CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

Diagnosis and Management of Infantile Hemangioma David H. Darrow, MD, DDS, Arin K. Greene, MD, Anthony J. Mancini, MD, Amy J. Nopper, MD, the SECTION ON DERMATOLOGY, SECTION ON OTOLARYNGOLOGY–HEAD AND NECK SURGERY, and SECTION ON PLASTIC SURGERY

abstract Infantile hemangiomas (IHs) are the most common tumors of childhood. Unlike other tumors, they have the unique ability to involute after proliferation, often leading primary care providers to assume they will resolve without intervention or consequence. Unfortunately, a subset of IHs rapidly develop complications, resulting in pain, functional impairment, or permanent disfigurement. As a result, the primary clinician has the task of determining which lesions require early consultation with a specialist. Although several recent reviews have been published, this clinical report is the first based on input from individuals representing the many specialties involved in the treatment of IH. Its purpose is to update the pediatric community regarding recent discoveries in IH pathogenesis, treatment, and clinical associations and

This document is copyrighted and is property of the American to provide a basis for clinical decision-making in the management of IH. Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. NOMENCLATURE

Clinical reports from the American Academy of Pediatrics benefit from The nomenclature and classification of vascular tumors and expertise and resources of liaisons and internal (American Academy malformations have evolved from clinical descriptions (“strawberry of Pediatrics) and external reviewers. However, clinical reports from the American Academy of Pediatrics may not reflect the views of the birthmark,”“salmon patch,”“cavernous hemangioma,” and “port wine liaisons or the organizations or government agencies that they stain”) to terminology based on their cellular features, natural history, and represent. clinical behavior. Originally described by Mulliken and Glowacki in 1982, The guidance in this report does not indicate an exclusive course of fi treatment or serve as a standard of medical care. Variations, taking the most current and widely accepted classi cation of vascular anomalies into account individual circumstances, may be appropriate. is that adopted by the International Society for the Study of Vascular 1 All clinical reports from the American Academy of Pediatrics Anomalies (Table 1). This system includes infantile hemangioma (IH) automatically expire 5 years after publication unless reaffirmed, among the vascular neoplasms, which are lesions characterized by revised, or retired at or before that time. abnormal proliferation of endothelial cells and aberrant blood vessel www.pediatrics.org/cgi/doi/10.1542/peds.2015-2485 architecture. In contrast, vascular malformations are structural anomalies DOI: 10.1542/peds.2015-2485 and inborn errors of vascular morphogenesis. PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Although IH is the most common neoplasm, this group also includes such Copyright © 2015 by the American Academy of Pediatrics tumors as congenital hemangiomas, pyogenic granulomas, tufted angiomas (TAs), and several types of hemangioendothelioma. Congenital FINANCIAL DISCLOSURE: The authors have indicated they do not have a financial relationship relevant to this article to disclose. hemangiomas are biologically and behaviorally distinct from IH. As fl POTENTIAL CONFLICT OF INTEREST: The authors have indicated they re ected in the name, congenital hemangiomas are present and fully have no potential conflicts of interest to disclose. formed at birth; they do not exhibit the postnatal proliferative phase

Downloaded from www.aappublications.org/news by guest on September 28, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS PEDIATRICS Volume 136, number 4, October 2015 characteristic of IH. The 2 variants are It is a reactive proliferating vascular and may grow slowly over the course the noninvoluting congenital lesion that is classified as a vascular of months to years, grow rapidly, hemangioma (NICH), which remains neoplasm (Table 1). This common spontaneously regress, or remain stable without growth or acquired vascular lesion of the skin dormant for years.14–16 Unlike KHE involution,2,3 and the rapidly and mucous membranes primarily and TA, IHs are not associated with involuting congenital hemangioma affects infants and children and is thrombocytopenia or coagulopathy. (RICH), which undergoes a rapid frequently misdiagnosed as IH. Vascular malformations are fi involution phase beginning in the rst Approximately 12% occur in infancy, congenital lesions, but some may 4 fi year of life (Fig 1). RICHs, in some and 42% present during the rst 5 become clinically apparent only later 10 cases, have been associated with years of life. Pyogenic granulomas in life, presumably because of slowly thrombocytopenia but with milder are most commonly located on the progressive ectasia resulting from and more transient coagulopathy head and neck, rapidly enlarge to intraluminal flow. They exhibit than that seen in Kasabach-Merritt a median size of 6.5 mm, frequently a normal rate of endothelial cell phenomenon (KMP; see discussion develop a pedunculated base, and, turnover throughout their natural that follows); rarely, they can be with erosion, are prone to bleeding history but expand as the patient fi 10 associated with congestive heart that is dif cult to control (Fig 2). grows. Vascular malformations do not 5,6 failure. Some RICHs show Pyogenic granulomas are seen with involute, and their growth may be incomplete involution, and it is higher frequency within the skin influenced by trauma, infection, and possible that RICH and NICH lie at containing capillary malformations. hormonal changes. Classification is opposite ends of the same clinical Two other distinct benign vascular based on the predominant vessel 7,8 spectrum. Both subtypes of neoplasms, kaposiform type: capillary or venulocapillary, congenital hemangioma were initially hemangioendothelioma (KHE) and venous, lymphatic, arterial, or believed to be variants of IH that TA, have been confused with IH. KHE mixed.17 As with vascular neoplasms, exhibited prenatal growth until North presents primarily in infancy but with the nomenclature of vascular 9 et al showed that, unlike IH, neither a far wider age range than IH, which malformations has led to great lesion expresses glucose transporter is usually apparent in the first month confusion. Capillary or protein isoform 1 (GLUT1). of life. KHE is considered a locally venulocapillary malformations have Pyogenic granuloma, also known as aggressive neoplasm that typically had numerous alternative lobular capillary hemangioma, is appears as a deep, soft tissue mass. designations, the most common being neither pyogenic nor granulomatous. This lesion has been associated with “port wine stain” and “nevus KMP,11 a potentially life-threatening flammeus.” Venous malformations consumptive coagulopathy have often been mistaken for IH, TABLE 1 Classification of Cutaneous characterized by severe platelet Vascular Anomalies, 2014 trapping. Before KHE was described Vascular malformations in the early 1990s, KMP was Venous malformations erroneously thought to occur in Lymphatic malformations association with IH. Capillary malformations Arteriovenous malformations and fistulae Histopathologically, KHE shows Mixed (combined) malformations infiltrating sheets of slender, GLUT1- Vascular tumors negative endothelial cells lining Benign slitlike capillaries.12 TAs are benign Infantile hemangioma (IH) vascular tumors that occur in infants, Congenital hemangioma (rapidly involuting [RICH]; non-involuting [NICH]) children, or young adults and are Lobulated capillary hemangiomas (LCH) usually located on the neck or the (pyogenic granuloma)* upper part of the thorax.13 Their Tufted angioma (TA) clinical appearance is variable and Others includes erythematous to violaceous Locally aggressive Kaposiform hemangioendothelioma (KHE) patches, plaques, and nodules. Kaposi sarcoma Histopathologically, TA shows well- Others defined tufts of capillaries in the Malignant dermis that lack cellular atypia or Angiosarcoma GLUT1 positivity and, like KHE, is Others FIGURE 1 associated with increased lymphatic Adapted from the International Society for the Study of RICH is fully formed at birth (A) and then Vascular Anomalies, 2014, ref 1 (issva.org/classification). vessels and a predisposition to KMP. involutes, mostly during the first year of life. B, *Reactive proliferating vascular lesion Both tumors behave unpredictably The same lesion seen at 8 months of age.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1061 termed “cavernous hemangiomas” years, especially predating the among female infants; however, and “venous hemangiomas” in the distinction between IH and the although older data suggest female- literature (Fig 3A). Lymphatic congenital hemangiomas. to-male ratios ranging from 3:1 to 5:1, malformations, which are subdivided “Hemangioma” has also been more recent studies suggest a range into microcystic and macrocystic inappropriately used to describe, in of 1.4:1 to 3:1.23,24 The gender varieties on the basis of predominant general terms, varieties of other discrepancy appears to be increased lacuna size, may also be mistaken for noninfantile hemangiomas and among children with PHACE IH when there is bleeding into vascular malformations. syndrome (Posterior fossa defects, vesicles at the surface of the skin or Hemangiomas, cerebrovascular mucosa (Fig 3B). These lesions have Arterial anomalies, Cardiovascular traditionally been referred to as anomalies including coarctation of “cystic hygromas” or Highlights of This Section the aorta, and Eye anomalies), in “lymphangiomas,” designations that which studies have found a 9:1 • Infantile hemangioma (IH) is inaccurately presume proliferative female-to-male ratio.25 There is not the currently accepted termi- potential, thereby perpetuating the adefinitive explanation for this nology for the lesions that are diagnostic confusion. gender difference. the focus of this clinical report. The use of various names for IH has Most studies report a significantly • Congenital hemangiomas are resulted in immense diagnostic biologically and behaviorally higher incidence in white confusion. For instance, the terms 23,24,26 distinct from IH. infants. On the basis of the “capillary hemangioma” and success of IH treatment using • Pyogenic granuloma is a re- “capillary angioma” have been used to b-blocker therapy, it has been active proliferating vascular refer to an IH that is located primarily proposed that black infants may lesion that is classified as in the dermis and is bright red in exhibit some form of “endogenous a vascular neoplasm and color. In contrast, the designations beta blockade,” and there are “ ” “ ” that may occasionally be cavernous or venous have molecular biological data to support inappropriately been used to define misdiagnosed as IH. this notion.27 an IH that, because of its depth below • Lesions diagnosed as “cav- the dermis, may impart a blue tinge to ernous hemangiomas” are The incidence of IH is increased the skin surface. In addition, deep usually, in fact, deep IHs or among preterm infants, affecting 22% venous and lymphatic malformations venous malformations. to 30% of infants weighing less than 24,28 as well as arteriovenous • Kasabach-Merritt phenome- 1 kg. Multivariate analysis has malformations have been incorrectly non or KMP (a consumptive revealed that low birth weight (LBW) diagnosed as deep IH. Finally, by coagulopathy) is not associ- is the major contributor to this risk; virtue of its sheer prevalence, the ated with IH but rather with there is a 25% increase in risk of term “hemangioma,” without the 2 other vascular neoplasms, developing an IH with every 500-g adjectival descriptor “infantile” or kaposiform hemangioendo- reduction in birth weight.29 Prenatal with the descriptor “juvenile,” has thelioma (KHE) and tufted factors have also been investigated been used in reference to IH for many angioma (TA). for their role in IH. Studies differ regarding an increased risk resulting from maternal chorionic villus sampling24,30 or amniocentesis,30,31 EPIDEMIOLOGY and any increased risk attributable to chorionic villus sampling appears to Studies of the incidence of IH, be limited to procedures performed including a prospective study and transcervically.31 Other possible a review incorporating 1 retrospective study and 2 cross- prenatal factors include older sectional cohorts, suggest that 4% to maternal age, multiple gestation 5% of infants are affected.18,19 Other pregnancy, placenta previa, and studies suggest that IH is observed in preeclampsia.24 Placental anomalies, 1% to 3% of newborn infants20,21 such as retroplacental hematoma, FIGURE 2 and 2.6% to 9.9% of older infarction, and dilated vascular Pyogenic granulomas have some clinical and children,22,23 but methodologic communications, have also been histologic features similar to IHs, but they are 32 generally smaller, pedunculated, and more shortcomings may have influenced associated with IH development. It likely to bleed. these findings. IHs are more common is theorized that the common thread

