Evaluation and Management of Infantile Hemangioma: An Overview. Anand Pandey, MS; Ajay N. Gangopadhyay, MCh; and Vijai D.

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1 FEATURE Evaluation and Management of Infantile Hemangioma: An Overview Anand Pandey, MS; Ajay N. Gangopadhyay, MCh; and Vijai D. Upadhyay, MS Infantile hemangiomas are the most common tumors of infancy and commonly last 7 to 9 years. Although their pathophysiology is not completely understood, recent studies have provided useful information regarding differential diagnosis, assessment approaches, and management options. To enhance understanding of infantile hemangiomas and highlight recent advances in knowledge of pathophysiology and newer diagnostic and therapeutic modalities, a literature search of pertinent articles published between 1985 and 2006 in PubMed was conducted using the term hemangioma with the words types, pathophysiology, treatment, and complications. Despite the generally benign nature of the condition, treatment is required for cosmetic and psychological reasons and requires differential diagnosis, particularly with regard to congenital hemangiomas and vascular and non-vascular tumors, to determine cause and address potential complications such as ulceration. Various emerging treatment modalities are available (interferon, vincristine, cyclophosphamide, bleomycin, imiquimod, becaplermin, and laser therapy) but steroids remain the treatment of choice in cases when hemangiomas require intervention. Overall prognosis in terms of healing hemangiomas using conservative measures is good. Additional research to better understand the pathophysiology and role of genetics is needed. Emerging treatment options should be evaluated through controlled studies to assess effects and side effects. KEYWORDS: hemangioma treatment, pathophysiology, complications, congenital Infantile hemangiomas are the most common tumors of infancy. These harmless birth marks appear soon after birth, proliferate for 8 to 18 months, and then steadily regress over next 5 to 8 years, leaving normal or slightly blemished skin. 1 The incidence of infantile hemangiomas is 10% to 12% in Caucasian infants and lower in dark-skinned infants. 2 The prevalence of infantile hemangioma is approximately 1% to 3% after the first few days of life and Ostomy Wound Management 2008;54(5):16 29 approximately 10% by the end of the first year. 3 Management of hemangiomas spans various specialties including dermatology and plastic, reconstructive, and pediatric surgery. Hemangiomas occur on the skin surface and resemble or can actually become true wounds if ulceration occurs; knowledge of this condition is imperative. To uncover some of the mysteries of the disease, recent advances in understanding its pathophysiology, and various emerging diagnostic Dr. Pandey is a Senior Resident; Dr. Gangopadhyay is a Professor; and Dr. Upadhyay is a Senior Resident, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India. Please address correspondence to: Professor AN Gangopadhyay, Department of Pediatric Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi U.P. India; gangulybhu@rediffmail.com. 16 OstomyWound Management

2 and therapeutic modalities, a literature search of PubMed was conducted of English-language articles published between 1985 to 2006 using the term hemangioma in conjunction with types, pathophysiology, treatment, and complications. Etiopathogenesis Hemangiomas are perhaps the least understood of all tumors seen in infancy. 4 The Greek physician Galen believed that vascular birthmarks of a baby were due to the emotions of the mother while the baby was in utero. Virchow, father of cellular pathology, designated all vascular anomalies angiomas. Wegner, Virchow s student, proposed the nomenclature lymphangioma. 2 A hemangioma comprises densely packed capillaries composed of endothelial cells and pericytes expanding in a lobular pattern. 5 Stimulators of angiogenesis such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bfgf), monocytochrome attractant protein-1, and insulinlike growth factor-2 (IGF-2) are upregulated 5 in proliferating hemangiomas. Genetic mutations also have been found to cause proliferation and dysregulation of angiogenesis. 6 Most hemangiomas occur sporadically; however, sometimes they appear to segregate as an autosomal dominant trait with high penetrance. They have been found to be linked to chromosome 5q Common expression of immunohistochemical markers (eg, glucose uptake transporter-1 [GLUT-1], merosin, FcRII, and Lewis Y antigen) may suggest that hemangiomas either derive or share a common precursor to the placenta. 