Seminars in Pediatric Surgery 23 (2014) 162–167
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Infantile and congenital hemangiomas Marilyn G. Liang, MDa, Ilona J. Frieden, MDb,n a b
Dermatology Program, Boston Children's Hospital, 300 Longwood Ave, Boston, Massachusetts 02115 Department of Dermatology, University of California San Francisco, San Francisco, California
a r t i c l e in f o
abstract
Keywords: Infantile hemangioma Congenital hemangioma PHACE LUMBAR PELVIS Propranolol
Infantile hemangiomas (IHs) are the most common benign vascular tumors of infancy. Since they predominantly involute without significant residua, the majority do not require treatment. Indications for intervention include ulceration, prevention of disfigurement, and impairment of function or vital structures. Some IHs have associated structural anomalies. When and which IH to treat requires knowledge of the natural history and clinical findings of increased risk. Congenital hemangiomas (CHs) are fully formed at birth. They also differ from IHs in their histological and immunohistochemical findings and thus represent a distinct clinical entity. Their clinical characteristics and management are also discussed. & 2014 Elsevier Inc. All rights reserved.
Introduction The term “hemangioma” has been used both correctly and incorrectly in the literature for a variety of vascular lesions. Infantile hemangiomas (IHs) are vascular tumors, usually absent at birth or present as a premonitory mark with rapid post-natal growth followed by slow involution. IHs are the most common tumor of infancy and childhood, occurring in 4% of children.1 While many clues have emerged regarding pathogenesis, many questions still remain. Therapy has changed dramatically in the past 5 years, and early treatment is critical for those requiring systemic medications as many interventions limit proliferation.
Infantile hemangioma Pathogenesis The pathogenesis of IH is not completely understood and is likely multifactorial. Several reviews have summarized recent advances.2 IHs are more common in females, supporting the hypothesis that estradiol increases endothelial cell proliferation.3 Vascular endothelial growth factor (VEGF), more than estradiol, invoked hemangioma-derived endothelial cell (HemEC) proliferation, but the combination of VEGF and estradiol was synergistic.4
Stromal cells isolated from proliferating IHs release VEGF.5 VEGF can bind receptors, such as vascular endothelial growth factor receptor (VEGFR)-2, which are expressed on proliferating IHs and HemECs and then can stimulate growth.6 There is increasing evidence that IHs arise due to an intrinsic defect in an endothelial or progenitor cell, through either a somatic (post-zygotic) mutation or a germline mutation.6 Twin studies showed no differences in concordance between monozygotic and dizygotic twins; however, there is a report of 3 families with autosomal-dominant inheritance of IH and linkage to 5q.7 Some evidence suggests that IHs are clonal tumors; HemECs from proliferating IHs in female infants display a nonrandom pattern of X-chromosomal inactivation.8 In contrast, non-endothelial cells showed a mixed inactivation pattern. Walter et al.9 also found clonality from cells in hemangioma tissue sections. Clonality in both tissue sections and in isolated HemECs supports the theory that genetic alterations, possibly somatic mutations, cause IH. In addition, IH can be associated with structural malformations, also suggesting early post-zygotic somatic mutation. Jinnin et al.6 identified mutations in the integrin-like receptor tumor endothelial marker 8 (TEM8) and in VEGFR-2 in a subset of HemECs and corresponding blood samples from patients with IHs. These “risk-factor” germline mutations may contribute to IH. Clinical
Disclosure: Pierre Fabre investigator and advisory board (MGL). Pierre Fabre consultant (IJF). n Corresponding author. E-mail address: [email protected] (M.G. Liang). http://dx.doi.org/10.1053/j.sempedsurg.2014.06.017 1055-8586/& 2014 Elsevier Inc. All rights reserved.
IHs are the most common tumor of infancy and childhood, with approximately 4% incidence in Caucasian infants. Many have a premonitory mark at birth (e.g., pale macule with telangiectasias,
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mottled vascular stain, or bruise-like area). Most superficial IHs are evident by 1–4 weeks of age while deep IHs often present at 2–3 months of age. Dependent on location, tumors may be brightly erythematous macules, papules, or plaques (superficial) or blue nodules (deep) or exhibit a combination of these features. Ulceration is the most common complication, is more common in perioral and perineal sites, and may even be the presenting finding before the development of an obvious IH.
anatomy and disfigure with fibrofatty residua, anetoderma, atrophy, erythema, hypopigmentation, and telangiectasias. Ulceration almost always causes scarring. Nasal tip lesions may splay the underlying cartilage, and revision is often necessary to correct the deformity. Ulceration of the columella and helix may also destroy the cartilage of the nasal septum and helix, respectively.
Epidemiology and natural history
Periorbital IHs may cause visual impairment most commonly by deformation of the cornea causing astigmatism. Other rarer ocular complications include visual axis obstruction, proptosis, and strabismus. Perioral IHs, particularly when ulcerated, may impair feeding. Patients with regional IHs in a lower facial, “beard” distribution are at risk for upper airway and subglottic involvement. Infants present within the first few weeks of life with noisy breathing, stridor, hoarse cry, and difficulty feeding. Ulcerated IHs of the perianal area may damage the anal sphincter and cause incontinence. Other severe complications include congestive heart failure with liver IH, visceral hemorrhage, abdominal compartment syndrome, gastrointestinal bleeding, and hypothyroidism.
Increased risk factors for IH include Caucasian race, female gender, prematurity, low birth weight, and being the product of multiple gestations. The female predominance is even higher in patients with PHACE association, 7:1.10 IHs classically grow in early infancy followed by spontaneous involution. IHs reach 80% of their final size by a mean age of 3 months11; however, many superficial IHs have an accelerated growth phase between 4 and 7 weeks, and many have completed the majority of growth by 2 months.12 Deep IHs typically appear 1 month later and proliferate for longer than superficial IHs. Rarely, some IHs have minimal proliferation, termed IHs with minimal or arrested growth (Figure 1). Based on these growth characteristics, initiation of systemic therapies—if needed—should ideally be initiated prior to 3 months of age. Involution gradually occurs over several years but in most cases is nearly complete by the age of 4 years.13 Risk stratification Because IHs are so heterogeneous in size, location, and growth characteristics, an approach to stratifying their risk of potential complications is needed (Table 1). Regional (also known as “segmental”) IHs are much more likely to develop complications, including ulceration, bleeding, visual compromise, auditory compromise, cardiac compromise, or airway obstruction, than localized IHs.14 Ulceration is the most common complication of IHs, occurring in approximately 10–15% of patients, usually developing by 4 months of age. Pain, bleeding, rarely profuse, and occasionally infection may complicate ulceration. Liver and airway are the most common extracutaneous sites. In general, patients with 5 or more IHs are screened for liver IHs by abdominal ultrasound. Other complications related to syndromic associations are discussed below. Disfigurement Permanent scarring and disfigurement are the most common adverse sequelae of IHs. Large facial IHs frequently distort normal
Fig. 1. Arrested IH in an infant with PHACE. (Color version of figure is available online.)
