DOI: 10.1111/j.1468-3083.2010.03650.

JEADV

REVIEW ARTICLE

Infantile haemangiomas: a challenge in paediatric dermatology

RA Schwartz,,* MI Sidor, ML Musumeci, RL Lin, G Micali

Dermatology, Pediatrics, Pathology and Preventive Medicine and Community Health, New Jersey Medical School, Newark, NJ, USA Department of Dermatology, New Jersey Medical School, Newark, NJ, USA Department of Dermatology, University of Catania, Italy *Correspondence: RA Schwartz. E-mail: roschwar@cal.berkeley.edu

Abstract
Infantile haemangiomas, common benign vascular tumours of childhood, are characterized by rapid growth during the rst year of life and a slow regression that is usually completed at 710 years of age. These tumours are composed of endothelial cells with high mitotic rates and stromal components such as broblasts, mast cells and pericytes. Haemangiomas become a challenge when they are part of a syndrome, are located in certain areas of the body or when complications develop. The above-mentioned factors also inuence the treatment modality used. However, although there remain many uncertainties regarding management, the b-adrenergic receptor blocker propranolol is a promising new candidate for rst-line systemic therapy. It produces such a dramatic and rapid response that the appearance of an infantile haemangioma should impart expeditious consideration of the risks and benets of its use. Received: 28 May 2007; Accepted: 27 December 2007

Keywords
paediatrics, vascular neoplasms

Conict of interest
None declared.

Introduction
Infantile haemangiomas (IHs) are the most common tumours of childhood. They are composed of endothelial cells with high mitotic rates and stromal components such as broblasts, mast cells and pericytes. IHs are characterized by rapid growth during the rst year of life (proliferating phase) and a slow regression that is usually completed at 710 years of age (involuting phase). Histological ndings seen during the proliferating phase include the presence of masses of compact capillaries lined by plump, rapidly dividing endothelial cells with and without lumens.1 As they involute, their vascular lumens dilate, endothelial cells atten and brous tissue is deposited. Microscopic examination of residual tissue shows a dense stroma of brofatty tissue, collagen and reticulin bres with few feeding and draining vessels.2 The term IH should be employed only for the benign vascular tumour described here. These vascular neoplasms are often rst evident as cutaneous birthmarks, as are vascular malformations. To differentiate these two entities, criteria were developed by Mulliken and Glowacki.1 The latest, modied version has been accepted by the International Society for the Study of Vascular

Anomalies. According to this set of criteria, vascular tumours are characterized by endothelial proliferation and rapid postnatal growth followed by involution.3 Vascular malformations have normal endothelial cell cycle and enlarge commensurately with child growth.

Epidemiology
Among the Caucasian population, IHs are present in 1.12.6% of neonates and in 1012% of infants by 12 months of age. The frequency is increased in preterm infants. The female to male ratio is variable from 1.4:1 to 4:1.36 A 21% incidence of IHs has been reported in infants who were subject to chorionic villus sampling.7 IHs are less common in those of African American or Asian descent than among Caucasians.8

Aetiology, pathology and genetics

Early growth of IHs is characterized by clonal expansion of endothelial cells and neovascularization.9 Markers for progenitor endothelial cells have been studied in these benign tumours. CD 133-2 is a progenitor endothelial cell marker increased in proliferating

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IHs, but not in involuted ones.9 Vascular endothelial growth factor and basic broblast growth factor play a role in angiogenesis.9,10 Expression of these factors is also increased in proliferating IHs, but not in involuted IHs. Transforming growth factor beta-1 expression is not changed and remains low in IHs.9 Abnormal changes in angiogenesis were also attributed to an increase in factors such as proliferating cell nuclear antigen, E selectin, insulin like growth factor 2 and type IV collagenase during the proliferative phase.1012 IHs have unique markers that are also expressed in placental tissue, but not found in other vascular neoplasms or in normal skin.13 These tissue-specic markers include glucose transporter 1, Lewis Y antigen, Fc gamma receptor II and merosin.13 The nding of shared antigens with placental tissue led to speculation that IHs develop either because of angioblasts abnormally differentiating toward placental vascular phenotypes or because of direct placenta cell embolization to foetal tissues. The second theory would coincide with the nding of increased IHs in infants subjected to chorionic foetal sampling in utero.7,1315 Identication of high levels of indoleamine 2,3-dioxygenase (IDO) in proliferating IHs raises the possibility of immune system involvement in progression of these benign tumours. IDO is an enzyme that catabolizes tryptophan, deprivation of which sensitizes T cells to death by apoptosis.16 T-cell proliferation in vitro is suppressed by cells expressing IDO.17 These ndings suggest that T-cell inhibition could play a role in the slow regression of IHs. Further support to the role of the immune system in the involution of IHs is given from reports in which topical application of imiquimod, an immune modulator that stimulates the activity of T cells, macrophages and natural killer cells, accelerated regression of proliferating IHs.18,19 The angiopoietin Tie system, known to play a critical role in embryonic vascular development, was investigated as a possible factor in pathogenesis of IHs. Changes to this system, which are specic for these benign tumours, include an increase in Tie 2 receptors, enhanced cellular responsiveness to angiopoietin 1 and altered regulation of angiopoietin 2.20 Mutational events account for a small portion of cases of IHs, which are believed to be mostly due to developmental errors that occur between the 4th week and 10th week of gestation.7 Autosomal dominant inheritance of this tumour was also reported in rare instances.21 Loss of heterozygosity on a specic locus of chromosome 5 was linked to development of IHs. Genes mapped to this locus include broblast growth factor receptor-4, platelet derived growth factor receptor-beta, and fms-related tyrosine kinase-4.22