8 This belief is supported by the fact that chorionic villous sampling increases the risk of hemangioma. 6 It has been shown that infantile hemangioma cells are LYVE-1, VEGF-receptor, and CD31- and CD34- positive similar to the embryonal cardinal vein, suggesting that these cells are arrested in an immature stage of vascular development, which leads to their rapid proliferation and development. 5,9 As the endothelial cells differentiate, an influx of mast cells, other various cells, and tissue inhibitors of metalloproteinase (TIMP) occurs. The TIMPs, interferon (IFN), and transformation growth factor (TGF) produced by mast cells terminate the endothelial cell Figure 1. Superficial hemangioma presenting as a well localized lesion. proliferation and passively induce involution and senescence of endothelial cells. Clinically, hemangioma shows early growth followed by spontaneous involution over time. Clinical features. Infantile hemangiomas appear during the neonatal period, usually within 2 weeks after delivery. They are more common in females than males (3:1 to 5:1 ratio). 10 Size usually varies from 0.5 cm to 5 cm. They can be extensive (ie, involve a large area or appear in many locations simultaneously). They have a characteristic pattern with early and rapid growth (proliferation) and then slow involution. Most hemangiomas are solitary but some infants can have more than one lesion. Superficial hemangiomas are recognized by their bright color (see Figure 1). Deep hemangiomas can present with normal to bluish skin hue related to location. The life cycle of hemangiomas features three phases proliferative, plateau, and involution. The proliferative phase begins after the appearance of the hemangioma and usually lasts 1 year. During the proliferative Ostomy Wound Management 2008;54(5):16 29 KEY POINTS Although generally harmless, the effects of infantile hemangioma on parents and children can be profound. Various tumors and tumor-like conditions should be considered when assessing infantile hemangioma. Treatment is guided by differential diagnosis, anatomical location of the lesion, and the presence or absence of complications. May 2008 Vol. 54 Issue 5 17

3 Figure 2. Healed hemangioma with obvious scarring. phase, the skin becomes irregular, raised, and bright crimson. The hemangioma then enters the plateau phase where growth slows; this can last 1 to 8 years. After the plateau phase, hemangiomas enter the involuting phase in which the color fades and the skin gradually pales with or without scarring. Literature review suggests that normal skin is restored in about 50% to 60% of children 11 ; the other 40% to 50% of hemangiomas leave permanent changes that include telangiectasia, yellowish hypoelastic patches, scars, and dermal atrophy (see Figure 2). Location. Hemangiomas are most commonly located on the head and neck (60%), 11 followed by trunk and extremities. They also can occur at extra-cutaneous sites including liver, gastrointestinal tract, central nervous system, pancreas, gall bladder, thymus, spleen, lymph nodes, lung, urinary bladder, and adrenal glands. Classification. Margileth 12 has classified infantile hemangiomas into three categories: strawberry, cavernous, and mixed. To eliminate some confusion, hemangiomas now are classified as superficial (strawberry type of Margileth present in superficial layers of skin); deep (cavernous type of Margileth present in deeper layers of skin); and mixed. Recently, hemangiomas have been further classified in the following manner 13 : Localized hemangiomas that seem to grow from a single focal point or are localized to an area without any apparent linear or developmental configuration Segmental hemangiomas or clusters of hemangiomas with a configuration demonstrating linear and/or geographic location over a specific cutaneous territory, usually associated with at least some plaque-like features Indeterminate hemangiomas not readily classified as either localized or segmental types Multifocal 10 or more cutaneous hemangiomas. Infantile hemangiomas must be differentiated from congenital hemangioma (CH), which can be classified as rapidly involuting congenital hemangioma (RICH) and non-involuting congenital hemangioma (NICH). 14 Both are rare types of hemangioma 15 ; incidence data are lacking. The incidence of RICH/NICH at the authors center is approximately 1% of all hemangiomas seen; NICH and RICH are almost equally distributed by gender and are usually solitary. 