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1062 FROM THE AMERICAN ACADEMY OF PEDIATRICS in these associations is placental hypoxia.32,33 Although often suggested as a risk factor, a family history of IH is reported in only 12% of cases24; however, familial clustering has been reported.34,35 Associations are also reported with maternal use of fertility drugs,36 use of erythropoetin,37 level of maternal education,36 breech presentation,23 and being the first born.23 FIGURE 3 A, The venous blood contained within a venous malformation imparts a bluish hue that may lead to Highlights of This Section misdiagnosis as a deep IH. B, Bleeding into surface vesicles of a lymphatic malformation may lead to misdiagnosis as an IH. • The incidence of in the gen- eral population is approxi- mately 5%. vasculogenesis, or the de novo This concept developed from • Risk factors for IH include formation of new blood vessels.39,40 research showing that molecular being white, being female, This theory is supported by studies markers characteristic of placental and having a low birth showing increased numbers of tissue, including GLUT1, Lewis Y weight. circulating EPCs in blood samples antigen, merosin, Fc-g receptor-IIb, 41 • Associations are also from children with IH. Additional indoleamine 2,3-deoxygenase, and reported with older mater- evidence comes from studies in which type III iodothyronine deiodinase, 3,9 nal age, multiple gestation multipotential stem cells derived were also present in IHs. Clinical pregnancy, placenta previa, from IH specimens (HemSCs) have evidence for this theory is suggested preeclampsia, use of fertility shown the ability to recapitulate by those studies showing an fi 42 drugs or erythropoietin, human IH in immunode cient mice. increased incidence of IH in breech presentation, and These HemSCs and cord blood EPCs association with chorionic villus being the first born. behave similarly to each other in sampling, placenta previa, and several in vitro assays, suggesting preeclampsia.24,30,31 that circulating EPCs could be the A unifying theory suggests that IH 42 origin of IH endothelial cells. The results from aberrant proliferation concept that IHs originate from and differentiation of a hemogenic PATHOGENESIS AND HISTOPATHOLOGY circulating multipotent progenitor endothelium with a neural crest cells could explain some of the Pathogenesis phenotype and a capacity for features they share with placental endothelial, hematopoetic, The pathogenesis of IH, despite blood vessels, because dysregulated mesenchymal, and neuronal intensive study, has not been circulating EPCs have also been differentiation. It is hypothesized that completely elucidated. Lines of implicated in many of the associated placental chorionic villus evidence support a cellular origin maternal and fetal comorbid mesenchymal core cells embolize to from either intrinsic endothelial conditions (preeclampsia, retinopathy the developing fetus and that the progenitor cells (EPCs) or angioblasts of prematurity, etc). HemSCs have timing of this embolization in relation of placental origin, but intrinsic and also been shown to have an to the migration of neural crest cells 43 extrinsic factors are also thought to adipogenic potential, which may along their somitic routes determines 38 contribute to their development. explain the presence of adipocytes the morphology of the IH (segmental fl Intrinsic factors include the in uence noted during involution. The stimulus versus localized [focal]; see section of angiogenic and vasculogenic for division of EPCs is unknown but entitled “Clinical Appearance”).44 factors within the IH. External factors may be a somatic mutation or The cytokine niche within the IH, include tissue hypoxia and abnormal signals from local tissues. including vascular endothelial growth fi developmental eld disturbances. The theory of placental origin factors (VEGFs), insulin-like growth The EPC theory holds that IHs suggests that fetal progenitor cells factors, the tumor necrosis develop from clonal expansion of arise from the disruption of the factor–related apoptosis-inducing circulating EPCs, resulting in placenta during gestation or birth. ligand-osteoprotegerin (TRAIL-OPG)

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1063 pathway, and the renin-angiotensin is an important sensor of hypoxia.9 Histopathology system, subsequently regulates GLUT1 has been shown to be Grossly proliferative and early growth of the IH and its response to upregulated in hypoxic zones of involutive IHs are well-circumscribed, pharmacologic therapies.44 Other mesenchymal tumors and in unencapsulated masses with red-to- – authors have also embraced the umbilical cord derived human tan cut surfaces. Later involutive “niche” concept, suggesting that mesenchymal stem cells under lesions are fibrofatty in consistency hypoxic conditions.49,50 Hypoxia- circulating EPCs find their way to and less defined. The histologic induced factors produced by certain locations that provide features of IH change dramatically as endothelial cells appear to play an conditions favorable for growth into they proceed through their natural important role in trafficking of placentalike tissues.44 In tissues such course of neonatal presentation, rapid progenitor cells to ischemic tissue. as the skin and liver, progenitor cells growth, and subsequent involution, These factors have been shown to be may encounter the cellular signals requiring interpretation within the upregulated in the blood (VEGF-A, and local tissue factors required to proper clinical context.52–54 There is MMP-9) and in IH tissue (stromal no sharp dividing line between stimulate their development. cell–derived factor 1a, MMP-9, VEGF-A, proliferation and involution, and On the basis of the rapid proliferation and hypoxia-inducible factor 1a) features of involution typically coexist of endothelial cells, earlier from children with proliferating IH.41 with features of proliferation during investigations of IH origin focused on In addition, it has been shown that much of the process. Early proliferative angiogenesis, the sprouting of the use of erythropoietin in preterm phase IHs are composed of well- endothelial cells from existing blood infants increases the risk of defined, unencapsulated masses of vessels. Such studies have shown an developing an IH.37 Thus, tissue capillaries lined by plump endothelial increased concentration of angiogenic ischemia resulting in cells rimmed by plump pericytes factors in IH, such as basic fibroblast neovascularization from circulating growth factor (bFGF), VEGF-A, EPCs has been proposed as the embedded within a multilaminated insulin-like growth factor, and matrix stimulus leading to the development basement membrane without metalloprotease (MMP) 9 within the of IH.41 Clinically, an area of pallor or associated smooth muscle cells (Fig 4). lesion during proliferation.45 Also decreased blood flow in the skin has Lesionsatthisstagemayatleast in this phase, investigators been noted to precede the focally resemble other rapidly growing have identified indoleamine development of IH, further vascular proliferations such as early 2,3-deoxygenase, a protein thought to supporting this hypothesis.51 pyogenic granulomas. The proliferating slow the involution of IH by inhibiting capillaries are arranged in lobules, fi cytotoxic T-lymphocyte response.46 separated by delicate brous septae or During involution, endothelial cell by normal intervening tissue. These apoptosis is accompanied by lesional capillaries, depending on tissue downregulation of angiogenic factors, location, intermingle nondestructively Highlights of This Section fi fi whereas inhibitors of angiogenesis with super cial skeletal muscle bers, • such as interferon-b and markers of may develop either from in- peripheral nerves, salivary glands, and cell maturation such as intercellular trinsic endothelial progenitor adipocytes. Endothelial cells and adhesion molecule 1 are cells (EPCs) or from angio- pericytes show variably enlarged upregulated.47 It has also been shown blasts of placental origin. nuclei and abundant clear cytoplasm. that involuting IHs exhibit decreased • IH growth is affected by in- Normally configured mitotic figures are production of nitric oxide, trinsic influences, such as relatively numerous (Fig 1B); and a potentiator of the VEGF pathway, as angiogenic and vasculogenic widespread expression of cell measured by reduced levels of factors within the IH, and by proliferation markers, such as Ki-67, endothelial nitric oxide synthase.48 external factors such as tis- confirm that both pericytes and endothelial cells are actively dividing. It has been hypothesized that hypoxia sue hypoxia and de- fi Because proliferative phase IHs are triggers a vascular response in velopmental eld high-flow lesions, although typically infants. As discussed above, LBW is disturbances. without significant arteriovenous a significant risk factor for IH, and in • A unifying theory proposes shunting, they often contain enlarged utero hypoxia is a common cause of that circulating EPCs migrate draining veins with thick, asymmetric LBW. Not surprisingly, there is to locations in which con- mounting evidence of the role of ditions are favorable for walls. hypoxia in the development of IH. growth into placentalike Involuting IHs present different GLUT1, a facilitative glucose tissues. diagnostic challenges. Mitotic figures transporter used as a marker for IH, wane, and apoptotic bodies and masts

