk factors for rebound to be deep IH and female sex.

Corticosteroids were the historic first-line of treatment for IH, first used in the late 1950s, but never approved by the U.S. FDA. Corticosteroid therapy has become less popular secondary to the acute and long-term side effects of steroids, but used at times when there is a contraindication to beta-blocker therapy. If systemic beta-blocker or steroid therapy proves ineffective, third-line systemic drugs such as interferon or vincristine are considerations but are rarely, if ever, used. These medications have a high risk of side effects; interferon is not recommended in children younger than 1 year of age because of the risk of neurologic problems such as spastic diplegia. ^,

Embolization is considered for large high-flow IH that cause congestive heart failure, such as multifocal or diffuse hepatic hemangiomas that have macrovascular shunts, particularly when there is little or only partial response to systemic beta-blocker therapy. The goal of embolization is to provide prompt control of heart failure as the therapeutic benefits of systemic agents accrue. This treatment has little or no role in hepatic hemangioma without heart failure. Drug therapy is used post-embolization until the child is approximately 1 year of age, when involution generally begins.

Pulsed dye laser therapy is primarily used to treat residual telangiectasia post-involution but can also be used to treat areas of ulceration in lesions slow to respond to other treatments. Carbon dioxide laser has been used to treat subglottic hemangioma during the proliferative phase as drug treatment is initiated.

Excision of proliferating lesions is rarely indicated, given the success of pharmacotherapy. The tumor is highly vascular, so there is a risk of blood loss. Anesthetic complications, scarring, and cosmesis in infants must be considered. A well-localized or pedunculated, ulcerated, or bleeding lesion may be excised if the resulting scar is esthetically placed and no worse than would be predicted if excision is done after involution is in process or complete. The ideal time for operative intervention is between 3 and 4 years of age. At this age the tumor is smaller and less vascular and it will no longer involute. In general, the deformity improves with time, which makes long-term memory of the procedure and self-esteem issues less likely. ^,

Circular hemangiomas with residual fibrofatty tissue or excess skin are best managed with circular excision and purse-string closure. The resultant scar can be revised 6 to 12 months later and closed linearly. This technique reduces the length of the linear scar relative to the initial diameter of the hemangioma. Initial linear excision of a circular hemangioma generates a scar nearly 3 times the diameter of the tumor.