Impairment of function
Syndromes associated with infantile hemangiomas Although most infantile hemangiomas occur solely as a cutaneous disease or—less frequently—with hepatic hemangiomas, a subset of these have associated structural abnormalities, several of which are highly relevant to surgical practice. These occur primarily in association with segmental IHs, which involve an anatomic territory, rather than arising from a single spatially confined focus (i.e., localized IH).14 Conceptually, these associations can be divided into 2 major malformation groupings: PHACE association (OMIM 606519), where IHs primarily involve the face and to a less extent the ventral torso and extremities, and LUMBAR association, a constellation of anomalies with IHs involving the lower body. PHACE association The acronym PHACE refers to posterior fossa brain malformations, hemangiomas of the face (typically large and segmental), arterial anomalies, cardiac anomalies, and coarctation of the aorta, and eye abnormalities.15 The association is referred to as “PHACES” when ventral developmental defects, such as sternal clefting or supraumbilical raphe, are present. Surgeons will often be called upon to manage the ventral developmental defects in PHACE, which are typically identified at birth. These ventral anomalies have also been called “sternal malformation/vascular dysplasia association.”16 The cause of PHACE remains unknown. For unclear reasons, PHACES has a stronger female predominance (between 5:1 and 9:1) relative to the 3:1 as seen in IH in general.17 Unlike IH, prematurity is not a specific risk factor, though it is also not per se protective against PHACE. The distribution of cutaneous hemangiomas and ventral developmental defects point to a so-called developmental field defect occurring between 4 and 6 weeks of gestational age as the likely explanation for this association.14 While the precise incidence of PHACE is not known, in a prospective study of 108 patients with facial hemangiomas larger than 22 cm2, all of whom had systematic investigation with MRI/ MRA of the head and neck, echocardiogram, and eye examination, 31% met diagnostic criteria.17 Consensus diagnostic criteria for PHACE have been proposed18 (Table 2). Approximately 90% of patients with PHACE have more than 1 extracutaneous manifestation; however, most do not have all of the findings indicated by the acronym PHACE.17 Other key features of PHACE of relevance to surgeons include an unexpectedly
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Table 1 Risk stratification of infantile hemangiomas (Modified from Luu and Frieden).51 Level of risk
Clinical features
Risk/rationale for concern
Low
Trunk, arms, and legs (in areas covered by clothing) o 5 cm
Low risk for disfigurement of functional compromise
Intermediate
Segmental 4 5 cm trunk, arm, and leg
Risk for ulceration Risk of permanent residual skin changes Ulceration risk Risk of disfigurement Lower but possible risk of functional compromise and/or ulceration
Body folds (neck, perineum, and axillae) Lateral face, scalp, hands, and feet High
Face—prominent dermal thickening or central facial
Permanent skin changes High risk of disfigurement Functional compromise and high risk of permanent disfigurement Associated structural anomalies (PHACE) High scarring risk Visual/airway compromise Associated structural anomalies (LUMBAR) Ulceration risk
Periorbital, perinasal, and perioral Segmental 4 5 cm face
Segmental 4 5 cm lumbosacral/perineum
high incidence of airway hemangiomas,19 microphthalmia, and other structural eye abnormalities including so-called morning glory disc anomaly. Cerebrovascular changes are the most common extracutaneous manifestation of PHACE, primarily dysgenesis, narrowing, anomalous course, or nonvisualization of the anterior cerebral circulation. The findings are typically ipsilateral to the IH.20 In a recent report of 150 patients in a PHACE Registry, 41% had cardiovascular anomalies, the most common of these were aberrant origin of the subclavian artery (21%) and coarctation of the aorta (19%). The aortic coarctation seen with PHACE is distinctive, most often involving long-segment narrowing of the transverse aorta without associated valvular disease. Intracardiac defects, most commonly, ventricular septal defects, can be seen but typically do not require intervention.21 The ventral developmental defects, seen in approximately 20–25% of patients are most commonly sternal malformations and supraumbilical raphe. The extent of severity varies from small sternal pits to extensive open defects requiring surgical correction. These are present at the time of birth, even before the hemangiomas become evident and thus may be the first presenting finding
in PHACE. Rarely other anomalies such as endocrinopathies including hypopituitarism, growth hormone deficiency, and hypothyroidism have been reported as has sensorineural hearing loss.22,23 Management is typically multidisciplinary, depending on the organ systems affected. In our experience, most patients with PHACE have IHs requiring systemic therapy for management of aggressive growth or ulceration. Propranolol has emerged as a first-line treatment of IHs, including several analyses that have demonstrated favorable outcomes compared with corticosteroids, the previous gold standard.24–27 However, caution should be taken in initiating propranolol in the setting of segmental IHs without adequate assessment of the cerebral vasculature (with MRI and MRA) and evaluation for cardiac and aortic anomalies (with echocardiogram or MRA). Although safe use of propranolol has been documented in a number of patients with PHACES,28 caution should be used; severe arterial or aortic disease could be a relative contraindication to the use of a beta-blocker or alternatively cause clinicians to proceed more cautiously to avoid hypotension which could precipitate an ischemic event (e.g., stroke).29
Table 2 Diagnostic criteria for PHACES (Adapted from Metry et al.)10 Definite PHACE: Facial hemangioma 45 cm in diameter plus 1 major criterion or 2 minor criteria Possible PHACE: Facial hemangioma 45 cm in diameter plus 1 minor criterion Hemangioma of the neck or upper torso plus 1 major criterion or 2 minor criteria No hemangioma plus 2 major criteria Organ system
Major criteria
Minor criteria
Cerebrovascular
Anomaly of major cerebral arteries Dysplasia Stenosis/occlusion Hypoplasia/aplasia Aberrant origin Persistent trigeminal artery Saccular aneurysm
Persistent embryonic artery other than trigeminal artery
Structural brain
Posterior fossa anomaly
Intracranial hemangioma Midline anomaly Neuronal migration disorder
Cardiovascular
Aortic arch anomaly Coarctation or aortic dysplasia Aberrant subclavian artery
Ocular
Posterior segment abnormality
Anterior segment abnormality
Ventral/midline
Sternal defect or supraumbilical raphe
Hypopituitarism Ectopic thyroid
Dandy–Walker complex
Ventricular septal defect Right aortic arch
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LUMBAR association
Imaging