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1064 FROM THE AMERICAN ACADEMY OF PEDIATRICS cellular linings. Epidermal atrophy Highlights of This Section and underlying fibrous scar tissue may be present if the lesion ulcerated • Proliferating IHs are well in the proliferative phase. Large circumscribed and lack arteries and veins modeled during the a capsule. high-flow proliferative phase do not • Involuting IHs are fibrofatty completely regress when the capillary and less defined. bed drops out and thus are often • GLUT1 is a commonly used present in involuting IH. This immunochemical marker for phenomenon, paired with loss of IH. FIGURE 4 endothelial mitotic activity, may lead Proliferative phase IH. Well-circumscribed lobules to mistaken histologic diagnosis as of closely packed capillaries composed of a vascular malformation. plump endothelial cells and pericytes are sep- Misdiagnosis can usually be avoided CLINICAL PRESENTATION, arated by normal-appearing dermal stromal COMPLICATIONS, AND ASSOCIATIONS elements (hematoxylin and eosin stain; original by considering overall histologic fi 3 magni cation 100; photo courtesy of Paula appearance and clinical history. Phases of Growth North, MD.) Ultimately, as discussed below, the issue can be resolved by GLUT1 IHs exhibit a characteristic life cycle. immunoreaction, because involuting Clinical observations have suggested that there are at least 2 dynamic cells increase in number during early infantile IHs, but not malformations, evolutionary phases, namely, involution.48,55 Lesional capillaries will show GLUT1 immunopositivity in proliferation and involution. begin to disappear. There is no residual lesion-type capillaries.9,56 Proliferation occurs during early evidence of thrombosis, and Histologic examination, accompanied infancy; gradual spontaneous inflammation is not prominent. As by routine immunohistochemical involution or regression starts by involution proceeds, lesional capillary studies, shows that proliferative 1 year of age.58–65 An intermediate basement membranes become thick phase infantile IHs are complex period between proliferation and and hyalinized and contain specks of cellular mixtures with large involution during mid-to-late infancy, apoptotic debris (Fig 5). Eventually complements of endothelial cells, often referred to as the “plateau” all that remains in an end-stage lesion pericytes, mast cells, and interstitial phase, more likely represents is loose fibrous or fibrofatty stroma, dendritic cells. Electron microscopy a period of temporary balance containing a few residual “ghost” reveals plump endothelial cells lining between individual cells that are vessels composed of residual, small lumina and resting on proliferating and those undergoing thickened rinds of basement a multilaminated basement involution and apoptosis.59–66 The membrane material containing membrane that envelops a cuff of process of involution takes several apoptotic debris and without intact pericytes. The endothelial cells of IH years and varies in duration. have been reported to immunoreact “ ” positively for normal endothelial Proliferative Phase (Up to 12 Months of markers of the blood vasculature, Age) such as CD31, CD34, factor fi VIII–related antigen (von Willebrand Premonitory ndings in the skin factor), and others.57 Currently, the during early infancy may include most useful and widely used localized blanching or localized immunohistochemical marker for the macular telangiectatic erythema. diagnosis of IH is GLUT1.9,57 GLUT1 is As endothelial cell proliferation strongly expressed by endothelial continues, the IH enlarges, becomes cells of IHs at all stages of their more elevated, and develops evolution and is not expressed by a rubbery consistency. During this other benign vascular anomalies and period, IHs often show surrounding FIGURE 5 reactive proliferations. GLUT1 pallor and dilatation of surrounding Involutive phase IH. Lesional capillaries are set veins. During rapid growth periods, fi immunohistochemistry is frequently within loose bro-adipose tissue and are less ulceration may arise, leading to pain densely packed than in the proliferative phase. used to distinguish IHs from other Note the thickened and hyalinized basement vascular neoplasms and provides and eventual scarring. membranes studded with apoptotic debris, convincing evidence that IHs are IHs typically have their clinical onset reflective of the involutive process. Residual lining endothelial cells are mitotically inactive. indeed as biologically distinctive as before 4 weeks of age.66,67 They (Photo courtesy of Paula North, MD) they are clinically distinctive. proliferate for variable periods of

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1065 time, depending in part on their morphology and configuration. However, most IH growth appears to occur between 1 and 2 months of age.68 A large prospective study has indicated that 80% of IH size is generally reached by 3 months, and most growth is completed by around 5 months of age.66 Deep IHs appear somewhat later and grow somewhat longer than their superficial counterparts.66

Involution Phase For most infants with IH, involution FIGURE 6 begins between 6 and 12 months of Cutaneous IHs may be classified on the basis of their depth. A, Superficial IHs are visible only at the age. Although the process continues skin surface and may be focal (as shown) or segmental. B, Deep IHs have no surface involvement. C, Mixed, or compound, IHs have both superficial and deep components. over years, the majority of tumor regression occurs before age 4.48,69,70 As IHs involute, most lesions flatten soft tissue depth.61,62,72 Superficial superficial and deep IHs. These and shrink from the center outward. IHs (Fig 6A) are those in which the observations indicate that deep IHs For those with a superficial component, surface of the tumor appears red and require a longer period of this is accompanied by “central there is little to no discernible monitoring than those with clearing” or graying of the surface. subcutaneous component; superficial morphology. Although IHs generally undergo historically, these IHs have been A specific subtype of superficial IH spontaneous regression, observations described as being of the has been variably referred to as an of “maximal involution” do not “ ” strawberry type. Deep IHs (Fig 6B) abortive, nonproliferative, arrested- necessarily imply complete are those in which the tumor resides growth, minimal-growth, nascent, resolution. Indeed, approximately deep to the skin surface, and their reticular, or telangiectatic IH.73–76 50% to 70% of IHs resolve, leaving subcutaneous location results in This type of IH presents as a macular, behind residual skin changes, a bluish surface hue or no evident telangiectatic patch that may be including telangiectasia, fibrofatty surface changes; historically, these accompanied by blanching of the tissue, redundant skin, anetoderma, “ ” have been referred to as cavernous, involved skin (Fig 7). Unlike most IHs, dyspigmentation, or scar.71 an imprecise term that is no longer abortive IHs lack an obvious commonly used. Combined, mixed, or significant proliferative phase. compound IHs (Fig 6C) are those in Approximately two-thirds of these fi Highlights of This Section which both super cial and deep lesions are situated on the lower components coexist. • IHs usually make their initial extremities. Many are accompanied fi appearance before 4 weeks Super cial IHs tend to appear earlier by localized, small papular regions of of age and complete most of and begin to involute sooner than vascular tissue growth, often around 77 their growth by 5 months of their deep counterparts, which, the periphery. Abortive IHs share age. by contrast, tend to arise later with more typical IHs characteristic and grow for longer periods surface markers (eg, GLUT1), • Involution of IHs begins as of time before involuting (on confirming that they are true IHs; the child approaches 12 average, approximately 1 month however, their growth phase may be months of age. In most cases, more).62,64,66 Investigations into arrested. Many of these telangiectatic the majority of involution is these differences confirm that these IHs also involute more rapidly, completed by age 4. timelines represent characteristic sometimes before 1 year of age.78 growth patterns for these IHs rather Nevertheless, complications such as than arising out of observational ulceration may occur. These IHs may bias.66 As might be expected, those also be segmental and occasionally Clinical Appearance IHs with a mixed morphology have have syndromic associations (see During the proliferative phase, IHs a growth pattern that is intermediate section entitled “IH Syndromes and can be classified on the basis of their between those associated with Associations”).79

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1066 FROM THE AMERICAN ACADEMY OF PEDIATRICS definitively focal or segmental are Multifocal cutaneous IHs are considered indeterminate. Multifocal frequently isolated to the skin but lesions are focal lesions occurring at may also serve as markers for more than 1 anatomic site. One large underlying hepatic involvement study found that most IHs (67.5%) are (Fig 9).88–91 Previous retrospective localized, whereas the remainder were reports26,81 suggested that the segmental (13%), indeterminate presence of a large or segmental (16.5%), or multifocal (3.6%).83 (.5 cm) cutaneous IH might prove Thepresenceofalarge,facial a useful marker for hepatic IHs. FIGURE 7 segmental IH is a hallmark sign of However, results from a large Abortive IHs are macular, telangiectatic patches 25 prospective study suggest that it is that have failed to fully proliferate. PHACE syndrome, whereas large segmental IHs of the anogenital and the number of cutaneous IHs rather lumbosacral areas may be associated than their size that is the more 92 IHs may also be classified on the basis with genitourinary system and predictive factor. When 5 or more of their anatomic configuration as spinal cord anomalies as part of IHs are present on cutaneous either localized (focal), segmental, other syndromes84–86 (see section examination, ultrasonography may indeterminate, or multifocal.26,80,81 entitled “IH Syndromes and be helpful in assessing potential 84,93 Localized (focal) IHs are discrete Associations”). More recently, it has hepatic involvement. lesions that seem to arise from been recognized that extracutaneous Hepatomegaly and congestive heart a single focal point, whereas manifestations may also arise in failure also suggest the presence of segmental lesions cover a territory association with segmental IHs liver IH. that is presumed to be determined by involving other anatomic sites, as embryonic neuroectodermal part of the so-called PHACE-without- placodes.82 Segmental IHs tend to face phenomenon.87 These patients Highlights of This Section involve a larger surface area of skin. may have segmental IHs of the upper • IHs are characterized as su- Segmental IHs of the face have been chest, shoulder, or arm in the perficial, deep, or mixed and observed to conform to unique absence of facial IH involvement and as focal, multifocal, or developmental units, which have in conjunction with structural heart segmental. been mapped into 4 distinct patterns: disease, aortic or other major vessel • Superficial IHs appear ear- frontotemporal, maxillary, anomalies, central nervous system lier and begin involution mandibular, and frontonasal and sternal defects, or eye sooner than their deeper 82 (Fig 8). Lesions that are not anomalies. counterparts. • Segmental IHs are more commonly involved in PHACE (see text for defini- tion) and other IH syn- dromes and associations. • The presence of more than 5 focal IHs suggests a higher risk of hepatic involvement.