15 They have a similar average diameter and a predilection for the same anatomical locations usually the head or limbs near a joint. By comparison, infantile hemangiomas occur more frequently in girls, their morphology is more variable, they often occur in multiple, and they may appear anywhere on the body. 16 RICH. Tumors diagnosed as RICH are fully grown in utero and do not undergo postnatal growth. They usually involute by age 14 months, leaving either atrophic or redundant skin. They may present as violaceous tumors with ecstatic veins, gray tumors with multiple tiny telangiectasias surrounding pale halo, or violaceous flat infiltrative tumors. Histopathologically, they present with small to large capillaries with moderately plump endothelial cells and pericytes. The involuting form is characterized by fibrous tissue and lobular loss with large and abnormal draining channels. 17,18 NICH. An involuting congenital hemangioma persists throughout the person s life. These hemangiomas are rare and present as solitary pink to purple tumors, often with coarse telangiectasia on overlying skin. They are warm, round to ovoid in shape, and have a central or peripheral pallor. They grow proportionately with the child but do not involute. Histopathological exam reveals lobular collection of small, thin-walled vessels with a large, often stellate central vessel. Interlobular areas contain predominantly dilated often dysplastic veins; arteries also are increased in number. Small arteries are seen shunting 18 OstomyWound Management

4 Age Gender Location Involution Invasiveness KMS GLUT 1 Histopathology Treatment TABLE 1 VASCULAR TUMORS: COMMON CHARACTERISTICS 15,20 Hemangioma 10 to 15 days after birth RICH At birth More common in females No preference No anatomical preference Head or limbs near Usually single joint Common Common Non-invasive Non-invasive Absent Absent Positive Negative Fine strands of connective Capillaries with tissue intralobular arterial moderately plump supply endothelial cells and pericytes Usually steroids Spontaneous involution directly into the lobular vessel or into an abnormal extralobular vein. 19 Differential diagnosis. Various tumors and tumorlike conditions should be considered when assessing/diagnosing infantile hemangioma. Vascular tumors. Vascular tumors include RICH, NICH, Kaposiform hemangioendothelioma (KHE), and tufted angioma (TA) (see Table 1). Recognition of congenital, nonprogressive hemangioma as an entity biologically distinct from infantile hemangioma has important implications for patient management. Rapidly involuting congenital hemangiomas generally involute spontaneously while NICH usually requires a surgical procedure. 20 Kaposiform hemangiothelioma and TA are histopathologically well characterized and both have proliferating lymphatic endothelial cells. Both are related to platelet entrapment, thrombocytopenia, and life-threatening Kasabach-Merritt syndrome (KMS), 21 a rare disease, usually of infants, in which a vascular tumor leads to decreased platelet counts and sometimes other bleeding problems when the tumors are large or growing rapidly. The combination of vascular tumor and consumptive thrombocytopenia defines KMS. Tumors can be found on the trunk, upper and lower extremities, retroperitoneum, NICH At birth No preference Head or limbs near joint Does not occur Non-invasive Absent Negative Lobular collection of small, thin walled vessels Surgery RICH = rapidly involuting congenital hemangioma; NICH = non-involuting congenital hemangioma; KHE = Kaposiform hemangiomaendothelioma; TA = tufted angioma KHE TA At birth or a few At birth or a few days after birth. days after birth No preference No preference Mostly on trunk As KHE but smaller Does not occur Invasive Present Negative Bland spindled cells forming slit-like spaces Does not occur Non-invasive Present Negative Cannonball distribution of dense capillary lobules Steroids in combination with Like KHE other modalities and cervical and facial areas. 22 Infants with KMS do not have a true hemangioma; rather, the affected area is the result of KH or TA. 23 Other vascular malformations to consider include arteriovenous malformation (AVM), lymphatic malformation (LM), venous malformation (VM), and capillary malformation (CM) (see Table 2). Non-vascular considerations. Non-vascular benign and malignant tumors such as angiosarcoma, infantile fibrosarcoma, infantile myofibromatosis, and rhabdomyosarcoma dermatofibrosarcoma protuberans also must be considered. Associated anomalies. Hemangiomas are found (albeit rarely) to be associated with certain malformations. These include posterior fossa malformations, cervicofacial hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and sternal clefting or supraumbilical raphe commonly grouped as PHACES 24 ;perineal hemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin problems commonly known as PELVIS 25 ; and recently described spinal dysraphism, anogenital anomalies, cutaneous anomalies, and renal and urologic anomalies associated with angioma of lumbosacral localization known as 20 OstomyWound Management