While PHACE association is seen almost exclusively with facial IH, a group of structural anomalies can also be seen in association with lower body IH. This group of anomalies has been variously called “LUMBAR” syndrome (lower body infantile hemangiomas, urogenital anomalies and ulceration, myelopathy, bony deformities, anorectal malformations and arterial anomalies, and rectal anomalies), PELVIS syndrome (perineal hemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag), and SACRAL syndrome (spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal and urologic anomalies, associated with “angioma” of lumbosacral localization).30–32 Of these acronyms, we prefer LUMBAR association in part because the highest risk area for spinal dysraphism is overlying the lumbosacral skin rather than the sacrum (Figure 2). Surgeons may be called upon to manage patients with LUMBAR due to several structural anomalies such as imperforate anus, abnormal genitalia, or cutaneous anomalies in association with spinal dysraphism. The initial presenting findings may be anal or genitourinary anomalies, with cutaneous evidence of hemangiomas developing days to weeks later. Often clues to the presence of a segmental hemangioma are visible in the form of premonitory marks such as areas of surrounding skin with blanching, telangiectasias, and vascular stain, with or without ulceration. Skin ulceration occurs in up to 50% of infants with perineal hemangiomas and can be a particularly difficult management issue.33,34 In addition to visible structural anomalies, infants with large or segmental IHs in the lumbosacral area have a high risk of tethered spinal cord and intraspinal hemangiomas and require further evaluation including MRI of the spine. In a recent prospective study, 50% of infants with IH overlying the lumbosacral area were found to have an associated intraspinal abnormality. Ultrasound was not as sensitive as MRI in detecting these anomalies.35 In very young infants (o3 months old), MRI may not be sensitive enough to detect tethered spinal cord, so if no sinus tracts or symptoms are present, consideration of deferring MRI to 4–6 months may be considered, or alternatively, repeat imaging may be considered in patients where there is a high index of suspicion of spinal dysraphism.36
A majority of IHs can be diagnosed clinically. Occasionally, deep IHs or hepatic lesions may be difficult to diagnose, and imaging can be helpful to distinguish vascular tumors from neoplastic lesions. Ultrasonography with Doppler study demonstrates a highflow pattern characteristic of IHs, differentiating them from solid tumors and vascular malformations. Magnetic resonance imaging (MRI) of IHs demonstrates a well-circumscribed, densely lobulated mass with an intermediate signal intensity on T1-weighted images and a moderately hyperintense signal on T2-weighted images. IHs also show contrast enhancement on MRI. Pathology If clinical and/or imaging are atypical, histopathology may be helpful for diagnosis. Hemangiomas are comprised of densely packed endothelial cells that form small capillaries. IHs have plump endothelial cells and endothelial proliferation, most marked during the growth phase, with a lobular architecture. Immunohistochemical staining for glucose transporter-1 protein (GLUT-1) is positive in IH endothelial cells and is negative in other vascular anomalies.37 Management A major challenge in managing IH is identification of which hemangiomas require treatment and which can be left to involute spontaneously without treatment (Table 1). Active observation and anticipatory guidance, “active non-intervention,” is the most common therapy. Parents are often distressed when no therapy is instituted, and numerous discussions may be needed on the natural history of IH and timing of possible therapies. Local therapies Ulceration is the most common complication of IH and should be treated to limit scarring, pain, and secondary infection. Topical antibiotics, occlusive dressings, pain medication, and/or oral antibiotics may be needed. Pulsed dye laser is sometimes useful to limit pain and accelerate healing; however, it may also initiate ulceration.38 Topical timolol and intralesional corticosteroid treatment may be useful in proliferating, small, focal IHs. Triamcinolone acetonide is the most frequently used, monthly only during the early proliferative phase. Corticosteroid injection on the eyelid has very rarely been associated with blindness by occlusion of the central retinal or ophthalmic arteries.39 Systemic therapies
Fig. 2. IH in an infant at risk for LUMBAR association. (Color version of figure is available online.)
The first-line treatment for IHs requiring systemic therapy is oral propranolol, which has largely replaced oral corticosteroids, the previous “gold standard.” Side effects of propranolol include hypotension, wheezing, hypoglycemia, bradycardia, sleep disturbance, somnolence, cool extremities, diarrhea, and gastroesophageal reflux. There are various approaches regarding method of initiation, dose, frequency, and monitoring of propranolol. Guidelines suggest outpatient initiation for infants older than 8 weeks of gestationally corrected age without co-morbid conditions, pretreatment electrocardiogram, 1–3 mg/kg/day divided 3 times daily, and blood pressure and heart rate monitoring for 2 h after initial dose and significant dose increases.40 Symptomatic hypoglycemia and hypoglycemic seizures have been reported and are wellknown side effects of propranolol.41 Rather than routine glucose monitoring, most experts recommend frequent feeding, cessation of medication if an infant is fasting or eating poorly, and not
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allowing prolonged periods of sleep as prevention strategies. Propranolol is given for the entire proliferative phase, often for 1 year or longer. Recurrence occurs in approximately 25% of patients, with those with deep IHs being at the highest risk for recurrence. Other systemic medications for IHs include corticosteroids, interferon, and vincristine. Side effects of corticosteroids include gastric irritation, delayed growth, irritability, Cushingoid facies, and hypertension. Hypertrophic cardiomyopathy, steroid myopathy, and pneumocystis carinii pneumonia are rarely reported. The most worrisome side effect of interferon is spastic diplegia. Vincristine requires a central line and may cause peripheral neuropathy, constipation, jaw pain, anemia, and leukopenia. Lesions that obstruct function, such as upper eyelid or airway hemangiomas, may be excised during the proliferative phase if failed or unable to use pharmacologic therapy. Excision may be needed in the involuting phase if permanent skin changes have occurred such as scarring or sessile IHs. In the involuted phase, pulsed dye laser therapy is useful for residual telangiectasias and erythema, fractionated laser may be used to improve some textural changes, and excision may be desired to treat fibrofatty residua, anetoderma, or scarring. IHs that have a steep ascent from normal to involved skin have the greatest risk for anetoderma skin changes. Fig. 3. Large RICH on the scalp of an infant. (Color version of figure is available online.)