FIGURE 8 (A) Patterns of segmental IH of the face extracted from image analysisdefined. Seg1 (fronto- FIGURE 9 temporal), Seg2 (maxillary), Seg3 (mandibular), and Seg4 (frontonasal). (B) An ulcerated segmental Multifocal cutaneous IHs in a child with IH of IH in the maxillary distribution. the liver.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1067 Complications to develop complications and 8 times usually results in scarring, with the 84 fi Although most IHs do not require more likely to receive treatment. risk of permanent dis gurement. As urgent treatment, a minority may Segmental lesions tend to have longer a result, prompt initiation of therapy develop function-threatening or life- proliferative phases, some with is essential in the management of fi threatening complications, signi cantly prolonged duration of ulcerating IHs. necessitating therapeutic growth as long as 10 to 44 months, The specific mechanisms resulting in intervention. One study determined and may therefore require IH ulceration are poorly understood. fi that approximately 24% of patients signi cantly longer treatment It has been hypothesized that 94 with IH who were referred to a group durations. ulceration may develop secondary to of tertiary care dermatology practices The size of the IH was also an increased tissue hypoxia, which leads experienced some complication important predictor of the need for to the development of dermal fibrosis related to their IH.84 It is therefore treatment in the aforementioned and then progresses to surface prudent for pediatric providers to cohort study, although this analysis breakdown.98 In such cases, early remain vigilant of possible did not appear to control for white discoloration of an IH, possibly complications and of risk factors that anatomic subtype.84 The mean size of representing superficial dermal may herald future complications. complicated IHs was 37.3 cm2, fibrosis, may be a premonitory sign of 2 99 Ulceration accounts for the majority compared with 19.1 cm for impending ulceration. Other of IH complications; others include uncomplicated IHs. In addition, IHs proposed mechanisms include bleeding, visual impairment, that received treatment of any type outgrowing of the blood supply or had a mean size of 30.4 cm2, which rapid expansion exceeding the elastic auditory impairment, congestive was 11.1 cm2 larger than those that capabilities of the skin.99,100 heart failure, and airway did not receive treatment. However, obstruction.84 Gastrointestinal Several studies have shown that the mean size of segmental IHs is bleeding has been reported as certain subsets of patients with IHs approximately 10 times that of a complication of segmental are at higher risk of ulceration. As localized IHs,66 suggesting that intestinal hemangiomatosis, in which discussed previously, superficial and morphology may indeed be a more the IH is typically situated in the segmental IHs have been found to important indicator of potential distribution of the mesenteric be at higher risk of complications. – arterial system.94 ulcerating.96 98,101 In addition, Anatomic location was also specific locations at higher risk of The single best predictor of a predictor of complications due to ulceration include the head, neck, complications and the need for IH.84 Facial IHs were complicated 1.7 perioral, and perineal/perianal therapeutic intervention for IH is times more frequently than nonfacial regions and intertriginous sites morphologic subtype.84 Focal IHs IHs; they were also 3.3 times more (Fig 10).96–98,102 The neck and have the potential to cause likely than their nonfacial anogenital regions sustain complications primarily by virtue of counterparts to receive some form of maceration and friction, which may their location on or near vital therapy, likely because of concerns contribute to the development of structures, such as the eye for cosmesis. Periocular IHs and ulceration. Ulceration has also been (amblyopia, astigmatism), nose those in the “beard” distribution are noted to occur more frequently in (anatomic distortion and also more likely to require infants younger than 4 months, cartilaginous destruction), ears intervention, as described below. In a period of time during which the IH (anatomic distortion and 1 study, perineal IHs were the most cartilaginous destruction), lips likely to ulcerate.95 (anatomic distortion and ulceration), airway (obstruction), or anogenital region (ulceration). On the face, focal Ulceration lesions are 3 times more common Ulceration, or breakdown of the IH than segmental IHs.81 Segmental IHs skin surface, occurs with an are more frequently complicated by estimated incidence of 5% to 21%.96 ulceration.84 A prospective cohort Ulceration was the most common study in 1058 patients undertaken to complication in a large prospective identify clinical characteristics cohort of children with IHs, predicting complications and need for occurring in 16% of the study 97 treatment found, after controlling for population. Ulceration can lead to FIGURE 10 size, that segmental IHs were 11 significant pain, bleeding, and Ulcerated segmental IH of the perineal/perianal times more likely than localized IHs secondary infection. Ulceration also region.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1068 FROM THE AMERICAN ACADEMY OF PEDIATRICS is actively proliferating.96–98 See the IHs had feeding and oral sensory develop noisy breathing or a hoarse section entitled “Management of problems that resulted in failure to cry.106 ” 105 Ulcerated IH for a discussion in thrive. The cutaneous findings associated greater detail. with underlying airway involvement, Airway Involvement and Obstruction when present, help to identify those Bleeding Airway IHs can occur in the presence patients at greatest risk of airway or absence of skin findings. IHs. Cutaneous IHs in a “beard” Although concern for potential Symptomatic obstructive airway IHs, distribution, defined as involving the bleeding in IH is common among including supra- and subglottic IHs, preauricular regions, chin, anterior caregivers and providers, it occurs usually present with progressive neck, or lower lip (Fig 11), have been rarely and almost exclusively in biphasic inspiratory and expiratory associated with airway ulcerated lesions. The majority of stridor during the first 6 to 12 weeks involvement.106,107 Infants with IHs bleeding that occurs in nonulcerated of age as the lesion is proliferating.105 within this distribution bilaterally IHs is minor and easily controllable Affected infants may also rapidly appear to be at an even higher risk of with pressure. The most common such scenario is an IH that has sustained minor surface trauma (ie, from friction or a fingernail), bled minimally, stopped bleeding spontaneously or with minimal sustained pressure, and subsequently presents with surface hemorrhagic crusting. In a large prospective study of ulcerated IHs, bleeding occurred in 41% of lesions but was clinically significant in only 2% of these cases.96,98 Significant bleeding requiring blood transfusion or other intervention is infrequently reported.98 Rare instances of life- threatening bleeding have been observed, including 1 report of ulceration of a segmental neck IH into arterial vessels, the bleeding from which necessitated transfusions, systemic and topical treatment of the IH, embolization, and surgical excision.102

Feeding Impairment Feeding impairment can occur in infants with IHs involving either the perioral region or the airway. Infants with ulcerated lip IHs may be unable to latch onto a nipple secondary to severe pain, which can lead to impaired feeding.103 Obstructive airway IHs may complicate breathing and swallowing, also leading to impaired feeding.104 In FIGURE 11 “ ” a small case series in infants with A, The presence of multiple IHs in the beard distribution is associated with a higher likelihood of airway involvement (reproduced with permission from J Pediatr. 1997;131(4):643–646 ©Elsevier).106 complicated facial IHs, several with B and C, Patient with airway involvement requiring tracheotomy is shown with “beard” involvement ulcerated perioral lesions or airway at the lip and chin (B) as well as the parotid area and neck (C).