maximum size; involution begins approximately at 12 18 months.23 In many infants, the growth phase of an IH begins just after birth; involution may start as soon as 36 months. The appearance of a supercial IH changes during the involuting phase. It becomes softer to palpation and changes coloration from red to grey. The rst signs of involution can be seen in its centre. After involution, brous and fatty tissue may persist. Involution occurs at a rate of about 10% per year and is usually complete when the child is 710 years old.24 It is difcult to predict the outcome, but 50% of patients will have residual changes.24,25 These alterations include telangiectasia, yellowish discolouration, atrophic wrinkling and alopecia.26

Clinical aspects
The appearance of IHs depends on their location within the skin. Those situated in the supercial dermis (supercial type IHs), because of their appearance as bright-red, raised nodules, are commonly termed strawberry haemangiomas (Fig. 1). IHs deep in the reticular dermis give an appearance of soft masses with a bluish tone with normal overlying skin (Fig. 2). In some instances, this neoplasm may have both supercial and deep elements (mixed type haemangioma). Supercial types of IHs are classied into localized and segmental forms. Localized IHs are generally small, whereas segmental IHs display a linear and or geographical distribution and typically cover an anatomic territory (Fig. 3). Clinically, they are more at and plaque like.27 Segmental IHs have a markedly higher risk of being life- or function-threatening and or having associated structural anomalies; they generally require more intensive and prolonged therapy and are linked with a poorer outcome.8 Children of Hispanic descent are more likely to have segmental ones than whites. Infants with facial segmental haemangiomas are also at

Growth characteristics
The course of IHs includes three stages: proliferating, involuting and involuted. In 30% of neonates, IHs are evident at birth. At 36 months of life, the growth phase begins and continues until 912 months of age. At this time, the IH usually reaches its

Figure 1 Supercial infantile haemangioma.

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Figure 2 Deep infantile haemangioma on the nose.

distinct categories of disease. Benign haemangiomatosis is asymptomatic or has no visceral involvement. It has a relatively good prognosis with complete regression often occurring by 3 years of age.30,31 In disseminated haemangiomatosis, visceral involvement may lead to life-threatening complications such as high output congestive heart failure, haemorrhage from haemangiomas of the gastrointestinal or respiratory tract, consumptive coagulopathy or obstructive hydrocephalus.32,33 The liver is the most commonly involved organ, but any other viscera can be affected. Disseminated neonatal haemangiomatosis may include cases with benign liver IHs, not complicated, involuting in about a year, with no need for medical treatment. This clinical presentation is far more frequent than with severe hepatic involvement. Patients with disseminated haemangiomatosis need appropriate imaging studies and close follow-up. Untreated mortality rates as high as 77% have been reported.26
PHACE(S) syndrome

The PHACE(S) syndrome (posterior fossa malformations, haemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities and sternal defects) includes facial IHs in association with other anomalies.34,35 All affected subjects have a segmental IH, but only one extracutaneous manifestation is needed to qualify for the diagnosis.36,37
SACRAL syndrome

The acronym SACRAL syndrome stands for IHs of lumbosacral localization in association with spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal and urological anomalies.38
PELVIS syndrome

Figure 3 Segmental infantile haemangioma.

Large perineal haemangiomas may constitute a distinctive group. The characteristic ndings of the PELVIS syndrome are perineal haemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus and skin tags.39

increased risk for extra-cutaneous haemangiomas that may occur anywhere, not restricted to the cephalic area.28 In general, 59% of IHs occur on the head and neck, 24% on the trunk, 10% on the lower extremities and 7% on upper extremities.24 Most are less than 2.0 cm in diameter with an appearance ranging from hypopigmented to bruise-like macules.25

Complications
Most IHs are not dangerous. In rare instances, they can lead to serious or life-threatening complications, especially if involving the airway, eye, lumbosacral region and liver (Table 1).27 Laryngeal involvement may be serious because of potential airway obstruction, rst evident in infants as a croup-like cough and progressive biphasic stridor. There may be an increased risk of airway involvement with IHs of mandible and neck.40 Infants should be observed closely for respiratory distress and evaluated with direct laryngoscopy if needed. Periorbital IHs have an adverse impact on the visual axis. Obstruction of the visual axis results in stimulus deprivation amblyopia.41,42 Pressure on the cornea can lead to astigmatism, which can cause permanent amblyopia. Other ophthalmic