5 TABLE 2 HEMANGIOMA AND VASCULAR MALFORMATIONS: COMMON CHARACTERISTICS 2 Types Age Gender Growth Hypothyroidism Effect of steroid Treatment Hemangioma Superficial, deep, and mixed Presents few days after birth More common in females Usually involute by 5 8 years Can present Steroid responsive Pharmacotherapy is initial choice CM = capillary malformation; VM = venous malformation; AVM = arteriovenous malformation; FPDL = flashlamp pulsed dye laser SACRAL. 26 The PELVIS and SACRAL malformations are only recently described; no incidence studies have been published. The description of PHACES appears mainly in case reports. 27,28 Of note: PHACES has been found to be associated with hypopituitarism. 24 A comparative summary of common characteristics of hemangioma and tumors is presented in Table 3. Age Gender Steroids Diagnosis H/P Treatment Hemangioma In infancy Vascular malformations Capillary, venous, and lymphatic malformations, arteriovenous malformations Usually present at birth No preference Persists throughout life None Steroid non-responsive Surgery prime modality of treatment except CM (FPDL is used) Other options: sclerotherapy for VM and embolization for AVM Diagnosis The diagnosis of hemangioma is clinical. The role of diagnostic modalities such as ultrasound and others occurs in the following situations: 1) at the time of surgery if needed to ascertain the extent of hemangioma; 2) to see the associated extracutaneous involvement if suspected; and 3) to differentiate hemangioma from vascular malformation where questioned. Diagnostic modalities. Ultrasound. Ultrasound is a non-invasive, inexpensive diagnostic method but cannot evaluate the full extent of hemangioma. However, it has been shown that lesions demonstrating high vessel density (more than five per square centimeter) and a peak arterial Doppler shift exceeding 2 khz were correctly diagnosed as hemangiomas, facilitating differentiation from other vascular conditions. 29 Computerized tomography. Computerized tomography (CT) is important in defining the extent of TABLE 3 HEMANGIOMA AND TUMORS: COMMON CHARACTERISTICS 2,64 Female predominant Responsive Clinical Multiple vascular channels Steroids RMS In children Chemotherapy/ surgery IFS In children Equal distribution Equal distribution between sexes between sexes Not responsive Not responsive FNAC/biopsy FNAC/biopsy Small round Spindle cells blue cells Surgery AS Uncommon in children Equal in both sexes Not responsive FNAC/biopsy Infiltrating vascular channels in dissection of collagen appearance Surgery DFT Uncommon in children Equal in both sexes Not responsive FNAC/biopsy Cartwheel distribution of spindle cells Surgery IMF Before 2 years Male predominant Not responsive FNAC/biopsy Stag horn appearance of spindle cells RMS=Rhabdomyosarcoma IFS=Infantile fibrosarcoma AS=Angiosarcoma DFT=Dermatofibrosarcoma protuberans Spontaneous involution/surgery IMF=Infantile myofibromatosis H/P=Histopathology FNAC=Fine needle aspiration cytology 22 OstomyWound Management

6 Page 23 D O N O T D U PL these lesions, both as a guide for the surgeon and for conservative follow-up. Characteristically, the CT is able to facilitate observation of homogeneous enhancement, absence of peripheral edema, and fat stranding to guide diagnosis of the few patients with unusual clinical presentations.30 Magnetic resonance imaging. Magnetic resonance imaging (MRI) is useful for demonstrating the precise anatomic extent of any vascular anomaly and its relationship to adjafigure 3. Hemangioma before cent soft tissues; MRI is and after steroid therapy. superior to CT for this puraffected right eye is noteworthy. pose. This modality also can differentiate between hemangioma and other vascular lesions. Magnetic resonance imaging has been shown to be ideal for triaging patients with vascular anomalies for appropriate management, including observation, endovascular therapy, or surgical excision.31 Recent controlled clinical studies 32,33 have explored use of urinary bfgf and serum VEGF as a marker of hemangioma proliferation, differentiation, and management. Both have been found to be helpful in differentiating hemangiomas from vascular malformations, staging hemangiomas, judging the efficacy of steroid therapy, and evaluating follow-up criteria for hemangiomas. Thyroid function test. Thyroid function test (TFT) may be necessary in cases involving large hemangiomas because these tumors have been shown to cause hypothyroidism33 due to the presence of type 3 iodothyronine deiodinase activity in the hemangioma tissue that can degrade thyroid hormone.34 Hemogram and liver function tests are required for liver or other visceral hemangioma. TE 2:53 PM A 5/2/08 IC 16-29_OWM0508_Pandey.qxd Treatment Hemangiomas, although often small at birth, enter a proliferative phase 10 to 15 days after birth in which