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1069 having associated airway compromise usually improves with anomalies. The best-known such involvement; in a recent series in treatment of both the heart failure association is PHACE (Online 17 infants with airway IHs, bilateral and the IH. Mendelian Inheritance in Man 114 involvement of the lower facial Diffuse lesions of the liver may also 606519). The disorder is also segment was present in 13 be associated with severe referred to as PHACES to include 106,108 (76%). Early referral to consumptive hypothyroidism caused potential ventral midline defects, fi S otolaryngology of infants with severe by excess production of type 3 speci cally ternal cleft and/ or S stridor and a cutaneous IH in the iodothyronine deiodinase. Liver IHs upraumbilical raphe. Originally “ ” “ ” beard distribution is advisable, are discussed in greater detail in the described as a syndrome, PHACE is because airway involvement can be subsection entitled “Liver” of “IHs more appropriately termed an life-threatening if diagnosis and With Special Anatomic Concerns.” association, although there are recent treatment are delayed. In less data suggesting that chromosomal symptomatic children, a high region 7q33 may provide a genetic kilovoltage radiograph of the airway susceptibility to exhibit the PHACE Highlights of This Section may be useful in identifying phenotype.115 subglottic IH. Airway IHs are • Segmental IHs are far more The spectrum of anomalies in PHACE discussed in greater detail in the likely than focal IHs to result syndrome and the ipsilateral subsection under “IHs With Special in a complication, usually relationship between such anomalies Anatomic Concerns” entitled ulceration. and cutaneous IH strongly suggest “Airway.” • Focal IHs cause complica- a “developmental field defect,” tions primarily by virtue of Visual Impairment and Other Ocular whereby an insult at a critical time in their location on or near vi- embryogenesis gives rise to similar Complications tal structures. developmental outcomes.116 The IHs occurring within the orbit have the • Facial IHs cause complica- precise timing of such an insult in potential to cause mechanical ptosis, tions more frequently than PHACE syndrome is speculative, but strabismus, anisometropia, or nonfacial IHs and are several both the anatomic IH patterns and astigmatism, which can quickly lead to times more likely to receive several of the associated structural the development of amblyopia.108 some form of therapy. abnormalities point to changes early Studies have identified specific • Minor bleeding from an during the first trimester, probably characteristics of periocular IHs, which ulcerated IH is common, but within the first 3 to 12 weeks of place the child at higher risk of rarely of clinical significance; gestation before or during early amblyopia. These include periocular bleeding from a non- vasculogenesis.117 PHACE syndrome IHs that are larger than 1 cm in ulcerated IH is rare. is now understood to be diameter, nasal location of the IH, • predominantly a congenital associated ptosis, eyelid margin Patients with an extensive “ ” vasculopathy. In fact, many of its change, or displacement of the IH in the beard distribu- features can be explained as globe.109–111 Orbital IHs are discussed tion are more likely to have downstream events of arteriopathy in greater detail in the subsection involvement of the airway. with resultant ischemia, and it has entitled “Eye and Orbit” under “IHs • High-risk periocular IHs are With Special Anatomic Concerns.” those that are that are larger been hypothesized that vascular than 1 cm in diameter, lo- dysplasia may be a key or even Congestive Heart Failure and cated near the nose, associ- primary event in the pathogenesis of 118 Hypothyroidism ated with ptosis or eyelid PHACE syndrome. Although rare, high-output congestive margin change, or displacing Consensus criteria were recently heart failure can occur in infants with the globe. developed for the diagnosis of PHACE large IHs as a result of arteriovenous • Diffuse IH of the liver may syndrome (Tables 2 and 3).25 Clinical shunting of a large blood volume be associated with severe examination of the skin and eyes as through the lesion. This complication consumptive well as detailed imaging of the head, has been reported in infants with hypothyroidism. neck, and chest are required to make large cutaneous IHs and RICHs and in the diagnosis. More than 90% of those with diffuse or multifocal infants with PHACE syndrome exhibit hepatic IHs.91,92,112,113 Symptomatic more than 1 extracutaneous anomaly, infants may present with difficulty IH Syndromes and Associations although very few manifest the feeding, poor growth, heart murmur, A small subset of children with IH will complete spectrum.119 In contrast to or hepatomegaly. The cardiac exhibit associated congenital nonsyndromic IH, PHACE syndrome

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1070 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 2 Consensus Algorithm for the Diagnosis of PHACE Syndrome is more common in full-term PHACE Syndrome Possible PHACE Syndrome singleton infants of normal birth Facial hemangioma Facial hemangioma Hemangioma of the No hemangioma plus weight, although females are still .5 cm in diameter .5 cm in diameter neck or upper 2 major criteria more commonly affected.120 plus 1 major criterion plus 1 minor torso plus 1 major The hallmark of PHACE syndrome is or 2 minor criteria criterion criterion or 2 fi minor criteria a large, segmental, often super cial Adapted from ref 25. IH, characteristically located on the face, scalp, and/or neck (Fig 12). PHACE syndrome–associated IHs most commonly affect facial segments 1 and/or 3, which also confers a particularly high risk of associated central nervous system TABLE 3 Consensus Diagnostic Criteria for PHACE Syndrome involvement.84,119 Organ System Major Criteria Minor Criteria PHACE syndrome is not exceedingly Cerebrovascular Anomaly of major cerebral arteries Persistent embryonic artery other rare, and probably even more Dysplasiaa of the large than trigeminal artery common than Sturge-Weber cerebral arteriesb Proatlantal intersegmental 121 Arterial stenosis or occlusion artery (types 1 and 2) syndrome. The segmental IH with or without moyamoya Primitive hypoglossal artery associated with PHACE is collaterals Primitive otic artery sometimes confused with the port Absence or moderate-severe wine stain associated with Sturge- hypoplasia of the large Weber syndrome, especially in the cerebral arteries fi Aberrant origin or course of newborn period before signi cant the large cerebral arteriesb IH proliferation or in cases of Persistent trigeminal artery “minimal growth” IH in which there Saccular aneurysms of any is an absence of significant cerebral arteries proliferation. The risk of PHACE Structural brain Posterior fossa anomaly Enhancing extraaxial lesion with syndrome in an infant presenting Dandy-Walker complex or features consistent with with a large, segmental IH ($22 cm2) unilateral/bilateral cerebellar intracranial hemangioma of the head or neck is approximately hypoplasia/dysplasia Midline anomalyc 120 Neuronal migration disorderd one-third.

Cardiovascular Aortic arch anomaly Ventricular septal defect Cerebrovascular anomalies, present Coarctation of aorta Right aortic arch (double aortic arch) in more than 90% of patients, are the Dysplasiaa most common extracutaneous feature Aneurysm of PHACE syndrome, followed by Aberrant origin of the subclavian cardiac anomalies (67%) and artery with or without a 84 vascular ring structural brain anomalies (52%). The most common arterial Ocular Posterior segment abnormality Anterior segment abnormality abnormality in PHACE syndrome is Persistent hyperplastic Microphthalmia primary vitreous Sclerocornea dysgenesis of the anterior circulation, Persistent fetal vasculature Coloboma particularly within the internal Retinal vascular anomalies Cataracts carotid artery.119 The neuroanatomic Morning glory disc anomaly and cerebrovascular anomalies Optic nerve hypoplasia observed in PHACE may lead to Coloboma Peripapillary staphyloma a number of neurologic sequelae, including motor and speech delays, Ventral or midline Sternal defect Hypopituitarism seizures, migraine-like headaches, Sternal cleft Ectopic thyroid and rarely, arterial ischemic Supraumbilical raphe 121 Sternal defects stroke. Hearing loss (conductive or Adapted from ref 25. sensorineural) has also been reported a Includes kinking, looping, tortuosity, and/or dolichoectasia. in PHACE syndrome, particularly b Internal carotid artery, middle cerebral artery, anterior cerebral artery, posterior cerebral artery, or vertebrobasilar when the IH involves the ear and system c Callosal agenesis or dysgenesis, septum pellucidum agenesis, pituitary malformation, or pituitary ectopia. periauricular scalp, which can be d Polymicrogyria, cortical dysplasia, or gray matter heterotopia. related to the presence of ipsilateral

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1071 to be segmental and often “minimal growth” in morphology.85 Such IHs were often extensive (eg, involving the entire leg) and showed additional potential for ulceration and, rarely, underdevelopment of the affected limb. Like PHACE syndrome, the cutaneous IHs and underlying anomalies showed regional correlation. Myelopathies, particularly spinal dysraphism, were the most common extracutaneous anomaly. Interestingly, arterial anomalies were noted in a minority of patients who were specifically studied FIGURE 12 A, Frontotemporal segmental IH typical of PHACE syndrome. B, Sternal clefting characteristic of for such anomalies, although the true PHACE syndrome (scar is congenital, not surgical). incidence and long-term risks are unknown. Imaging is region-specific; intracranial IH involving auditory risk infants, progressive MRI is useful in delineating the extent structures. It has been suggested that cerebrovascular changes may be of lumbosacral involvement and children with PHACE syndrome and identified early, and neurosurgical potential myelopathy, whereas periauricular IH be evaluated with revascularization procedures can be additional imaging with MRA may be both MRI and audiometric testing.122 performed to potentially reduce arterial warranted for infants with extensive – Cardiovascular anomalies are the ischemic stroke related morbidity and lower limb involvement to assess for 125 second most common extracutaneous mortality. Thepresenceofsevere arterial anomalies. manifestation of PHACE syndrome. The cerebrovascularand/orcardiovascular aortic coarctation observed differs from arterial anomalies in patients with classic coarctation in that it occurs in PHACE syndrome may preclude the use Highlights of This Section amoreproximallocation,often of propranolol for treatment of IH in • PHACE syndrome includes involves the arteries feeding the upper this population, or require dose features of Posterior fossa extremities, and affects longer modification. (see section entitled defects, Hemangiomas, cere- segments, which may preclude “Medical Therapy for IH”). brovascular Arterial anoma- detection based on a blood pressure L LUMBAR syndrome ( ower body IH lies, Cardiovascular gradient between the upper and lower U and other cutaneous defects, rogenital anomalies including co- extremities. The aortic anomalies in M anomalies and ulceration, yelopathy, arctation of the aorta, and PHACE syndrome are often noted to be Bony deformities, Anorectal Eye anomalies. particularly unusual and severe, often malformations and arterial anomalies, • The hallmark of PHACE requiring surgical repair; thus, detailed and Renal anomalies) may be best imaging of the arch is essential.123 syndrome is a large, seg- considered the “lowerhalfofthebody” mental IH, characteristically Even in asymptomatic infants, MRI or 85 variant of PHACE syndrome. located on the face, scalp, magnetic resonance angiography LUMBAR has also been previously and/or neck. (MRA) of the head and neck is described under the competing • indicated, especially given the known acronyms SACRAL87 (Spinal The most common extra- potential for progressive vasculopathy dysraphism, Anogenital anomalies, cutaneous features of PHACE and resultant ischemic events in a small Cutaneous anomalies, Renal and syndrome are cerebrovascu- subset of severely affected patients.124 urologic anomalies, associated with lar anomalies, followed by Arterial ischemic stroke, a rare but Angioma of Lumbosacral localization) cardiac anomalies and devastating complication, appears to be and PELVIS86 (Perineal hemangioma, structural brain anomalies. more likely in patients with PHACE External genitalia malformations, • LUMBAR syndrome may be who exhibit significant narrowing or Lipomyelomeningocele, Vesicorenal best considered the “lower nonvisualization of large cerebral abnormalities, Imperforate anus, Skin half of the body” variant of arteries, especially when more than 1 tag). The IHs are usually segmental PHACE syndrome and may vessel is involved and/or if there are lumbosacral or anogenital lesions. In an be associated with urogeni- associated cardiovascular morbidities analysis of 24 new patients and tal, anal, skeletal, and spinal such as coarctation of the aorta.125 a review of 29 published cases, IHs in cord anomalies. Through serial neuroimaging of high- association with LUMBAR were noted