Syndromes in association with IHs

IHs may be a part of a larger syndrome, becoming an additional challenge.
Haemangiomatosis

Haemangiomatosis is a condition characterized by multiple IHs. They appear bright red and range from a few to hundreds.29 Benign and disseminated neonatal haemangiomatosis are two

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Table 1 Sites at high risk for complications of infantile haemangioma

Sites Head, neck, perineum, lip Airway Eye Complications Ulceration Airway obstruction Astigmatism, amblyopia, tear duct obstruction, proptosis, ptosis, strabismus and myopia Spinal dysraphism, tethered spinal cord and genitourinary anomalies Hepatomegaly, congestive heart failure, thyroid abnormalities

Lumbosacral region Liver

complications associated with periorbital IHs include tear duct obstruction, proptosis, ptosis, strabismus and myopia.4143 Infants with these IHs are in need of immediate ophthalmological evaluation. Patients with lumbosacral IHs should be evaluated for spinal dysraphism, tethered spinal cord and genitourinary anomalies. Initially, infants may be asymptomatic, but progressive neurological damage will take place if a tethered cord is not released. Magnetic resonance imaging (MRI) is the study of choice for evaluation of spinal cord IHs. Spinal dysraphism syndrome includes anomalies such as abnormal genitalia, rectal stulas, anorectal and renal abnormalities.44,45 Liver involvement may lead to hepatomegaly or congestive heart failure (CHF) or may be asymptomatic.46,47 If a child has jaundice, the possibility of porta hepatis obstruction should be considered.46,47 Initial management should involve systemic corticosteroid treatment. If necessary, CHF should be treated with diuretics and digitalis. Surgical intervention may include hepatic artery ligation or hepatic resection. With aggressive treatment, the mortality of this condition decreases from 80% to 20%.46,47 Thyroid abnormalities in association with hepatic IHs have been reported. Hypothyroidism can be caused by high levels of type 3 iodothyronine deiodinase activity found in haemangioma tissue.48 Even though the incidence of hypothyroidism in these tumours is low, infants with hepatic haemangiomas should be screened because untreated hypothyroidism can lead to irreversible loss of intelligence in this patient population.48 Ulceration is the most frequent complication of IHs (Fig. 4). Generally, ulceration is relatively minor; in severe cases, it can lead to soft tissue destruction and scarring, functional impairment and pain. Ulceration can be complicated by bleeding and infection. An incidence of ulceration of 12.4% (46) of 379 IHs in 317 infants has been observed at a major paediatric dermatology referral centre.49 Infants with mixed or supercial type haemangiomas should be followed closely, especially during the rst 9 months of life, when problematic ulceration is most likely to occur. Ulceration of IHs tends to occur disproportionately in segmental haemangiomas of the head and neck, and in haemangiomas of the perineum and lip, with 2435% incidence.49

Figure 4 Eroding infantile haemangioma on the arm of a child.

Evaluation
History and physical examinations are sufcient to diagnose IHs in 95% of cases.33 Laboratory tests (full blood count, liver function test and stool occult blood test) may be performed if gastrointestinal, hepatic or respiratory tract involvement is suspected, but are not indicated for the common cutaneous haemangiomas. Thyroid function screening should be considered for infants with either very large cutaneous or hepatic IHs.24 When diagnosis cannot be made based on history and physical examination, imaging studies may be utilized. The most cost-effective imaging technique is ultrasound with Doppler interrogation, but the results are operator-dependent.50 MRI with contrast use is a helpful imaging modality that can be used to localize the haemangioma and detect nervous system abnormalities.50 Tissue biopsy is not utilized widely for diagnosis because of high risk of bleeding, but is occasionally employed for differentiation of atypical haemangiomas from soft tissue and other tumours.51

Differential diagnosis
Conditions that should be taken under consideration when evaluating patients for IHs include vascular malformations such as port-wine stains and other vascular tumours, such as congenital haemangiomas52 (non-involuting53 and rapidly involuting haemangiomas), pyogenic granulomas (lobular capillary haemangiomas),54 endovascular papillary angioendotheliomas (Dabska tumours),55,56 kaposiform haemangioendotheliomas, tufted angiomas and vascularized soft-tissue tumours (myobromatosis, lipoblastoma, brosarcoma, rhabdomyosarcoma) (Table 2).