7 Figure 4. Ulcerated facial hemangioma. Central ulceration is clearly visible. growth may be rapid and unpredictable. Furthermore, involution often takes many years, with attendant psychological sequelae to the child. This is aggravated by the fact that most hemangiomas affect the head and neck and are visible and difficult to conceal. Thus, treatment is required. 35 Figure 5. Very large periorbital hemangioma causing visual field Corticosteroids. obstruction and pressure effects Corticosteroids are the on eye ball. mainstay of treatment. Although their mode of action is incompletely understood, they been shown in animal studies to inhibit interleukin 6 (IL 6) and VEGF via glucocorticoid receptors in rat cornea. 36 Corticosteroids also inhibit phospholipase A2, which releases arachidonic acid, the precursor to the proangiogenic prostaglandin. 37 In vitro study 38 has shown corticosteroids inhibit metalloproteinases that promote angiogenesis by breaking down the extracellular matrix. In animal studies of adrenalectomized rats, 39 steroids have been shown to sensitize the vascular bed to vasoconstricting agents. Corticosteroids can be used systematically, intralesionally, or topically. The standard-of-care 40 oral agent is prednisolone, 2 to 3 mg/kg, for up to 6 months 41 ; however, the authors have used it in doses of 1 to 2 mg/kg in the same time frame with good results as documented in a 10-year case series. 42 Triamcinolone is administered intralesionally in monthly doses of 1 to 2 mg/kg41 for up to six injections. Although safety and effectiveness data are insufficient, topical use of clobetasol has been described with good results in a retrospective clinical case series 43 (see Figure 3). Additionally, in clinical study especially of superficial hemangiomas, 44 the authors have noted the beneficial effect of topical mometasone. Complications. Complications of systemic corticosteroidal therapy include cushingoid facies, personality changes, gastric irritation, infection, weight gain, hypertension, hypertrophic cardiomyopathy, and retarded growth. 45 These complications are usually short-term and, in the authors experience, no serious long-term complications are seen in doses of 1 to 3 mg/kg. Relatively minor complications related to intralesional steroid use include hypopigmentation, cutaneous atrophy, infection ; major complications, which are extremely rare, include growth retardation, Cushing s syndrome, and anaphylactic shock. 48 Occlusion of the retinal artery has been reported 49 and high injection pressure can be problematic. 50 Topical steroids have been associated with skin atrophy, striae, and telangiectasia, among other conditions. 51 Interferon alpha 2a (IFN alpha 2a). Interferon is used as second-line drug when the condition does not respond to steroids. Given in doses of 2 to 3 million units/m 2 body surface area (BSA), interferon can be used during both the proliferative and involuting phases to reduce the size of the hemangioma. A non-randomized trial and meta-analysis 52,53 have demonstrated 50% to 90% regression in approximately 60% of treated patients but include reports of neurological complications like spastic diplegia, especially in first year of life. Bleomycin. Used intralesionally, bleomycin acts by inducing fibrosis and has been shown in a case series 54 of 14 patients to achieve 60% to 90% response in 85% of patients, working especially well in complicated hemangiomas. Complications include scarring and hyperpigmentation. Other non-steroidal agents. Other agents that have been found useful for lesions not responding to steroids include vincristine 55 and cyclophosphamide, OstomyWound Management