Congenital hemangiomas—Rapidly and non-involuting Unlike infantile hemangiomas, which are very common, congenital hemangiomas (CHs) are uncommon vascular tumors. In contrast to infantile hemangiomas, which are either absent or present as a premonitory mark, CHs are present and fully grown at birth. They often present as a thickened plaque or exophytic mass, located on the head, neck, or extremities. They may even be diagnosed or at least suspected in utero usually during the third trimester of pregnancy.42 Based upon their natural history, 2 major subtypes of CHs have been recognized: rapidly involuting congenital hemangiomas (RICHs) and non-involuting congenital hemangiomas (NICHs).43,44 However, this binary division has recently been called into question as some RICHs do not involute completely, rather they flatten but persist in a partially involuted state, resembling NICHs in most other respects.45 The majority of RICHs involute by 1 year of age rather than by age 4–6 years as seen in IHs. In most cases, RICHs involute completely by the age of 14 months, whereas NICHs do not regress but grow in proportion with the child and may require eventual excision. The exact incidence of cutaneous CHs is not known. The pathogenesis is similarly not understood. In addition to their presence as fully formed tumors at birth, histopathologic findings clearly separate them from IHs. They lack glucose transporter-1 protein (GLUT-1), which is present in virtually all IHs. Both RICHs and NICHs have a similar histopathologic appearance of small to large lobules of capillary proliferations embedded in a dense fibrous stroma and surrounded by large dysplastic vessels.46,47 Focal thrombosis and calcifications may be seen, and stromal hemosiderin deposits are common. Clinical features Congenital hemangiomas (CHs) are fully grown at birth. They usually present as solitary, plaque-like or exophytic lesions of size varying from a few centimeters to more than 10 cm (Figure 3). Several morphologic variants of RICHs have been described: a raised violaceous soft-tissue mass with prominent draining peripheral veins; a soft-tissue mass with overlying prominent, coarse telangiectasias admixed with a blanched skin, frequently with a
halo of blanched skin at the periphery of the tumor; or a pink to violaceous soft-tissue tumor with a deeper dermal or subcutaneous infiltration. RICHs typically are warm on palpation.47 Ulceration, if present, is a worrisome finding since it can result in life-threatening hemorrhage. Transient coagulopathy with thrombocytopenia is occasionally present; however, it is not typically as sustained or severe as that seen in Kasabach–Merritt phenomenon. The involution of a RICH typically starts a few days to a few weeks after birth and, in most cases, is complete in 6–14 months. In rare instances, involution may occur in utero resulting in areas of redundancy, lack of elasticity, atrophy and hypopigmentation, or persistent telangiectasias, common outcomes in RICH after involution is completed. Other local sequelae include permanent alopecia (if in hair-bearing areas) and milia formation.43,47,48 The clinical findings in NICHs can resemble those of RICHs, but differ in that NICHs are usually less exophytic, and in many cases are flat slightly indurated round to oval plaques with an admixture of small telangiectasias and pallor as surface features. They do not resolve spontaneously and usually grow proportionately with the somatic growth. In most cases, the diagnosis of congenital hemangioma (CH) is based upon clinical findings; however, imaging studies, particularly ultrasonography and MRI, may be helpful when the diagnosis is unclear. On ultrasonography, both RICHs and NICHs show a predominantly heterogeneous sonographic structure, diffuse vascularity, high vessel density, and occasionally, calcifications,49 and high-flow MRI demonstrates heterogeneous enhancement, hyperintensity on T2-weighted sequences, flow voids, and absence of peripheral edema. Relative to IHs, CHs have less well-circumscribed borders. The differential diagnosis of congenital hemangiomas (CHs) includes other benign vascular tumors, vascular malformations, and benign and malignant nonvascular tumors.50 If the diagnosis is still uncertain, lesional biopsy for histologic examination may be needed, but it should be performed with caution in a controlled setting (e.g., an operating room), given the risk of profuse bleeding. Management is based upon tumor size and location and whether there are any complications present. For RICHs, serial observation is often the best approach. Disfigurement from residual skin changes may require surgical reconstruction. Pulsed dye
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laser treatment can be somewhat helpful in reducing the appearance of superficial telangiectasias. Most NICHs do not need treatment, but occasionally they are disfiguring or intermittent or persistent pain is present. Pulsed dye laser may help diminish superficial discoloration; however, for thicker, or more symptomatic lesions, surgical excision is the treatment of choice.
Conclusion Infantile hemangiomas are very common benign tumors of infancy seen by a diverse range of providers. Understanding the associated syndromes and anatomic anomalies is essential to ensure comprehensive care of the patient. Most hemangiomas do not require treatment as they regress spontaneously and do not leave significant residua. Ulceration, impairment of vital structures, and potential disfigurement are considered indications for treatment. The use of propranolol has changed the treatment paradigm for IH; however, it should be used judiciously, and patients must be closely monitored for adverse effects. It is important to appreciate the differences in presentation and management between congenital hemangiomas and more typical IHs. References 1. Kanada KN, Merin MR, Munden A, Friedlander SF. A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature. J Pediatr. 2012;161:240–245. 2. Greenberger S, Bischoff J. Pathogenesis of infantile hemangioma. Br J Dermatol. 2013;169:12–19. 3. Sasaki GH, Pang CY, Wittliff JL. Pathogenesis and treatment of infant skin strawberry hemangiomas: clinical and in vitro studies of hormonal effects. Plast Reconstr Surg. 1984;73:359–368. 4. Xiao X, Liu J, Sheng M. Synergistic effect of estrogen and VEGF on the proliferation of hemangioma vascular endothelial cells. J Pediatr Surg. 2004;39:1107–1110. 5. Berard M, Sordello S, Ortega N, et al. Vascular endothelial growth factor confers a growth advantage in vitro and in vivo to stromal cells cultured from neonatal hemangiomas. Am J Pathol. 1997;150:1315–1326. 6. Jinnin M, Medici D, Park L, et al. Suppressed NFAT-dependent VEGR1 expression and constitutive VEGR2 signaling in infantile hemangioma. Nat Med. 2008; 14:1236–1246. 7. Walter JW, Blei F, Anderson JL, et al. Genetic mapping of a novel familial form of infantile hemangioma. Am J Med Genet. 1999;82:77–83. 8. Boye E, Yu Y, Paranya G, et al. Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest. 2001;107:745–752. 9. Walter JW, North PE, Waner M, et al. Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer. 2002;33:295–303. 10. Metry DW, Haggstrom AN, Drolet BA, et al. A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications. Am J Med Genet A. 2006;140A:975–986. 11. Chang LC, Haggstrom AN, Drolet BA, et al. Growth characteristics of infantile hemangiomas: implications for management. Pediatrics. 2008;122:360–367. 12. Tollefson MM, Frieden IJ. Early growth of infantile hemangiomas: what parents' photographs tell us. Pediatrics. 2012;130:e314–e320. 13. Couto RA, Maclellan RA, Zurakowski D, et al. Infantile hemangioma: clinical assessment of the involuting phase and implications for management. Plastic Reconstr Surg. 2012;130:619–624. 14. Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics. 2006;118:882–887. 15. 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. 1996;132:307–311. 16. Torre M, Rapuzzi G, Carlucci M, Pio L, Jasonni V. Phenotypic spectrum and management of sternal cleft: literature review and presentation of a new series. Eur J Cardiothorac Surg. 2012;41:4–9. 17. Haggstrom AN, Garzon MC, Baselga E, et al. Risk for PHACE syndrome in infants with large facial hemangiomas. Pediatrics. 2010;126:e418–e426. 18. Metry D, Heyer G, Hess C, et al. Consensus statement on diagnostic criteria for PHACE syndrome. Pediatrics. 2009;124:1447–1456. 19. Durr ML, Meyer AK, Huoh KC, Frieden IJ, Rosbe KW. Airway hemangiomas in PHACE syndrome. Laryngoscope. 2012;122:2323–2329. 20. Hess CP, Fullerton HJ, Metry DW, et al. Cervical and intracranial arterial anomalies in 70 patients with PHACE syndrome. Am J Neuroradiol. 2010;31:1980–1986.