Management and Treatment

Most IHs are in anatomically neutral locations and involute without intervention. Prevention of life-threatening complications or permanent disgurement and avoidance of aggressive or scarring treatments are the goals of management. Treatment of ulceration

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Table 2 Differential diagnosis of infantile haemangiomas (IHs) of the skin

Differential diagnosis of IHs of the skin Vascular malformation Port-wine stains Vascular tumour Congenital haemangiomas (non-involuting and rapidly involuting haemangiomas) Pyogenic granulomas Endovascular papillary angioendotheliomas (Dabska tumours) Kaposiform haemangioendotheliomas Tufted angiomas Vascularized soft-tissue tumour Myobromatosis Lipoblastoma Fibrosarcoma Rhabdomyosarcoma

Table 3 Management options for infantile haemangiomas

Management options First-line therapy Corticosteroids (topical, intralesional, systemic) Propranolol Interferon-alpha (2a-2b) Laser therapy Surgical therapy Cyclophosphamide Imiquimod Vincristine Timolol maleate solution

Second-line therapy

Other therapy

is also important.49 Therapy depends on several factors including the presence of associated anomalies and life-threatening or function-threatening complications. Indications for early medical intervention include large facial IHs or those located in nose, airway or eyes. In these instances, early medical therapy may prevent life-threatening complications, severe pain or visible residual scars (Table 3).40,55,57,58 Regular follow-up visits are needed to provide continuous reassurance and monitor the course of the lesion. IHs can have a great psychological impact on the patient and parents; therefore, education about this condition plays an important role in the management. Systemic glucocorticoids are the rst-line therapy.5,59 Efcacy rates as high as 84% have been reported when doses of 2.9 mg kg of prednisone were used for IHs in the proliferative phase.60 Approximately 35% of patients will develop complications, consisting of irritability, cushingoid appearance and adrenal suppression.61 Upon completion of treatment with corticosteroids, patients require stress doses for several months to avoid adrenal crisis. Hypertension is another problem observed in infants treated with high doses of steroids.62 Intralesional triamcinolone has been utilized in treatment of periorbital IHs.63 The treatment is effective, but it is contraindicated because of the risk of retinal artery occlusion, eyelid necrosis,

temporary eyelid dyspigmentation and subcutaneous fat atrophy.63 On the contrary, fast growing haemangiomas of the lips can be treated with intralesional steroids.64 Some recommend the use of a 50:50 mix of triamcinolone (40 mg mL) and betamethasone (6 mg mL) at doses of 3 5 mg kg per treatment every 46 weeks.65,66 Topical potent class 1 corticosteroids can improve a thin supercial IH, but not a deep component. Betamethasone dipropionate 0.05%, clobetasol propionate 0.05% or halobetasol propionate are efcacious in supercial IHs and can be used relatively safely for low-risk IHs.67 Adverse reactions include cutaneous atrophy and striae.24 Interferon (IFN) alfa-2a may be indicated for IHs that did not respond to glucocorticoid therapy or for life-threatening complications.6870 Subcutaneous dose of 13 million units m2 is recommended. IFN is not used on regular basis because of the risk for neurotoxicity (agitation, irritability, seizures or permanent spastic diplegia) and side effects such as neutropenia, elevated liver enzymes, fever and malaise.6873 Laser and surgical therapies represent a therapeutic option for treatment of IH, but have a limited role.3 The ash-lamp, pumped, pulse-dye laser (FPDL) has shown some efcacy in supercial IHs and residual ones.74 Treatments are spaced at 23 week intervals for those proliferating and at 46 weeks for non-proliferating ones.54 Usual treatment consists of short pulses of light at wavelengths of 585 nm for a duration of 0.45 ms.75,76 Some of the side effects of FPDL include atrophic scarring and ulceration with subsequent pain and scarring.74,77,78 FPDL exhibits limited depth of penetration and is not indicated for deep IHs.76,77,79,80 Whether treating uncomplicated IHs with FPDL is more effective than a conservative approach is still not demonstrated.75 For deep IHs, the neodymium:yttrium-aluminiumgarnet laser has been used with promising results.80,81 Excision should be performed to produce better results than conservative or medical treatment. The optimal timing for surgical excision is still an area under discussion.3 Indications for surgical intervention include abnormal scar or excess tissue following natural involution, ulcerated neoplasms that bleed excessively or those that interfere with development and or activities such as tumours of the eye, ear or larynx.19,74,8287 Facial deformities can have a psychological impact on school-age children, a factor when deciding on the best timing for resection. A circular excision with purse-string closure, using a single 4-0 or 5-0 suture, has been reported to result in a 15% decrease in the area and 72% decrease in length of the scar when compared with a standard lenticular excision.82 There are other treatment options. Recently, low-dose cyclophosphamide has been successfully used in association with IFN alfa-2a in cases of IHs of the orbit.88 Vincristine is another therapeutic choice, currently preferred to IFN, in infants with lifethreatening cases non-responders to corticosteroids treatment.89 Imiquimod, a new topical agent, has been shown to accelerate the regression of proliferating IHs.17,90 Potential efcacy of omega-3