8 Figure 6. Large hemangioma of the tongue. Lesions like this often cause airway obstruction. according to a prospective study and one case report, respectively. Use of immunomodulators is at present in the experimental phase; noteworthy among these are becaplermin 0.01% gel, 57 a recombinant human platelet-derived growth factor used topically to achieve healing of ulcers in ulcerated hemangioma (not the hemangioma itself); and imiquimod 5% cream, 58 an immune response modifier. Laser therapy. Lasers have been used to treat hemangioma. A case series 59 involving 548 patients has shown that small and/or superficial hemangiomas are the most responsive as compared to the commonly used flashlamp-pumped pulsed dye laser (FPDL). Overall, the role of laser therapy in treatment is controversial and needs further evaluation. 60 Surgery. Surgery is used to improve cosmetic results on residual masses persisting after medication. Excision during the proliferative phase is not recommended due to the tendency of hemangiomas to bleed excessively when disrupted. Complications Ulceration. Ulceration is the most common complication of hemangioma. It occurs in 5% to 15% of cases, 61 is more common in female patients, 62 and can occur spontaneously or during the course of treatment. Ulcerations usually occur on facial and perineal lesions and in large (>6 cm approximately) hemangiomas 63 (see Figure 4). Treatment includes local wound care, infection management, specific therapeutic modalities (systemic and intralesional steroids, FPDL, IFN alpha 2a), and pain management. Visual obstruction. Hemangiomas can obstruct vision related to the visual axis, astigmatism from direct pressure on the anterior segment from eyelid involvement, and/or unilateral myopia (see Figure 5). Strabismus can result either secondary to amblyopia or from paralysis of extra-ocular muscles infiltrated by an orbital hemangioma if treatment is not initiated. Ophthalmic consultation is needed. 65 Airway obstruction. Large hemangiomas may press on airways (see Figure 6). Treatment consists of steroids, IFN, and other modalities. Intubation or tracheostomy may be required. 66 Output failure. Large visceral hemangiomas can cause high output cardiac failure because of arteriovenous shunting, leading to greater venous return and extra load on the heart. 2 Psychological impact. Hemangiomas can have great psychological impact. In a prospective study 13 of 25 children, parents of children with hemangiomas experienced feelings of disbelief, panic, or fear associated with the growth of the lesion, as well as feelings of sadness, guilt, personal shame, and sense of aloneness. Public reaction also creates problems and may force parents to confront varied aspects of social stigmatization. Physicians are faced with specific challenges in providing effective anticipatory guidance and support to parents. The evolution of the hemangioma, combined with a general prognosis, should be discussed. Counseling has been found to be important for both parents and children. Serial photographs showing the resolution of the hemangioma can be quite compelling and encouraging. 11 Prognosis The majority of uncomplicated hemangiomas involute. Residual changes that persist can be addressed through surgery for cosmetic or psychological concerns. Conclusion Infantile hemangioma is a benign condition with significant cosmetic and psychological impact. Complete assessment must be performed to differentiate hemangioma from other related conditions and to provide appropriate treatment. Complications such as ulceration, visual and airway obstruction, output May 2008 Vol. 54 Issue 5 25

9 failure, and psychological concerns also necessitate treatment that can involve wound care, infection and pain management, therapeutic modalities, and appropriate specialty and surgical consultation and intervention. Additional research is needed to enhance understanding of the pathophysiology and role of genetics, which remain incompletely understood. Studies regarding the relationship of CH to infantile hemangioma also are needed. Emerging treatment options that include interferon, vincristine, cyclophosphamide, bleomycin, imiquimod, becaplermin, and laser therapy, as well as evolving diagnostic modalities, should be evaluated in controlled studies to determine their effects and side effects. Overall, the majority of patients with hemangiomas have a positive prognosis. - OWM References 1. Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med. 1992;28;326(22): Klement G, Fishman SJ. Vascular anomalies: hemangioma and malformations. In: Grosfeld JL, O Neill Jr JA, Fonkalsrud EW, Coran AG (eds). Pediatric Surgery, 6th Edition. Philadelphia, Pa: Mosby Elsevier 2006: Senthilkumar M, Thappa DM. Vascular nevi in children. Indian J Dermatol Venereol Leprol. 2006;72(1): Marchuk DA. Pathogenesis of hemangioma. J Clin Invest. 