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1072 FROM THE AMERICAN ACADEMY OF PEDIATRICS IMAGING OF IH high-flow feeding arteries and CLINICAL APPROACH TO IH The diagnosis of IH is generally made draining veins. With administration of The traditional clinical approach to on the basis of history and clinical intravenous gadolinium, lesion IH has been one of “benign appearance. Occasionally, imaging of enhancement is usually early, with neglect.”60 The observation that, as the lesion may be required when the intense and uniform enhancement on a neoplasm, IH has the unique diagnosis is uncertain, when delayed images; however, diffuse or ability to undergo involution has evaluation of extent is necessary, or multifocal hepatic lesions may show led many practitioners to believe when response to therapy needs to be early enhancement peripherally and that the best management is to monitored. IH-associated anomalies, delayed filling centrally (centripetal “leave it alone and it will go away.” such as spinal dysraphism, enhancement).91 Nonenhancing However, 1 study from a group of anogenitourinary anomalies, and regions may represent thrombosis or referral pediatric dermatology PHACE syndrome, are also best necrosis. During the involution phase, practices suggests that more than imaged with MRI. However, the risk of as deposits of fat replace the lesion, one-third of patients with IH early exposure to anesthesia is foci of increased signal can be seen on require some sort of a consideration in determining the T1-weighted images, and postcontrast intervention.84 Hence, although urgency and type of imaging for IH. images reveal less avid enhancement. this number may reflect referral bias, it is clear that some IHs are Ultrasonography is a reasonable Computed tomography (CT) is associated with a high risk of initial imaging modality for mentioned only because it is diagnosing IH, because it is complications or permanent occasionally ordered when inexpensive and does not require disfigurement. In many such cases, a diagnosis of IH is not expected. CT sedation. The sonogram generally early intervention may be justified findings are similar to those on MRI, reveals a well-defined high-flow to potentially arrest the growth of including well-defined and avidly parenchymal mass with possible the lesion, reduce associated shunting. During the involution enhancing lesions during the complications, and avoid years of phase, areas of increased echogenicity proliferating phase and less psychosocial concerns. pronounced enhancement during the (fat replacement) can be seen within The first consideration in the the lesions. Gray scale and color involution phase. Although these studies are shorter in duration than management of IH is whether Doppler ultrasonography have also intervention is necessary. The demonstrated utility in monitoring MRI (reducing the likelihood that general anesthesia will be necessary), indications for intervention include the response of IH to medical the following: (1) emergency 127 CT carries the disadvantage of therapy. Ultrasonography is also treatment of potentially life- a good first-line modality to screen exposing young children to ionizing radiation and its attendant risks. threatening complications; (2) patients with multifocal IHs for liver urgent treatment of existing or or visceral involvement, although MRI imminent functional impairment, is preferable to assess complicated or pain, or bleeding; (3) evaluation to 128 Highlights of This Section extensive visceral lesions. identify structural anomalies • Imaging of IH is not usually The extent of the lesion and the potentially associated with IH; and necessary. surrounding anatomy are better (4)electivetreatmenttoreducethe shown on MRI. The most useful • When imaging of IH is per- likelihood of long-term or sequences include T1-weighted formed, ultrasound is gen- permanent disfigurement. Life- images with and without fat erally the preferred modality threatening lesions include saturation, T1-weighted images with for diagnosis, whereas MRI obstructing IHs of the airway as fat saturation post–gadolinium is better to assess extent of well as liver IHs associated with administration, T2-weighted images the lesion. high-output congestive heart with fat saturation, and flow-sensitive • Imaging may be required failure and severe hypothyroidism. sequences such as gradient echo or when the diagnosis is un- Pain and bleeding are examples of MRA.129 Proliferating IHs typically certain, when evaluation of urgent sequelae that occur as appear as well-defined masses with extent is necessary, when a result of ulceration; affected features of high flow and intermediate the IH is a possible marker children may have failure to thrive signal intensity on T1-weighted of PHACE or LUMBAR syn- as well. Other examples of images and high signal intensity on drome, or when response to functional impairment include T2-weighted images.130,131 Flow voids therapy needs to be ocular impairment (loss of visual may be apparent on T2-weighted and monitored. axis leading to deprivation flow-sensitive sequences, along with amblyopia, astigmatism,

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1073 FIGURE 13 Uncomplicated IHs. These lesions generally do not require medical or surgical intervention.

strabismus, visual field cuts), ones in early infancy.132 For less complication and urgency of impaired feeding because of concerning IHs, providers may intervention; potential for adverse involvement of the lips or mouth, wish to counsel the family psychosocial consequences; parental and reduced mobility because of regarding changes of importance, preference; and clinician experience. complicated involvement of the such as rapid growth or ulceration, A Cochrane review found a dearth of extremities. Structural anomalies of and to establish with the family well-designed clinical trials on which concern include spinal dysraphism ameanstoseethechildonshort appropriate interventions for IH could associated with lumbosacral IHs as notice if such changes are be determined.133 well as anomalies associated with observed. Whether IH affects the psychosocial “ ” PHACE and other IH syndromes. Central to the decision of whether well-being of affected patients, and the Long-term and permanent to intervene is a discussion of the age at which it may do so, is uncertain. disfigurement is a concern with IHs risks, benefits, and alternatives Some authors suggest that “children of certain anatomic sites (eyelid, associated with each of these first represent and reflect on nasal tip, lip, breast, genitalia) and choices and with each potential themselves as independent, objective with severe ulceration, because intervention. Proper informed entities” in the latter half of the second these will ultimately leave a scar of year of life134 and that the emotional similar size. consent from the family is paramount in achieving responses of others may affect ’ Most IHs are uncomplicated and a successful and satisfying a child s mood even earlier than 12 135 are not likely to fall into any of physician-patient relationship as months of age. Thus, there may be these categories (Fig 13); the well as a good therapeutic result. some effect on the child even before practice of initial observation or entering preschool. In contrast, “watchful waiting” is reasonable Once a decision has been made to a review of the existing literature on for such lesions. However, intervene, the second consideration is psychosocial ramifications of IH was because the clinical presentation which therapeutic modalities are most less concerning.136 Among the 7 of IH can change within days, appropriate. There is no formula or studies cited, questionnaires that were it is prudent for pediatric algorithm that easily addresses all of validated but not specificforIH providers to reexamine frequently, the factors in this decision; as a result, revealed few or no signs of as often as weekly, those the treatment plan is customized for psychosocial impact in children with children with lesions at high risk each patient. Relevant factors include IHs. The authors did note that the of causing functional or age and medical condition of the studies were conducted in small cosmetically critical changes, patient; growth phase, location, groups of parents, and all were flawed because many uncomplicated and size of the lesion or lesions; in one way or another. In a small study, lesions may become complicated degree of skin involvement; severity of quality of life among children 5 to 8

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1074 FROM THE AMERICAN ACADEMY OF PEDIATRICS years of age who had IHs of the head patients who have undergone early Highlights of This Section and neck measuring 2 cm or greater surgery and in whom residual IH • was compared with that of normal intentionally or inadvertently remains The indications for in- controls. Although the questionnaires postoperatively, there is potential for tervention for IH include the were not disease-specific, the authors additional growth of the lesion after following: 1. emergency treatment of found no differences in quality-of-life the procedure. In addition, because 137 potentially life- indices or in self-perception scores. IHs are benign lesions with the threatening Further complicating this subject is potential to involute, surgeons do not the fact that quality-of-life complications; always endeavor to obtain disease-free investigations in young children 2. urgent treatment of margins, instead allowing involution require proxy reporting that often existing or imminent to assist in achieving the final result. reflects quality of life as perceived by functional impairment, On occasion, in surgery for well- the proxy rather than the child. Thus, pain, or bleeding; fi involuted IHs, tissue may even be left no de nitive statement can be made 3. evaluation to identify fi behind intentionally, using the regarding psychosocial rami cations structural anomalies po- fibrofatty remnant to serve as filler to of IH; however, many clinicians who tentially associated with preserve normal tissue contours. specialize in the field will consider IH; and treatment of those IHs projected to be Lesion-related factors, such as 4. elective treatment to re- cosmetically significant beyond 4 location, size, and degree of skin duce the likelihood of years of age.70 involvement or ulceration, often long-term or permanent Details related to IH stage have been dictate the feasibility of a given disfigurement. addressed in a study examining treatment modality. For example, • There is no algorithm to de- 66 growth characteristics of IHs. The a pedunculated eyelid lesion termine the most appropri- largest increase in IH size occurred at causing ptosis or ectropion or ate intervention for IH. a mean age of 3 months, and by 5 a small, ulcerated lesion that is Factors affecting this choice months of age both segmental and certain to scar may lend itself include the following: localized IHs had reached 80% of better to early surgical excision 1. age of the patient, their final size. As a result, therapy rather than medical therapy. 2. growth phase of the lesion, initiated after the early proliferative Conversely, an extensively phase is less likely to be effective in 3. location and size of the ulcerated segmental IH or a lesion controlling the growth of the lesion or lesion, of the genitalia is more in prevention of complications. Age 4. degree of skin appropriately addressed with and stage are also factors in the involvement, medical therapy. effectiveness of pharmacotherapy for 5. severity of complication IH. Early experience with systemic Parental preference is another and urgency of steroids for IH suggested that critical factor in treatment intervention, younger children had a better selection, more so in elective cases 6. potential for adverse 138,139 response to therapy, and than in those that are emergencies psychosocial most studies of their mechanism of or urgent cases. Parents will often consequences, action suggest they inhibit have strong feelings, particularly 7. parental preference, and components of the proliferative about surgical intervention or 140 8. physician experience. process. Similar data for systemic medical therapy, that will propranolol therapy are not yet have a major effect on treatment available, but proposed mechanisms planning for the child. Similarly, the of its action also suggest primary choice of treatment may be activity during proliferation.139,141 influenced by the experience of the Conversely, recent retrospective MANAGEMENT OF ULCERATED IHS treating provider and his or her studies indicate that b-blocker The management of ulcerated IHs familiarity with the diversity of therapy for IH can be effective potential interventions. For these includes attention to wound care, beyond the proliferative phase as 96 reasons, it may be preferable for pain, and IH growth. Unfortunately, well.142,143 complicated IHs to be managed by there are no high-quality studies to Age and growth phase are also a practitioner or team who has guide care of the ulcer, and therefore considerations when surgery for IH is experience with all of the available treatment preferences are often being considered. For example, in therapeutic options. based on case experience.132