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fatty acids in IHs has been hypothesized but more research is needed to determine the anti-angiogenic properties of these acids.91 Since rst serendipitously observed to be of extraordinary value for IHs in 2008,92 the oral use of the b-adrenergic receptor blocker propranolol has stimulated considerable acclaim.9398 The rapid and dramatically effective results of its use, combined with favorable initial safety prole, mandate it being gingerly lauded as a new rst-line therapy. Oral propranolol given 2 to 3 mg per kg per day produces with 24 hours a change in IH color from intense red to purple with a softening on palpation. Dyspnea and hemodynamic compromise, if present, may regress within 48 hours. If there is palpebral occlusion, spontaneous ocular opening may occur within 7 days.97 However, the potential for death and serious cardiovascular, respiratory and other morbidity from b-adrenergic receptor blocker usage must be considered.92

References
1 Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classication based on endothelial characteristics. Plast Reconstr Surg 1982; 69: 412422. 2 Lo K, Mihm M, Fay A. Current theories on the pathogenesis of infantile hemangioma. Semin Ophthalmol 2009; 24: 172177. 3 Frieden IJ, Haggstrom AN, Drolet BA et al. Infantile hemangiomas: current knowledge, future directions. Proceedings of a research workshop on infantile hemangiomas, April 79, 2005, Bethesda, Maryland, USA. Pediatr Dermatol 2005; 22: 383406. 4 Holmdahl K. Cutaneous hemangiomas in premature and mature infants. Acta Paediatr Scand 1955; 44: 370. 5 Pandey A, Gangopadhyay AN, Gopal SC et al. Twenty years experience of steroids in infantile hemangioma a developing countrys perspective. J Pediatr Surg 2009; 44: 688694. 6 Amir J, Metzker A, Krikler R. Strawberry hemangioma in preterm infants. Pediatr Dermatol 1986; 3: 331332. 7 Burton BK, Schulz CJ, Angle B, Burd LI. An increased incidence of haemangiomas in infants born following chorionic villus sampling (CVS). Prenat Diagn 1995; 15: 209214. 8 Chiller KG, Passaro D, Frieden J. Hemangiomas of infancy: clinical characteristics, morphologic subtypes and their relationship to race, ethnicity, and sex. Arch Dermatol 2002; 138: 15671576. 9 Yu Y, Flint AF, Mulliken JB, Wu JK, Bischoff J. Endothelial progenitor cells in infantile hemangioma. Blood 2004; 103: 13731375. 10 Przewratil P, Sitkiewicz A, Andrzejewska E. Local serum levels of vascular endothelial growth factor in infantile hemangioma: intriguing mechanism of endothelial growth. Cytokine 2010; 49: 141147. 11 Takahashi K, Mulliken JB, Kozakewich HP. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest 1994; 93: 23572364. 12 Schwartz RA, Lin RL, Wei TJ, Dardik H. Arterial vascular malformations including hemangiomas and lymphangiomas. eMedicine Pediatrics [WWW document] 2010. URL http://emedicine.medscape.com/ article/1018071-overview (last accessed: 09 March 2010). 13 North PE, Waner M, Mizeracki A et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol 2001; 137: 559570. 14 North PE, Waner M, Mizeracki A, Mihm MC. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000; 31: 1122. 15 Regnier S, Dupin N, Le Danff C, Wassef M, Enjolras O, Aractingi S. Endothelial cells in infantile haemangiomas originate from the child and not from mother (a uorescence in situ hybridization-based study). Br J Dermatol 2007; 157: 158160. 16 Lee GK, Park HJ. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 2002; 107: 452460. 17 Ritter MR, Moreno SK. Identifying potential regulators of infantile hemangioma progression through large-scale expression analysis: a possible role for the immune system and indoleamine 2,3 dioxygenase (IDO) during involution. Lymphat Res Biol 2003; 1: 291299. 18 Martinez M. Infantile hemangioma: clinical resolution with 5% imiquimod cream. Arch Dermatol 2002; 138: 881884. 19 Sauder DN. Mechanism of action and emerging role of immune response modier therapy in dermatologic conditions. J Cutan Med Surg 2004; 8(Suppl. 3): 312. 20 Yu Y, Varughese J, Brown LF, Mulliken JB, Bischoff J. Increased Tie2 expression, enhanced response to angiopoietin-1, and dysregulated angiopoietin-2 expression in hemangioma-derived endothelial cells. Am J Pathol 2001; 159: 22712280. 21 Blei F, Walter J, Orlow SJ, Marchuk DA. Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. Arch Dermatol 1998; 134: 718722.