2001;107(6): Dadras SS, North PE, Bertoncini J, Mihm MC, Detmar M. Infantile hemangiomas are arrested in an early developmental vascular differentiation state. Mod Pathol. 2004;17(9): Burton BK, Schulz CJ, Angle B, Burd LI. An increased incidence of hemangiomas in infants born following chorionic villus sampling (CVS). Prenat Diagn. 1995;15(3): Walter JW, Blei F, Anderson JL, Orlow SJ, Speer MC, Marchuk DA. Genetic mapping of a novel familial form of infantile hemangioma. Am J Med Genet. 1999;1;82(1): North PE, Waner M, Mizeracki A. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. 2001;137(5): Takahashi K, Mulliken JB, Kozakewich HP, Rogers RA, Folkman J, Ezekowitz RA. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest. 1994;93(6): Phung TL, Hochman M, Mihm MC. Current knowledge of the pathogenesis of infantile hemangiomas. Arch Facial Plast Surg. 2005;7(5): Tanner JL, Dechert MP, Frieden IJ. Growing up with a facial hemangioma: parent and child coping and adaptation. Pediatrics. 1998;101(3 Pt 1): Margileth AM, Museles M. Cutaneous hemangiomas in children. Diagnosis and conservative management. JAMA. 1965;194(5): Chiller KG, Passaro D, Frieden IF. Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol. 2002;138(12): Enjolras O, Picard A, Soupre V. Congenital hemangiomas and other rare infantile vascular tumors. Ann Chir Plast Esthet. 2006;51(4-5): Krol A, MacArthur CJ. Congenital hemangiomas: rapidly involuting and noninvoluting congenital hemangiomas. Arch Facial Plast Surg. 2005;7(5): Mulliken JB, Enjolras O. Congenital hemangiomas and infantile hemangioma: missing links. J Am Acad Dermatol. 2004;50(6): Boon LM, Enjolras O, Mulliken JB. Congenital hemangiomas: evidence of accelerated involution. J Pediatr. 1996;128(3): Berenguer B, Mulliken JB, Enjolras O, et al. Rapidly involuting congenital hemangiomas: clinical and histopathologic features. Pediatr Dev Pathol. 2003;6(6): Enjolras O, Mulliken JB, Boon LM, Wassef M, Kozakewich HP, Burrows PE. Non-involuting congenital hemangiomas: a rare cutaneous vascular anomaly. Plast Reconstr Surg. 2001;107(7): Brix M, Soupre V, Enjolras O, Vazquez MP. Antenatal diagnosis of rapidly involuting congenital hemangiomas (RICH). Rev Stomatol Chir Maxillofac. 2007;108(2): Metry DW, Hebert AA. Benign cutaneous vascular tumors of infancy. When to worry, what to do. Arch Dermatol. 2000;136(7): Hall G. Kasabach-Merritt syndrome: pathogenesis and management. Br J Haematol. 2001;112(4): Enjolras O, Wassef M, Mazoyer E, et al. Infants with Kasabach-Merritt syndrome do not have true hemangiomas. J Pediatr. 1997;130(4): Goddard DS, Liang MG, Chamlin SL, Svoren BM, Spack NP, Mulliken JB. Hypopituitarism in PHACES association. Pediatr Dermatol. 2006;23(5): OstomyWound Management

10 25. Girard C, Ignore M, Guillot B, Bessis D. PELVIS syndrome. Arch Dermatol. 2006;142(7): Stockman A, Boralevi F, Taieb A, Leaute-Labreze C. SACRAL syndrome: spinal dysraphism, anogenital, cutaneous, renal, and urologic anomalies associated with an angioma of lumbosacral localization. Dermatology. 2007;214(1): Judd CD, Chapman PR, Koch B, Shea CJ. Intracranial infantile hemangiomas associated with PHACE syndrome. Am J Neuroradiol. 2007;28(1): Weon YC, Chung JI, Kim HJ, Byun HS. Agenesis of bilateral internal carotid arteries and posterior fossa abnormality in a patient with facial capillary hemangioma: presumed incomplete phenotypic expression of PHACE syndrome. Am J Neuroradiol. 2005;26(10): Dubois J, Patriquin HB, Garel L, et al. Soft-tissue hemangiomas in infants and children: diagnosis using Doppler sonography. Am J Roentgenol. 1998;171(1): Gorincour G, Kokta V, Rypens F, Garel L, Powell J, Dubois J. Imaging characteristics of two subtypes of congenital hemangiomas: rapidly involuting congenital hemangiomas and non-involuting congenital hemangiomas. Pediatr Radiol. 2005;35(12): Huston J, Forbes GS, Ruefenacht DA, Jack CR, Lie JT, Clay RP. Magnetic resonance imaging of facial vascular anomalies. Mayo Clin Proc. 1992;67(8): Zhang L, Lin XX, Qi ZL, et al. Role of urinary basic fibroblast growth factor in differentiating hemangiomas from vascular malformation. Zhonghua Wai Ke Za Zhi. 2006;44(3): Zhang L, Lin X, Wang W, et al. Circulating level of vascular endothelial growth factor in differentiating hemangioma from vascular malformation patients. Plast Reconstr Surg. 2005;116(1): Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med. 2000;343(3): Pienaar C, Graham R, Geldenhuys S, Hudson DA. Intralesional bleomycin for the treatment of hemangiomas. Plast Reconstr Surg. 2006;117(1): Ebrahem Q, Minamoto A, Hoppe G, Anand-Apte B, Sears JE. Triamcinolone acetonide inhibits IL-6- and VEGF-induced angiogenesis downstream of the IL-6 and VEGF receptors. Invest Ophthalmol Vis Sci. 2006;47(11): Crum R, Szabo S, Folkman J. A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment. Science. 