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Propranolol versus corticosteroids in the treatment of infantile hemangioma: a systematic review and meta-analysis. Plast Reconstr Surg. 2013;131:601–613. 27. Lou Y, Peng WJ, Cao Y, Cao DS, Xie J, Li HH. The effectiveness of propranolol in treating infantile hemangiomas: a meta-analysis including 35 studies. Br J Clin Pharmacol. 2014;78:44–57. 28. Metry D, Frieden IJ, Hess C, et al. Propranolol use in PHACE syndrome with cervical and intracranial arterial anomalies: collective experience in 32 infants. Pediatr Dermatol. 2013;30:71–89. 29. Siegel DH, Tefft KA, Kelly T, et al. Stroke in children with posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (PHACE) syndrome: a systematic review of the literature. Stroke. 2012;43:1672–1674. 30. Girard C, Bigorre M, Guillot B, Bessis D. PELVIS syndrome. Arch Dermatol. 2006; 142:884–888. 31. Iacobas I, Burrows PE, Frieden IJ, et al. LUMBAR: association between cutaneous infantile hemangiomas of the lower body and regional congenital anomalies. J Pediatr. 2010;157:795–801. 32. Stockman A, Boralevi F, Taïeb A, Léauté-Labrèze C. SACRAL syndrome: spinal dysraphism, anogenital, cutaneous, renal and urologic anomalies, associated with an angioma of lumbosacral localization. Dermatology. 2007;214:40–45. 33. Halbert AR, Chan JJ. Anogenital and buttock ulceration in infancy. Australas J Dermatol. 2002;43:1–6 [quiz 7–8]. 34. Maguiness SM, Frieden IJ. Management of difficult infantile haemangiomas. Arch Dis Child. 2012;97:266–271. 35. Drolet BA, Chamlin SL, Garzon MC, et al. Prospective study of spinal anomalies in children with infantile hemangiomas of the lumbosacral skin. J Pediatr. 2010;157:789–794. 36. Schumacher WE, Drolet BA, Maheshwari M, et al. Spinal dysraphism associated with the cutaneous lumbosacral infantile hemangioma: a neuroradiological review. Pediatr Radiol. 2012;42:315–320. 37. North PE, Waner M, Mizeracki A, Mihm MC Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol. 2000; 31:11–22. 38. Witman PM, Wagner AM, Scherer K, et al. Complications following pulsed dye laser treatment of superficial hemangiomas. Lasers Surg Med. 2006;38:116–123. 39. Schorr N, Seiff SR. Central retinal artery occlusion associated with periocular corticosteroid injection for juvenile hemangioma. Ophthalmic Surg. 1986;17: 229–231. 40. Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131: 128–140. 41. Holland KE, Frieden IJ, Frommelt PC, et al. Hypoglycemia in children taking propranolol for the treatment of infantile hemangioma. Arch Dermatol. 2010;146:775–778. 42. Elia D, Garel C, Enjolras O, et al. Prenatal imaging findings in rapidly involuting congenital hemangioma of the skull. Ultrasound Obstet Gynecol. 2008;31: 572–575. 43. Boon LM, Enjolras O, Mulliken JB. Congenital hemangioma: evidence of accelerated involution. J Pediatr. 1996;128:329–335. 44. Enjolras O, Mulliken JB, Boon LM, et al. Noninvoluting congenital hemangioma: a rare cutaneous vascular anomaly. Plast Reconstr Surg. 2001;107:1647–1654. 45. Nasseri E, Piram M, McCuaig CC, Kokta V, Dubois J, Powell J. Partially involuting congenital hemangiomas: a report of 8 cases and review of the literature. J Am Acad Dermatol. 2014;70:75–79. 46. North PE, Waner M, James CA, et al. Congenital nonprogressive hemangioma: a distinct clinicopathologic entity unlike infantile hemangioma. Arch Dermatol. 2001;137:1607–1620. 47. Berenguer B, Mulliken JB, Enjolras O, et al. Rapidly involuting congenital hemangioma: clinical and histopathologic features. Pediatr Dev Pathol. 2003; 6:495–510. 48. Lopez-Gutierrez JC, Diaz M, Ros Z. Giant rapidly involuting congenital hemangioma of the face: 15-year follow-up. Arch Facial Plast Surg. 2005;7:316–318. 49. Gorincour G, Kokta V, Rypens F, et al. Imaging characteristics of two subtypes of congenital hemangiomas: rapidly involuting congenital hemangiomas and non-involuting congenital hemangiomas. Pediatr Radiol. 2005;35:1178–1185. 50. Frieden IJ, Rogers M, Garzon MC. Conditions masquerading as infantile haemangioma: part 2. Australas J Dermatol. 2009;50:153–168. 51. Luu M, Frieden IJ. Haemangioma: clinical course, complications and management. Br J Dermatol. 2013;169:20–30.
Contents lists available at ScienceDirect
Seminars in Pediatric Surgery journal homepage: www.elsevier.com/locate/sempedsurg
Infantile and congenital hemangiomas Marilyn G. Liang, MDa, Ilona J. Frieden, MDb,n a b
Dermatology Program, Boston Children's Hospital, 300 Longwood Ave, Boston, Massachusetts 02115 Department of Dermatology, University of California San Francisco, San Francisco, California
a r t i c l e in f o
abstract
Keywords: Infantile hemangioma Congenital hemangioma PHACE LUMBAR PELVIS Propranolol
Infantile hemangiomas (IHs) are the most common benign vascular tumors of infancy. Since they predominantly involute without significant residua, the majority do not require treatment. Indications for intervention include ulceration, prevention of disfigurement, and impairment of function or vital structures. Some IHs have associated structural anomalies. When and which IH to treat requires knowledge of the natural history and clinical findings of increased risk. Congenital hemangiomas (CHs) are fully formed at birth. They also differ from IHs in their histological and immunohistochemical findings and thus represent a distinct clinical entity. Their clinical characteristics and management are also discussed. & 2014 Elsevier Inc. All rights reserved.
Introduction The term “hemangioma” has been used both correctly and incorrectly in the literature for a variety of vascular lesions. Infantile hemangiomas (IHs) are vascular tumors, usually absent at birth or present as a premonitory mark with rapid post-natal growth followed by slow involution. IHs are the most common tumor of infancy and childhood, occurring in 4% of children.1 While many clues have emerged regarding pathogenesis, many questions still remain. Therapy has changed dramatically in the past 5 years, and early treatment is critical for those requiring systemic medications as many interventions limit proliferation.
Infantile hemangioma Pathogenesis The pathogenesis of IH is not completely understood and is likely multifactorial. Several reviews have summarized recent advances.2 IHs are more common in females, supporting the hypothesis that estradiol increases endothelial cell proliferation.3 Vascular endothelial growth factor (VEGF), more than estradiol, invoked hemangioma-derived endothelial cell (HemEC) proliferation, but the combination of VEGF and estradiol was synergistic.4
Stromal cells isolated from proliferating IHs release VEGF.5 VEGF can bind receptors, such as vascular endothelial growth factor receptor (VEGFR)-2, which are expressed on proliferating IHs and HemECs and then can stimulate growth.6 There is increasing evidence that IHs arise due to an intrinsic defect in an endothelial or progenitor cell, through either a somatic (post-zygotic) mutation or a germline mutation.6 Twin studies showed no differences in concordance between monozygotic and dizygotic twins; however, there is a report of 3 families with autosomal-dominant inheritance of IH and linkage to 5q.7 Some evidence suggests that IHs are clonal tumors; HemECs from proliferating IHs in female infants display a nonrandom pattern of X-chromosomal inactivation.8 In contrast, non-endothelial cells showed a mixed inactivation pattern. Walter et al.9 also found clonality from cells in hemangioma tissue sections. Clonality in both tissue sections and in isolated HemECs supports the theory that genetic alterations, possibly somatic mutations, cause IH. In addition, IH can be associated with structural malformations, also suggesting early post-zygotic somatic mutation. Jinnin et al.6 identified mutations in the integrin-like receptor tumor endothelial marker 8 (TEM8) and in VEGFR-2 in a subset of HemECs and corresponding blood samples from patients with IHs. These “risk-factor” germline mutations may contribute to IH. Clinical
Disclosure: Pierre Fabre investigator and advisory board (MGL). Pierre Fabre consultant (IJF). n Corresponding author. E-mail address: [email protected] (M.G. Liang). http://dx.doi.org/10.1053/j.sempedsurg.2014.06.017 1055-8586/& 2014 Elsevier Inc. All rights reserved.