Treatment of ulceration
Treatment of ulceration falls into three categories: halt proliferation, alter the local environment and manage the associated pain.3 Local wound care is the mainstay of treatment.86,87,99 Compresses utilized for debridement of the ulcers can be used along with topical agents such as bacitracin and mupirocin.87,99 Becaplermin gel (0.01%), a recombinant human platelet derived growth factor, is approved for lower extremity diabetic neuropathic ulcers. It may be efcacious for ulcerated perineal IHs.100 Pulsed dye laser can accelerate healing.101 Remarkably, propranolol use can produce complete healing within 2 months.97

Conclusions
IHs are benign vascular tumours of childhood that develop due to abnormal changes in angiogenesis. Their pathogenesis has been studied widely with some of the processes responsible elucidated. IHs follow a predictable course with proliferative and involution phases. The outcome is difcult to predict, but approximately 50% of patients will have residual changes. These benign neoplasms are often a cause of distress for parents and may have a negative psychological impact on school-age children. Education and regular monitoring should be an important part of therapy. Follow-up should be particularly close during the proliferative phase in the rst trimesters of life to be able to determine early which IHs should be quickly and actively treated employing systemic steroids, oral propranolol, a topical steroid or beta-blocker, surgical approaches, or other options. Propranolol use imparts a consistently striking expeditious therapeutic response, shortening the natural course with good clinical tolerance. Sagacious early treatment for signicant IHs should be exhorted. Later use can be propitious prior to surgery. However, propranolol is a medication with signicant systemic effects that must be employed only when necessary and, if so, with caution and suitable monitoring.

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22 Berg JN, Walter JW, Thisanagayam U et al. Evidence for loss of heterozygosity of 5q in sporadic haemangiomas: are somatic mutations involved in haemangioma formation? J Clin Pathol 2001; 54: 249 252. 23 Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med 1999; 341: 173181. 24 Chan YC, Giam YC. Guidelines of care for cutaneous hemangiomas. Ann Acad Med 2005; 34: 117123. 25 Bowers RE, Graham EA, Tomlinson KM. The natural history of the strawberry naevus. Arch Dermatol 1960; 82: 667680. 26 Bruckner AL, Frieden IJ. Hemangiomas of infancy. J Am Acad Dermatol 2003; 48: 477493. 27 Haggstrom AN, Lammer EJ, Schneider RA, Marcucio R, Frieden IJ. Patterns of infantile hemangiomas: new clues to hemangioma patho genesis and embryonic facial development. Pediatrics 2006; 117: 698 703. 28 Metry DW, Hawrot A, Altman C, Frieden IJ. Association of solitary, segmental hemangiomas of the skin with visceral hemangiomatosis. Arch Dermatol 2004; 140: 591596. 29 Martinez-Perez D, Fein NA, Boon LM, Mulliken JB. Not all hemangiomas look like strawberries: uncommon presentations of the most common tumor of infancy. Pediatr Dermatol 1995; 12: 16. 30 Golitz LE, Rudikoff J, OMeara OP. Diffuse neonatal hemangiomatosis. Pediatr Dermatol 1986; 3: 145152. 31 Leung AK, Rafaat M. Benign neonatal hemangiomatosis. Pediatr Dermatol 2003; 20: 161163. 32 Lopriore E, Markhorst DG. Diffuse neonatal hemangiomatosis: new view on diagnostic criteria and prognosis. Acta Paediatr 1999; 88: 9397. 33 Lin RL, Schwartz RA. Hemangiomas of infancy: a clinical review. Acta Dermatovenerol Croat 2006; 14: 109116. 34 Burrows PE, Robertson RL, Mulliken JB. Cerebral vasculopathy and neurologic sequalae in infants with cervicofacial hemangioma: report of eight patients. Radiology 1998; 207: 601607. 35 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: 307311. 36 Metry D, Heyer G, Hess C et al. Consensus statement on diagnostic criteria for PHACE syndrome. Pediatrics 2009; 124: 14471456. 37 Haggstrom AN, Drolet BA, Baselga E et al. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics 2006; 118: 882887. 38 Drolet B, Garzon M. SACRAL syndrome. Dermatology 2007; 215: 360. 39 Girard C, Bigorre M, Guillot B, Bessis D. PELVIS Syndrome. Arch Dermatol 2006; 142: 884888. 40 Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a beard distribution. J Pediatr 1997; 131: 643646. 41 Verbraak FD, Schlingemann RO, de Smet MD, Keunen JE. Single spot PDT in patients with circumscribed choroidal haemangioma and near normal visual acuity. Graefes Arch Clin Exp Ophthalmol 2006; 244: 11781182. 42 Shields J. Photodynamic therapy for choroidal hemangioma. Graefes Arch Clin Exp Ophthalmol 2006; 244: 10711072. 43 Goldberg NS, Rosanova MA. Periorbital hemangiomas. Dermatol Clin 1992; 10: 653661. 44 Albright AL, Gartner JC. Lumbar cutaneous hemangiomas as indicators of tethered spinal cords. Pediatrics 1989; 83: 977980. 45 Bouchard S, Yazbeck S, Lallier M. Perineal hemangioma, anorectal malformation, and genital anomaly: a new association? J Pediatr Surg 1999; 34: 11331335. 46 Stanley P, Geer GD, Miller JH. Infantile hepatic hemangiomas: clinical features, radiologic investigations, and treatment of 20 patients. Cancer 1989; 64: 936949.