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1075 Approaches to ulcerated IHs are Pain control is a significant issue in MEDICAL THERAPY FOR IH summarized in Table 4. infants with ulcerated IH. Pain can be severe and can disrupt sleep as well Background Some clinicians liken the as interfere with daily activities and/ Medical therapy for IH includes management of ulceration to that of or function. For example, ulceration both topical and systemic superficial burns and suggest culture located on the lips or oral mucosa administration of medications. and diligent wound care. In 1 study, may affect oral intake or feeding, Topical agents may be 16% of ulcerated IHs were whereas interference with urination a consideration for smaller, more considered to be infected on clinical or stooling may be seen in the setting superficial IHs or those for which grounds, and cultures revealed of perineal ulcerations. Oral pathogens in half of these cases.98 systemic therapy is contraindicated. acetaminophen and cautious use of Reepithelialization may be facilitated Systemic therapy is usually initiated topical 2.5% lidocaine ointment may by debriding crusts with the use of for large IHs, those with a high risk be effective in managing the pain of warm compresses. The ulcer is then of functional impairment or ulceration.96 With more severe fi covered with a barrier to prevent dis gurement, and those refractory ulceration, the use of narcotics may excessive drying, control pain, reduce to other initial therapies. be indicated for inadequately the risk of trauma and potential Beginning in the 1960s, systemic and controlled pain. Collaboration with bleeding, and reduce the risk of intralesional steroids were the experts in pain management may be bacterial colonization or infection. cornerstone of medical therapy for useful in this high-risk group of Such treatments may consist of IH. Shrinkage of IH with systemic infants. topical antibiotics or anesthetics, corticosteroid therapy was first wound dressings, barrier creams, or observed serendipitously among all of the above. Most ulcerations patients with improve with this conservative hemangioendotheliomas (KMP) approach to wound care. Highlights of This Section treated for thrombocytopenia in the Because ulceration is usually • Management of ulcerated IH late 1950s and early 1960s.152 In associated with proliferation of the consists primarily of the 1967, Zarem and Edgerton153 treated IH, therapies to curb its growth are following: 7 consecutive children with oral often used. Several case series have (1) barrier dressings, prednisolone for enlarging IHs. All 7 reported successful treatment of IH (2) pain control, and experienced cessation of lesional growth and no rebound growth after ulceration with propranolol (3) control of IH growth. therapy.144–146 Topical timolol has treatment. On the basis of this result, • Adjuvant therapies may in- been reported to be successful for Fost and Esterly138 treated 6 children clude the following: ulceration,147 but its absorption is with oral prednisone for extensive 1. topical agents, including unpredictable in this setting. Systemic IHs. All but 1 had dramatic regression antibiotics, anesthetics, or steroids may also be a reasonable after only 2 weeks of therapy. wound dressings, and alternative. Subsequent studies have continued to 2. pulsed dye laser. show efficacy, although physicians In refractory cases, pulsed-dye laser have raised concerns about potential (PDL) therapy may also be effective in managing ulcerated IHs.96,148–150 In a prospective study in 78 children, TABLE 4 Treatment Options in the Management of Ulcerated IH 91% of the patients responded to Wound Care Adjuvant Therapies laser therapy with a mean number of Dressings Antimicrobials 2.0 treatments.148 Thus, PDL therapy White petrolatum–impregnated gauze Metronidazole gel has been used as both monotherapy Nonadherent dressings (eg, Mepitel [Mölnlycke Mupirocin, gentamicin, bacitracin ointment and as adjunctive therapy in Health Care; Gothenburg, Sweden], Telfa Pain control [Covidien/Medtronic; Minneapolis, MN]) Topical managing ulcerated IHs; however, it Hydrocolloid dressings (eg, DuoDERM Anesthetics (eg, lidocaine, benzocaine) has been recommended that laser [ConvaTec; Luxembourg]) Oral therapy be used with caution in Topical agents Acetaminophen with or without narcotics patients with proliferating IHs because White petrolatum, Aquaphor [Beiersdorf Inc.; Other of the risks of atrophic scarring and/or Hamburg, Germany], Silver Becaplermin gel sulfadiazine (Silvadene; Monarch Topical timolol 151 ulceration. Surgical excision may Pharmaceuticals; Bristol, TN) PDL also be a consideration for small Early excision ulcerations that are poorly responsive Oral propranolol or steroids to medical therapy. Adapted from ref 368.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1076 FROM THE AMERICAN ACADEMY OF PEDIATRICS adverse effects of steroids become the first-line medical therapy; target hemangioma), compared with administered in large doses for long however, optimal dosing, treatment a 4% rate among those treated with periods of time. timing and duration, and risk of placebo.172 Another randomized trial In the late 1980s and early 1990s, complications have not yet been in 40 patients found a marked interferon-a showed some promise in established in randomized trials, and improvement in IH volume, redness, recommendations for monitoring are and elevation among those taking the treatment of steroid-resistant still evolving.161 An oral formulation propranolol compared with those IHs. This drug is a cytokine free of alcohol, sugar, and paraben taking placebo.173 In a 2011 produced by leukocytes that play developed for use in children comprehensive review of the a role in the innate immune (Hemangeol; Pierre Fabre, Castres, literature, response to propranolol response against viruses. When France) received approval from the therapy was evaluated in 79 articles synthetic interferon-a2a was used to US Food and Drug Administration in but quantified in only 6.160 Positive treat patients with HIV, an March 2014. There is a paucity of responses in all treated patients improvement in their Kaposi data regarding other b-adrenergic were reported in 86% of sarcoma lesions was noted.154 blockers.162 publications; the remaining 14% Because interferon-induced genes discussed at least some treatment are upregulated during involution of failures. In total, 19 of 1175 patients IH, there was a theoretical basis for Mode of Action in IH in these publications were reported its mechanism of action in IH,152 and as treatment failures, suggesting anecdotal reports as well as clinical The mode of action of propranolol in a 1.6% treatment failure rate.160 trials subsequently documented its the treatment of IH is unknown. Moreover, lightening of the color and efficacy in vascular lesions, including Proposed mechanisms include softening of the tumor was noted in IHs refractory to corticosteroid vasoconstriction, inhibition of most children within hours to days of therapy.156,157 However, it is now angiogenesis (via suppression of the initial dose of clear that significant neurologic VEGF-A and downregulation of MMPs propranolol.158,159,173,174 After toxicities, including impairment of and interleukin [IL] 6), regulation of initiation of propranolol therapy, higher cortical and motor function, the renin-angiotensin system, and progressive improvement has been can occur and generally preclude its inhibition of nitric oxide production; noted for at least 3 months in most use as a first-line therapy. propranolol’s ability to stimulate apoptosis is patients.158,159,173,174 Like systemic In 2008, Léauté-Labrèze et al158 equivocal.44,49,140,141,159,161,163–167 corticosteroids, propranolol appears reported their serendipitous Investigators have shown the presence to stabilize IHs in their growth phase; observation that oral propranolol, of b2-adrenergic receptors on however, it may also be effective after a nonselective blocker of capillary endothelial cells in proliferation has ended. In 1 study b-adrenergic receptors used for proliferating IH, and vascular that assigned visual analog scores to decades to treat cardiac disorders in endothelial cell growth factors, which IHs in children treated with children, is effective and well are elevated in rapidly growing IHs, propranolol at ages 7 to 120 months, tolerated in the management of IH. are suppressed in the presence of more than half of the patients A year later, they reported their b-adrenergic receptor achieved a greater rate of experience with 32 infants with blockade.158–160,168 It has also been improvement in their scores after severe IH who were treated with suggested that propranolol may starting the medication.143 Other propranolol at 2 to 3 mg/kg per day prevent the differentiation of IH stem authors have also reported similar 159 in 2 to 3 divided doses. These cells into endothelial cells or observations.142,175 infants responded well with a rapid, pericytes,169 reduce contractility of consistent, therapeutic effect and pericytes,170 and/or promote minimal adverse effects. Since that adipogenesis.140,165,171 Pretreatment Assessment, time, there have been numerous Contraindications, and Risks of Therapy additional reports of the safe and A complete history and physical effective use of propranolol for the Efficacy examination, with special attention to treatment of medically complex as In a randomized controlled trial of the cardiac and pulmonary systems, well as cosmetically significant oral propranolol in 460 infants aged 1 aid in assessing a child’s candidacy IHs.160 to 5 months with IH, patients for propranolol initiation. administered a dose of 3.4 mg/kg per Electrocardiography is often ordered b -Adrenergic Blockers day exhibited a 60% rate of as well, particularly in younger For most clinicians treating successful treatment (complete or infants, those with a low heart rate, complicated IHs, propranolol has nearly complete resolution of the and those with an examination or