IHs are the most common tumor of infancy and childhood, with approximately 4% incidence in Caucasian infants. Many have a premonitory mark at birth (e.g., pale macule with telangiectasias,
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mottled vascular stain, or bruise-like area). Most superficial IHs are evident by 1–4 weeks of age while deep IHs often present at 2–3 months of age. Dependent on location, tumors may be brightly erythematous macules, papules, or plaques (superficial) or blue nodules (deep) or exhibit a combination of these features. Ulceration is the most common complication, is more common in perioral and perineal sites, and may even be the presenting finding before the development of an obvious IH.
anatomy and disfigure with fibrofatty residua, anetoderma, atrophy, erythema, hypopigmentation, and telangiectasias. Ulceration almost always causes scarring. Nasal tip lesions may splay the underlying cartilage, and revision is often necessary to correct the deformity. Ulceration of the columella and helix may also destroy the cartilage of the nasal septum and helix, respectively.
Epidemiology and natural history
Periorbital IHs may cause visual impairment most commonly by deformation of the cornea causing astigmatism. Other rarer ocular complications include visual axis obstruction, proptosis, and strabismus. Perioral IHs, particularly when ulcerated, may impair feeding. Patients with regional IHs in a lower facial, “beard” distribution are at risk for upper airway and subglottic involvement. Infants present within the first few weeks of life with noisy breathing, stridor, hoarse cry, and difficulty feeding. Ulcerated IHs of the perianal area may damage the anal sphincter and cause incontinence. Other severe complications include congestive heart failure with liver IH, visceral hemorrhage, abdominal compartment syndrome, gastrointestinal bleeding, and hypothyroidism.
Increased risk factors for IH include Caucasian race, female gender, prematurity, low birth weight, and being the product of multiple gestations. The female predominance is even higher in patients with PHACE association, 7:1.10 IHs classically grow in early infancy followed by spontaneous involution. IHs reach 80% of their final size by a mean age of 3 months11; however, many superficial IHs have an accelerated growth phase between 4 and 7 weeks, and many have completed the majority of growth by 2 months.12 Deep IHs typically appear 1 month later and proliferate for longer than superficial IHs. Rarely, some IHs have minimal proliferation, termed IHs with minimal or arrested growth (Figure 1). Based on these growth characteristics, initiation of systemic therapies—if needed—should ideally be initiated prior to 3 months of age. Involution gradually occurs over several years but in most cases is nearly complete by the age of 4 years.13 Risk stratification Because IHs are so heterogeneous in size, location, and growth characteristics, an approach to stratifying their risk of potential complications is needed (Table 1). Regional (also known as “segmental”) IHs are much more likely to develop complications, including ulceration, bleeding, visual compromise, auditory compromise, cardiac compromise, or airway obstruction, than localized IHs.14 Ulceration is the most common complication of IHs, occurring in approximately 10–15% of patients, usually developing by 4 months of age. Pain, bleeding, rarely profuse, and occasionally infection may complicate ulceration. Liver and airway are the most common extracutaneous sites. In general, patients with 5 or more IHs are screened for liver IHs by abdominal ultrasound. Other complications related to syndromic associations are discussed below. Disfigurement Permanent scarring and disfigurement are the most common adverse sequelae of IHs. Large facial IHs frequently distort normal
Fig. 1. Arrested IH in an infant with PHACE. (Color version of figure is available online.)
Impairment of function
Syndromes associated with infantile hemangiomas Although most infantile hemangiomas occur solely as a cutaneous disease or—less frequently—with hepatic hemangiomas, a subset of these have associated structural abnormalities, several of which are highly relevant to surgical practice. These occur primarily in association with segmental IHs, which involve an anatomic territory, rather than arising from a single spatially confined focus (i.e., localized IH).14 Conceptually, these associations can be divided into 2 major malformation groupings: PHACE association (OMIM 606519), where IHs primarily involve the face and to a less extent the ventral torso and extremities, and LUMBAR association, a constellation of anomalies with IHs involving the lower body. PHACE association The acronym PHACE refers to posterior fossa brain malformations, hemangiomas of the face (typically large and segmental), arterial anomalies, cardiac anomalies, and coarctation of the aorta, and eye abnormalities.15 The association is referred to as “PHACES” when ventral developmental defects, such as sternal clefting or supraumbilical raphe, are present. Surgeons will often be called upon to manage the ventral developmental defects in PHACE, which are typically identified at birth. These ventral anomalies have also been called “sternal malformation/vascular dysplasia association.”16 The cause of PHACE remains unknown. For unclear reasons, PHACES has a stronger female predominance (between 5:1 and 9:1) relative to the 3:1 as seen in IH in general.17 Unlike IH, prematurity is not a specific risk factor, though it is also not per se protective against PHACE. The distribution of cutaneous hemangiomas and ventral developmental defects point to a so-called developmental field defect occurring between 4 and 6 weeks of gestational age as the likely explanation for this association.14 While the precise incidence of PHACE is not known, in a prospective study of 108 patients with facial hemangiomas larger than 22 cm2, all of whom had systematic investigation with MRI/ MRA of the head and neck, echocardiogram, and eye examination, 31% met diagnostic criteria.17 Consensus diagnostic criteria for PHACE have been proposed18 (Table 2). Approximately 90% of patients with PHACE have more than 1 extracutaneous manifestation; however, most do not have all of the findings indicated by the acronym PHACE.17 Other key features of PHACE of relevance to surgeons include an unexpectedly
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Table 1 Risk stratification of infantile hemangiomas (Modified from Luu and Frieden).51 Level of risk
Clinical features
Risk/rationale for concern
Low
Trunk, arms, and legs (in areas covered by clothing) o 5 cm
Low risk for disfigurement of functional compromise
Intermediate
Segmental 4 5 cm trunk, arm, and leg
Risk for ulceration Risk of permanent residual skin changes Ulceration risk Risk of disfigurement Lower but possible risk of functional compromise and/or ulceration
Body folds (neck, perineum, and axillae) Lateral face, scalp, hands, and feet High
Face—prominent dermal thickening or central facial
Permanent skin changes High risk of disfigurement Functional compromise and high risk of permanent disfigurement Associated structural anomalies (PHACE) High scarring risk Visual/airway compromise Associated structural anomalies (LUMBAR) Ulceration risk
Periorbital, perinasal, and perioral Segmental 4 5 cm face
Segmental 4 5 cm lumbosacral/perineum