47 Boon LM, Burrows PE, Paltiel HJ. Hepatic vascular anomalies in infancy: a twenty-seven year experience. J Pediatr 1996; 129: 346 354. 48 Huang SA, Tu HM, Harney JW. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000; 343: 185189. 49 Shin HT, Orlow SJ, Chang MW. Ulcerated haemangioma of infancy: a retrospective review of 47 patients. Br J Dermatol 2007; 156: 1050 1052. 50 Burrows PE, Laor T, Paltiel H, Robertson RL. Diagnostic imaging in the evaluation of vascular birthmarks. Dermatol Clin 1998; 16: 455488. 51 Kern S, Niemeyer C, Darge K et al. Differentiation of vascular birthmarks by MR imaging. An investigation of hemangiomas, venous and lymphatic malformations. Acta Radiol 2000; 41: 453457. 52 Mulliken JB, Enjolras O. Congenital hemangiomas and infantile hemangioma: missing links. J Am Acad Dermatol 2004; 50: 875882. 53 Enjolras O, Mulliken JB, Boon LM et al. Noninvoluting congenital hemangioma: a rare cutaneous vascular anomaly. Plast Reconstr Surg 2001; 107: 16471654. 54 Lin RL, Janniger CK. Pyogenic granuloma. Cutis 2004; 74: 229233. 55 Schwartz RA. Dabska tumor. eMedicine Dermatology [WWW document] 2010. URL http://emedicine.medscape.com/article/ 1112873-overview (last accessed: 09 March 2010). 56 Schwartz RA, Dabska C, Dabska M. The Dabska tumor: a thirty-year retrospect. Dermatology 2000; 201: 15. 57 Smolinski KN, Yan AC. Hemangiomas of infancy: clinical and biologic characteristics. Clin Pediatr 2005; 44: 747766. 58 Haik BG, Karcioglu ZA, Gordon RA, Pechous BP. Capillary hemangioma (infantile periocular hemangioma). Surv Ophthalmol 1994; 38: 399426. 59 Musumeci ML, Pulvirenti N, Micali G. Trattamento degli emangiomi ` in eta pediatrica con corticosteroidi per via generale. G Ital Dermatol Venereol 2002; 137: 421426. 60 Bennett ML, Fleischer AB Jr, Chamlin SL, Frieden IJ. Oral corticosteroid use is effective for cutaneous hemangiomas: an evidence-based evaluation. Arch Dermatol 2001; 137: 12081213. 61 Boon LM, MacDonald DM, Mulliken JB. Complications of systemic corticosteroid therapy for problematic hemangioma. Plast Reconstr Surg 1999; 104: 16161623. 62 Thedenat B, Leaute-Labreze C, Boralevi F et al. Surveillance tensionelle des nourrisons traites par corticotherapie generale pour un hemangiome. Ann Dermatol Venereol 2002; 129: 183185. 63 Reyes BA, Vazquez-Botet M, Capo H. Intralesional steroids in cutaneous hemangioma. J Dermatol Surg Oncol 1989; 15: 828832. 64 Chen MT, Yeong EK, Horng SY. Intralesional corticosteroid therapy in proliferating head and neck hemangiomas: a review of 155 cases. J Pediatr Surg 2000; 35: 420423. 65 Enjolras O, Mulliken JB. The current management of vascular birthmarks. Pediatr Dermatol 1993; 10: 311313. 66 Sloan GM, Reinisch JF, Nichter LS et al. Intralesional corticosteroid therapy for infantile hemangiomas. Plast Reconstr Surg 1989; 83: 459 467. 67 Garzon MC, Lucky AW, Hawrot A, Frieden IJ. Ultrapotent topical corticosteroid treatment of hemangiomas of infancy. J Am Acad Dermatol 2005; 52: 281286. 68 Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 1992; 326: 14561463. 69 Chang E, Boyd A, Nelson CC. Successful treatment of infantile hemangiomas with interferon-alpha-2b. J Pediatr Hematol Oncol 1997; 19: 237244. 70 Tamayo L, Ortiz DM, Orozco-Covarrubias L. Therapeutic efcacy of interferon alfa-2b in infants with life- threatening giant hemangiomas. Arch Dermatol 1997; 133: 15671571.

JEADV 2010, 24, 631638

2010 The Authors Journal compilation 2010 European Academy of Dermatology and Venereology

638

Schwartz et al.