1985;230(4732): Jones EW, Orkin M. Tufted angioma (angioblastoma). A benign progressive angioma not to be confused with Kaposi s sarcoma or low grade angiosarcoma. J Am Acad Dermatol. 1989;20(2 Pt 1): Edgerton MT. The treatment of hemangiomas with special reference to the role of steroid therapy. Ann Surg. 1976;183(5): Blei F, Chianese J. Corticosteroid toxicity in infants treated for endangering hemangiomas: experience and guidelines for monitoring. Int Pediatr. 1999;14: Bennett ML, Fleischer AB, Chamlin SL, Frieden IJ. Oral corticosteroid use is effective for cutaneous hemangiomas: an evidence-based evaluation. Arch Dermatol. 2001;137(9): Gangopadhyay AN, Sinha CK, Gopal SC, Gupta DK, Sahoo SP, Ahmad M. Role of steroid in childhood hemangioma: a 10-year review. Int Surg. 1997;82(1): Garzon MC, Lucky AW, Hawrot A, Frieden IJ. Ultrapotent topical corticosteroid treatment of hemangiomas of infancy. J Am Acad Dermatol. 2005;52(2): Pandey A, Gangopadhyay AN, Sharma SP, et al. Evaluation of topical steroids in treatment of superficial hemangioma. Skinmed (In Press). 45. Boon LM, MacDonald DM, Mulliken JB. Complications of systemic corticosteroid therapy for problematic hemangioma. Plast Reconstr Surg. 1999;104(6): Sloan GM, Reinisch JF, Nichter LS, Saber WL, Lew K, Morwood DT. Intralesional corticosteroid therapy for infantile hemangiomas. Plast Reconstr Surg. 1989;83(3): Chowdri NA, Darzi MA, Fazili Z, Iqbal S. Intralesional corticosteroid therapy for childhood cutaneous hemangiomas. Ann Plast Surg. 1994;33(1): 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(3): Egbert JE, Schwartz GS, Walsh AW. Diagnosis and treatment of an ophthalmic artery occlusion during an intralesional injection of corticosteroid into an eyelid capillary hemangioma. Am J Ophthalmol. 1996;121(6): Egbert JE, Paul S, Enqel WK, Summers CG. High injection pressure during intralesional injection of corticosteroids into capillary hemangiomas. Arch Ophthalmol. 2001;119(5): Nnoruka E, Okoye O. Topical steroid abuse: its use as a depigmenting agent. J Natl Med Assoc. 28 OstomyWound Management

11 2:53 PM Page 29 D O N O T D U PL IC 2006;98(6): Greinwald JH Jr, Burke DK, Bonthius DJ, Bauman NM, Smith RJ. An update on the treatment of hemangiomas in children with interferon alfa-2a. Arch Otolaryngol Head Neck Surg. 1999;125(1): Michaud AP, Bauman NM, Burke DK, Manaligod JM, Smith RJ. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope. 2004;114(7): Sarihan H, Mocan H, Yildiz K, Abes M, Akyazici R. A new treatment with bleomycin for complicated cutaneous hemangioma in children. Eur J Pediatr Surg. 1997;7(3): Enjolras O, Breviere GM, Roger G, et al. Vincristine treatment for function- and life-threatening infantile hemangioma. Arch Pediatr. 2004;11(2): Hurvitz SA, Hurvitz CH, Sloninsky L, Sanford MC. Successful treatment with cyclophosphamide of life threatening diffuse hemangiomatosis involving the liver. J Pediatr Hematol Oncol. 2000;22(6): 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(7): Ho NT, Lansang P, Pope E. Topical imiquimod in the treatment of infantile hemangiomas: a retrospective study. J Am Acad Dermatol. 2007;56(1): Hohenleutner S, Badur- Ganter E, Landthaler M, Hohenleutner U. Long-term results in the treatment of childhood hemangioma with the flashlamp-pumped pulsed dye laser: an evaluation of 617 cases. Lasers Surg Med. 2001;28(3): Batta K, Goodyear HM, Moss C, William HC, Hiller L, Waters R. Randomized controlled study of early pulsed dye laser treatment of uncomplicated childhood hemangiomas: results of a 1-year analysis. Lancet. 2002;17;360(9332): 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(7): Wananukul S, Chatproedprai S. Ulcerated hemangiomas: clinical features and management. J Med Assoc Thai. 2002;85(11): Kim HJ, Colombo M, Frieden IJ. Ulcerated hemangiomas: clinical characteristics and response to therapy. J Am Acad Dermatol. 2001;44(6): Calonje E, MacKie RM. Soft tissue tumors and tumor like conditions. In: Burns T, Breathnach S, Cox N, Griffiths C (eds). Rook s Text Book of Dermatology, 7th edition. Oxford, UK: Oxford Blackwell;2004: Morrell AJ, Willshaw HE. Normalisation of refractive error after steroid injection for adnexal hemangiomas. Br J Ophthalmol. 1991;75(5): Al-Seibeih K, Manoukian J. Systemic steroids for the management of obstructive subglottic hemangioma. J Otolaryngol. 2000;29(6): TE 5/2/08 A 16-29_OWM0508_Pandey.qxd May 2008 Vol. 54 Issue 5 29