high incidence of airway hemangiomas,19 microphthalmia, and other structural eye abnormalities including so-called morning glory disc anomaly. Cerebrovascular changes are the most common extracutaneous manifestation of PHACE, primarily dysgenesis, narrowing, anomalous course, or nonvisualization of the anterior cerebral circulation. The findings are typically ipsilateral to the IH.20 In a recent report of 150 patients in a PHACE Registry, 41% had cardiovascular anomalies, the most common of these were aberrant origin of the subclavian artery (21%) and coarctation of the aorta (19%). The aortic coarctation seen with PHACE is distinctive, most often involving long-segment narrowing of the transverse aorta without associated valvular disease. Intracardiac defects, most commonly, ventricular septal defects, can be seen but typically do not require intervention.21 The ventral developmental defects, seen in approximately 20–25% of patients are most commonly sternal malformations and supraumbilical raphe. The extent of severity varies from small sternal pits to extensive open defects requiring surgical correction. These are present at the time of birth, even before the hemangiomas become evident and thus may be the first presenting finding
in PHACE. Rarely other anomalies such as endocrinopathies including hypopituitarism, growth hormone deficiency, and hypothyroidism have been reported as has sensorineural hearing loss.22,23 Management is typically multidisciplinary, depending on the organ systems affected. In our experience, most patients with PHACE have IHs requiring systemic therapy for management of aggressive growth or ulceration. Propranolol has emerged as a first-line treatment of IHs, including several analyses that have demonstrated favorable outcomes compared with corticosteroids, the previous gold standard.24–27 However, caution should be taken in initiating propranolol in the setting of segmental IHs without adequate assessment of the cerebral vasculature (with MRI and MRA) and evaluation for cardiac and aortic anomalies (with echocardiogram or MRA). Although safe use of propranolol has been documented in a number of patients with PHACES,28 caution should be used; severe arterial or aortic disease could be a relative contraindication to the use of a beta-blocker or alternatively cause clinicians to proceed more cautiously to avoid hypotension which could precipitate an ischemic event (e.g., stroke).29
Table 2 Diagnostic criteria for PHACES (Adapted from Metry et al.)10 Definite PHACE: Facial hemangioma 45 cm in diameter plus 1 major criterion or 2 minor criteria Possible PHACE: Facial hemangioma 45 cm in diameter plus 1 minor criterion Hemangioma of the neck or upper torso plus 1 major criterion or 2 minor criteria No hemangioma plus 2 major criteria Organ system
Major criteria
Minor criteria
Cerebrovascular
Anomaly of major cerebral arteries Dysplasia Stenosis/occlusion Hypoplasia/aplasia Aberrant origin Persistent trigeminal artery Saccular aneurysm
Persistent embryonic artery other than trigeminal artery
Structural brain
Posterior fossa anomaly
Intracranial hemangioma Midline anomaly Neuronal migration disorder
Cardiovascular
Aortic arch anomaly Coarctation or aortic dysplasia Aberrant subclavian artery
Ocular
Posterior segment abnormality
Anterior segment abnormality
Ventral/midline
Sternal defect or supraumbilical raphe
Hypopituitarism Ectopic thyroid
Dandy–Walker complex
Ventricular septal defect Right aortic arch
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LUMBAR association
Imaging
While PHACE association is seen almost exclusively with facial IH, a group of structural anomalies can also be seen in association with lower body IH. This group of anomalies has been variously called “LUMBAR” syndrome (lower body infantile hemangiomas, urogenital anomalies and ulceration, myelopathy, bony deformities, anorectal malformations and arterial anomalies, and rectal anomalies), PELVIS syndrome (perineal hemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag), and SACRAL syndrome (spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal and urologic anomalies, associated with “angioma” of lumbosacral localization).30–32 Of these acronyms, we prefer LUMBAR association in part because the highest risk area for spinal dysraphism is overlying the lumbosacral skin rather than the sacrum (Figure 2). Surgeons may be called upon to manage patients with LUMBAR due to several structural anomalies such as imperforate anus, abnormal genitalia, or cutaneous anomalies in association with spinal dysraphism. The initial presenting findings may be anal or genitourinary anomalies, with cutaneous evidence of hemangiomas developing days to weeks later. Often clues to the presence of a segmental hemangioma are visible in the form of premonitory marks such as areas of surrounding skin with blanching, telangiectasias, and vascular stain, with or without ulceration. Skin ulceration occurs in up to 50% of infants with perineal hemangiomas and can be a particularly difficult management issue.33,34 In addition to visible structural anomalies, infants with large or segmental IHs in the lumbosacral area have a high risk of tethered spinal cord and intraspinal hemangiomas and require further evaluation including MRI of the spine. In a recent prospective study, 50% of infants with IH overlying the lumbosacral area were found to have an associated intraspinal abnormality. Ultrasound was not as sensitive as MRI in detecting these anomalies.35 In very young infants (o3 months old), MRI may not be sensitive enough to detect tethered spinal cord, so if no sinus tracts or symptoms are present, consideration of deferring MRI to 4–6 months may be considered, or alternatively, repeat imaging may be considered in patients where there is a high index of suspicion of spinal dysraphism.36
A majority of IHs can be diagnosed clinically. Occasionally, deep IHs or hepatic lesions may be difficult to diagnose, and imaging can be helpful to distinguish vascular tumors from neoplastic lesions. Ultrasonography with Doppler study demonstrates a highflow pattern characteristic of IHs, differentiating them from solid tumors and vascular malformations. Magnetic resonance imaging (MRI) of IHs demonstrates a well-circumscribed, densely lobulated mass with an intermediate signal intensity on T1-weighted images and a moderately hyperintense signal on T2-weighted images. IHs also show contrast enhancement on MRI. Pathology If clinical and/or imaging are atypical, histopathology may be helpful for diagnosis. Hemangiomas are comprised of densely packed endothelial cells that form small capillaries. IHs have plump endothelial cells and endothelial proliferation, most marked during the growth phase, with a lobular architecture. Immunohistochemical staining for glucose transporter-1 protein (GLUT-1) is positive in IH endothelial cells and is negative in other vascular anomalies.37 Management A major challenge in managing IH is identification of which hemangiomas require treatment and which can be left to involute spontaneously without treatment (Table 1). Active observation and anticipatory guidance, “active non-intervention,” is the most common therapy. Parents are often distressed when no therapy is instituted, and numerous discussions may be needed on the natural history of IH and timing of possible therapies. Local therapies Ulceration is the most common complication of IH and should be treated to limit scarring, pain, and secondary infection. Topical antibiotics, occlusive dressings, pain medication, and/or oral antibiotics may be needed. Pulsed dye laser is sometimes useful to limit pain and accelerate healing; however, it may also initiate ulceration.38 Topical timolol and intralesional corticosteroid treatment may be useful in proliferating, small, focal IHs. Triamcinolone acetonide is the most frequently used, monthly only during the early proliferative phase. Corticosteroid injection on the eyelid has very rarely been associated with blindness by occlusion of the central retinal or ophthalmic arteries.39 Systemic therapies
Fig. 2. IH in an infant at risk for LUMBAR association. (Color version of figure is available online.)