71 Dubois J, Hershon L, Carmant L et al. Toxicity prole of interferon alfa-2b in children: a prospective evaluation. J Pediatr 1999; 135: 782 785. 72 Barlow CF, Priebe CJ, Mulliken JB. Spastic diplegia as a complication of interferon alfa-2a treatment of hemangiomas of infancy. J Pediatr 1998; 132: 527530. 73 Michaud AP, Bauman NM, Burke DK, Manaligod JM, Smith RJ. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope 2004; 114: 12311236. 74 Anderson RR. Infant hemangiomas: a controversy worth solving. Lasers Surg Med 2006; 38: 9293. 75 Batta K, Goodyear HM, Moss C et al. Randomised controlled study of early pulsed dye laser treatment of uncomplicated childhood haemangiomas: results of a 1-year analysis. Lancet 2002; 360: 521527. 76 Spicer MS, Goldberg DJ, Janniger CK. Lasers in pediatric dermatology. Cutis 1995; 55: 270272. 278-280. 77 Al Buainian H, Verhaeghe E, Dierckxsens L, Naeyaert JM. Early treatment of hemangiomas with lasers. A review. Dermatology 2003; 206: 370373. 78 Glassberg E, Lask G, Rabinowitz LG, Tunnessen WW. Capillary hemangiomas: case study of a novel laser treatment and a review of therapeutic options. J Dermatol Surg Oncol 1989; 15: 12141223. 79 Spicer MS, Goldberg DJ. Lasers in dermatology. J Am Acad Dermatol 1996; 34: 125. 80 Ashinoff R, Geronemus RG. Failure of the ashlamp-pumped pulsed dye laser to prevent progression to deep hemangioma. Pediatr Dermatol 1993; 10: 7780. 81 Landthaler M, Hiana D, Brunner R et al. Neodymium-YAG laser therapy for vascular lesions. J Am Acad Dermatol 1986; 14: 107117. 82 Mulliken JB, Rogers GF, Marler JJ. Circular excision of hemangioma and purse-string closure: the smallest possible scar. Plast Reconstr Surg 2002; 109: 15441554. discussion 1555. 83 Rizzo R, Micali G, Incorpora G, Parano E, Pavone L. A very aggressive form of facial hemangioma. Pediatr Dermatol 1988; 5: 263265. 84 Altman RS, Schwartz RA. Childhood hemangiomas. Cutis 2003; 72: 201205. 85 Faverova R, Prochazka J, Feit J. A new look on the vascular anomalies in children. Ces-Slov Dermatol 2005; 80: 217221. 86 Morelli JG, Tan OT, Yohn JJ. Treatment of ulcerated hemangiomas infancy. Arch Pediatr Adolesc Med 1994; 148: 11041105. 87 Kim HJ, Colombo M, Frieden IJ. Ulcerated hemangiomas: clinical characteristics and response to therapy. J Am Acad Dermatol 2001; 4: 962972.

88 Wilson MW, Hoehn ME, Haik BG, Rieman M, Reiss U. Low-dose cyclophosphamide and interferon alfa 2a for the treatment of capillary hemangioma of the orbit. Ophthalmology 2007; 114: 10071011. 89 Brandling-Bennett HA, Metry DW, Baselga E, Lucky AW, Adams DM, Cordisco MR, Frieden IJ. Infantile hemangiomas with unusually prolonged growth phase: a case series. Arch Dermatol 2008; 144: 16321637. 90 Senchak AJ, Dann M, Cable B, Bessinger G. Successful treatment of cutaneous hemangioma of infancy with topical imiquimod 5%: A report of 3 cases. Ear Nose Throat J 2010; 89: E21E25. 91 Sterescu A. The potential efcacy of omega-3 fatty acids as antiangiogenic agents in benign vascular tumors of infancy. Med Hypotheses 2006; 66: 11211124. ` 92 Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo J-B, Taeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008; 17: 26492651. 93 Holmes WJ, Mishra A, Gorst C, Liew SH. Propranolol as rst-line treatment for infantile hemangiomas. Plast Reconstr Surg 2010; 125: 420421. 94 Truong MT, Chang KW, Berk DR, Heerema-McKenney A, Bruckner AL. Propranolol for the treatment of a life-threatening subglottic and mediastinal infantile hemangioma. J Pediatr 2010; 156: 335338. 95 Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol 2010; 128: 255256. 96 Maturo S, Hartnick C. Initial experience using propranolol as the sole treatment for infantile airway hemangiomas. Int J Pediatr Otorhinolaryngol 2010; 74: 323325. 97 Sans V, Dumas de la Roque E, Berge J, Grenier N, Boralevi F, Mazereeuw-Hautier J, Lipsker D, Dupuis E, Ezzedine K, Vergnes P, ` Taeb A, Leaute-Labreze C. Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics 2009 Aug 10. [Epub ahead of print; doi:10.1542/peds.2008-3458]. 98 Salhi A, Enjolras O, Labreze C, Taieb A, Lachkhem M, et al. Efcacite et tolerance du propranolol dans le traitement des hemangiomes infan tiles. Etude preliminaire chez 38 patients. Ann Dermatol Venereol 2009; 136S: F38F39. 99 Wananukul S, Chatproedprai S. Ulcerated hemangiomas: clinical features and management. J Med Assoc Thai 2002; 85: 12201225. 100 Metz BJ, Rubenstein MC, Levy ML, Metry DW. Response of ulcerated perineal hemangiomas of infancy to becaplermin gel, a recombinant human platelet-derived growth factor. Arch Dermatol 2004; 140: 867 870. 101 David LR, Malek MM, Argenta LC. Efcacy of pulse dye laser therapy for the treatment of ulcerated haemangiomas: a review of 78 patients. Br J Plast Surg 2003; 56: 317327.

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