The first-line treatment for IHs requiring systemic therapy is oral propranolol, which has largely replaced oral corticosteroids, the previous “gold standard.” Side effects of propranolol include hypotension, wheezing, hypoglycemia, bradycardia, sleep disturbance, somnolence, cool extremities, diarrhea, and gastroesophageal reflux. There are various approaches regarding method of initiation, dose, frequency, and monitoring of propranolol. Guidelines suggest outpatient initiation for infants older than 8 weeks of gestationally corrected age without co-morbid conditions, pretreatment electrocardiogram, 1–3 mg/kg/day divided 3 times daily, and blood pressure and heart rate monitoring for 2 h after initial dose and significant dose increases.40 Symptomatic hypoglycemia and hypoglycemic seizures have been reported and are wellknown side effects of propranolol.41 Rather than routine glucose monitoring, most experts recommend frequent feeding, cessation of medication if an infant is fasting or eating poorly, and not
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allowing prolonged periods of sleep as prevention strategies. Propranolol is given for the entire proliferative phase, often for 1 year or longer. Recurrence occurs in approximately 25% of patients, with those with deep IHs being at the highest risk for recurrence. Other systemic medications for IHs include corticosteroids, interferon, and vincristine. Side effects of corticosteroids include gastric irritation, delayed growth, irritability, Cushingoid facies, and hypertension. Hypertrophic cardiomyopathy, steroid myopathy, and pneumocystis carinii pneumonia are rarely reported. The most worrisome side effect of interferon is spastic diplegia. Vincristine requires a central line and may cause peripheral neuropathy, constipation, jaw pain, anemia, and leukopenia. Lesions that obstruct function, such as upper eyelid or airway hemangiomas, may be excised during the proliferative phase if failed or unable to use pharmacologic therapy. Excision may be needed in the involuting phase if permanent skin changes have occurred such as scarring or sessile IHs. In the involuted phase, pulsed dye laser therapy is useful for residual telangiectasias and erythema, fractionated laser may be used to improve some textural changes, and excision may be desired to treat fibrofatty residua, anetoderma, or scarring. IHs that have a steep ascent from normal to involved skin have the greatest risk for anetoderma skin changes. Fig. 3. Large RICH on the scalp of an infant. (Color version of figure is available online.)
Congenital hemangiomas—Rapidly and non-involuting Unlike infantile hemangiomas, which are very common, congenital hemangiomas (CHs) are uncommon vascular tumors. In contrast to infantile hemangiomas, which are either absent or present as a premonitory mark, CHs are present and fully grown at birth. They often present as a thickened plaque or exophytic mass, located on the head, neck, or extremities. They may even be diagnosed or at least suspected in utero usually during the third trimester of pregnancy.42 Based upon their natural history, 2 major subtypes of CHs have been recognized: rapidly involuting congenital hemangiomas (RICHs) and non-involuting congenital hemangiomas (NICHs).43,44 However, this binary division has recently been called into question as some RICHs do not involute completely, rather they flatten but persist in a partially involuted state, resembling NICHs in most other respects.45 The majority of RICHs involute by 1 year of age rather than by age 4–6 years as seen in IHs. In most cases, RICHs involute completely by the age of 14 months, whereas NICHs do not regress but grow in proportion with the child and may require eventual excision. The exact incidence of cutaneous CHs is not known. The pathogenesis is similarly not understood. In addition to their presence as fully formed tumors at birth, histopathologic findings clearly separate them from IHs. They lack glucose transporter-1 protein (GLUT-1), which is present in virtually all IHs. Both RICHs and NICHs have a similar histopathologic appearance of small to large lobules of capillary proliferations embedded in a dense fibrous stroma and surrounded by large dysplastic vessels.46,47 Focal thrombosis and calcifications may be seen, and stromal hemosiderin deposits are common. Clinical features Congenital hemangiomas (CHs) are fully grown at birth. They usually present as solitary, plaque-like or exophytic lesions of size varying from a few centimeters to more than 10 cm (Figure 3). Several morphologic variants of RICHs have been described: a raised violaceous soft-tissue mass with prominent draining peripheral veins; a soft-tissue mass with overlying prominent, coarse telangiectasias admixed with a blanched skin, frequently with a
halo of blanched skin at the periphery of the tumor; or a pink to violaceous soft-tissue tumor with a deeper dermal or subcutaneous infiltration. RICHs typically are warm on palpation.47 Ulceration, if present, is a worrisome finding since it can result in life-threatening hemorrhage. Transient coagulopathy with thrombocytopenia is occasionally present; however, it is not typically as sustained or severe as that seen in Kasabach–Merritt phenomenon. The involution of a RICH typically starts a few days to a few weeks after birth and, in most cases, is complete in 6–14 months. In rare instances, involution may occur in utero resulting in areas of redundancy, lack of elasticity, atrophy and hypopigmentation, or persistent telangiectasias, common outcomes in RICH after involution is completed. Other local sequelae include permanent alopecia (if in hair-bearing areas) and milia formation.43,47,48 The clinical findings in NICHs can resemble those of RICHs, but differ in that NICHs are usually less exophytic, and in many cases are flat slightly indurated round to oval plaques with an admixture of small telangiectasias and pallor as surface features. They do not resolve spontaneously and usually grow proportionately with the somatic growth. In most cases, the diagnosis of congenital hemangioma (CH) is based upon clinical findings; however, imaging studies, particularly ultrasonography and MRI, may be helpful when the diagnosis is unclear. On ultrasonography, both RICHs and NICHs show a predominantly heterogeneous sonographic structure, diffuse vascularity, high vessel density, and occasionally, calcifications,49 and high-flow MRI demonstrates heterogeneous enhancement, hyperintensity on T2-weighted sequences, flow voids, and absence of peripheral edema. Relative to IHs, CHs have less well-circumscribed borders. The differential diagnosis of congenital hemangiomas (CHs) includes other benign vascular tumors, vascular malformations, and benign and malignant nonvascular tumors.50 If the diagnosis is still uncertain, lesional biopsy for histologic examination may be needed, but it should be performed with caution in a controlled setting (e.g., an operating room), given the risk of profuse bleeding. Management is based upon tumor size and location and whether there are any complications present. For RICHs, serial observation is often the best approach. Disfigurement from residual skin changes may require surgical reconstruction. Pulsed dye
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laser treatment can be somewhat helpful in reducing the appearance of superficial telangiectasias. Most NICHs do not need treatment, but occasionally they are disfiguring or intermittent or persistent pain is present. Pulsed dye laser may help diminish superficial discoloration; however, for thicker, or more symptomatic lesions, surgical excision is the treatment of choice.
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