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1077 TABLE 5 Contraindications and Potential generally asymptomatic and do not each dosage increase of $0.5 mg/kg Complications Associated With require intervention.177 Less common per day. Heart rates or blood Propranolol Therapy complications include bronchospasm pressure measurements lower than Contraindications Complications and hypoglycemia, the latter of which 2SDsfromthemeansuggestthe Sinus bradycardia Sinus bradycardia has the potential to induce need for cardiologic evaluation. It Hypotension Hypotension seizures.159,161,180,181 In a systematic should be noted that, where there Greater than Diarrhea was controversy, the group first-degree Cool extremities review of propranolol treatment of heart block Sleep disturbance IH, there were 371 total adverse recommended the most Heart failure Reactive airways effects reported in 1189 patients.182 conservative approach to Cardiogenic shock Hypoglycemia/seizures Those most commonly reported were propranolol initiation. Reactive airways sleep disturbance (136 patients), Hypoglycemia Theriskofhypoglycemiamaybe Hypersensitivity acrocyanosis (61 patients), reduced by administering to propranolol hypotension (39 patients, including 5 propranolol and feeding children “ ” hydrochloride considered symptomatic ), at intervals not to exceed 8 hours Adapted from ref 161. bradycardia (8 patients, including 1 (or 6 hours in younger infants).161 considered symptomatic), and Children with any acute illness, respiratory events including especially one interfering with infections, wheezing, and stridor (35 family history consistent with normal oral intake or one patients). congenital heart disease.161 Some associated with vomiting or clinicians also prefer to have diarrhea, will require close a cardiology consultation before monitoring and often a temporary Initiation of Therapy and Dosing starting the medication. However, decrease in dosing or cessation of pretreatment cardiac screening Although the optimal setting for the therapy. appears to be of limited value in initiation of propranolol has yet to be established, a consensus group patients with an unremarkable Duration of Therapy cardiac history and has suggested that inpatient examination.176–179 Relative hospitalization be considered for The most dramatic improvement contraindications to the use of infants 8 weeks of age or younger, using propranolol for IH occurs ’ propranolol for IH include preterm infants less than 48 weeks within 3 to 4 months of initiation of cardiogenic shock, sinus bradycardia, postconceptional age, those with therapy. However, many hypotension, heart block greater than poor social support, and those with investigators continue therapy until the first degree, heart failure, cardiac or pulmonary risk patients reach an age when IH would 161 bronchial asthma, and known factors. The group normally begin to regress without hypersensitivity to the drug recommended initiating therapy at treatment. Hence, treatment is often (Table 5).161 Special precautions have adoseof1mg/kgperday,with continued until at least 8 to 12 been suggested for children escalation to a target dose of 1 to months of age, which, in most 3 mg/kg per day, although this studies, equated to 3 to 12 months of diagnosed with PHACE syndrome and recommendation was made prior to therapy.160,172 For discontinuation of significant intracranial vascular the FDA approval of Hemangeol, therapy, most practitioners taper anomalies because of the theoretically which is dosed maximally at 3.4 mg/kg propranolol gradually over a period increased risk of acute ischemic per day. The optimal dose for of 1 to 3 weeks, primarily in an stroke.161 maintenance has yet to be effort to prevent rebound sinus Experience in the management of established. The group’s tachycardia. Rebound growth of hundreds of infants with IH has recommended dosing frequency was IH has been observed in 6% to shown propranolol to have an 3 times daily; however, the drug has 25% of children, often well after excellent safety profile and high also been dosed twice daily and their first birthday, leading some tolerability. The most commonly showed both safety and clinicians to wean propranolol over reported adverse effects of efficacy.172,183,184 Because the peak weeks to months.185–189 Rebound propranolol are sleep disturbance effect of oral propranolol on heart growth may be more likely in and coolness and mottling of the rate and blood pressure is 1 to 3 patients whose IH exhibited a long distal extremities. The use of hours after administration, the proliferative stage and a large b-blockers can be also be associated group suggested that these subcutaneous component.185 In such with adverse cardiac effects, measurements be taken at cases, reinitiation of therapy for including bradycardia and baseline, 1 and 2 hours after the variable periods of time may be hypotension, both of which are first dose, and 1 and 2 hours after necessary.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1078 FROM THE AMERICAN ACADEMY OF PEDIATRICS Topical b-Adrenergic Blockers The diversity of these effects may Highlights of This Section Several investigators have account for the variability in response, • Propranolol, administered reported success using topical particularly with the stage of the orally at a dose of 1 to b-blockers in the treatment of IH. treated lesion. Steroids inhibit 3.4 mg/kg per day, is effica- Timolol maleate is a nonselective neovessel growth in cultured human cious in reducing the size IH biopsies197 and IL-6–mediated b-adrenergic receptor inhibitor and color intensity of IH. neovascularization in a rat corneal available in a concentration of • model.198 Corticosteroids also inhibit 0.25% and 0.5%, which has been The mechanism of propran- ’ the expression of proangiogenic used by pediatric olol s effect on IH likely proteins, including VEGF-A, urokinase ophthalmologists in the United involves several processes, plasminogen activator receptor, States for more than 30 years as including vasoconstriction, monocyte chemoattractant protein-1, a first-line therapy in children with inhibition of angiogenesis, IL-6, and MMP-1, from human IH stem glaucoma. In recent years, an and stimulation of cells in a murine model.40,197 In extended-release gel-forming apoptosis. addition, glucocorticoids inhibit the solution has become available in • Common side effects of pro- antiadipocytic differentiation effect of concentrations of 0.25% and 0.5%. pranolol include sleep dis- preadipocyte factor 1199,200 and Systemic absorption of the gel- turbance and discoloration promote adipogenesis by increasing forming solution is significantly with cooling of the hands the expression of peroxisome lower than that of the solution, and and feet. proliferator activated receptor.201,202 absorption through intact skin is • Contraindications to the use This activity is thought to explain the likely much less than that through of propranolol for IH include development of the fibrofatty the conjunctivae and lacrimal cardiogenic shock, sinus residuum during involution of the 190 duct. bradycardia, hypotension, vascular components of IH. Case reports and case series have heart block greater than fi shown a good response of IH to rst-degree, heart failure, Systemic Corticosteroids bronchial asthma, and twice-daily topical application of Systemic therapy with corticosteroids timolol.191–195 In a randomized known hypersensitivity to the drug. for large and complicated IHs has, in controlled trial, timolol was more many centers, been supplanted by • A consensus report suggests effective than placebo in reducing systemic b-blockers. Nevertheless, that heart rate and blood the size and color intensity of small steroids have played a significant role fi 196 pressure be determined at super cial IHs. Laboratory in IH management over the past few baseline, 1 and 2 hours after studies were not monitored in the decades, and properly dosed and the first dose of propranolol, majority of studies, and only 1 monitored, they remain an effective and 1 and 2 hours after infant in 1 large series developed modality in the management of IH, each dosage increase a transient sleep disturbance. especially in patients in whom of $0.5 mg/kg per day. Responses were best in patients b-blocker therapy is risky or • who had superficial IHs, used the Administration of pro- contraindicated.203 One report in 60 0.5% gel-forming solution, and pranolol with feedings, and children with IHs treated with either 3 applied the medication for more holding doses if oral intake or 5 mg/kg per day of oral prednisone than 3 months.195 Many is compromised, reduces the found an excellent response in 68% experts now consider topical likelihood of hypoglycemia. and a good response in 25%; therapy timolol gel-forming solution • Topical application of timolol failed in 7%.204 A systematic literature areasonableconsiderationfor has shown efficacy in the review showed an 84% response rate uncomplicated, superficial IHs for management of superficial IHs. at an average dose of 2.9 mg/kg per which treatment is desired but the day of oral prednisone.205 Another risk-to-benefit ratio is too great to recent article reported the response to justify systemic b-blocker therapy. systemic corticosteroids was However, there are valid concerns Corticosteroid Therapy significant in 30% to 53% of cases, regarding the bioavailability of the The precise mechanism of action of equivocal in 35% to 40%, and drug when used topically in glucocorticoids in the treatment of IHs negligible in the remainder.206 In neonates and infants, especially in remains largely unknown. Evidence a prospective, randomized, the treatment of larger or ulcerated suggests that corticosteroid therapy investigator-blinded trial comparing lesions and those on or near has several effects on IH, involving prednisolone and propranolol dosed mucous membranes.190 both vasculogenesis and adipogenesis. at 2.0 mg/kg per day, the drugs

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1079 showed similar efficacy for reducing localized complications involving the occurs in lesions of the upper eyelid, the area of symptomatic IH; however, overlying skin or underlying tissues. with 3 cases of retinal embolization although prednisolone showed However, in appropriately selected having been reported after an a somewhat faster response rate, lesions, many authors consider injection of corticosteroids into IHs in propranolol was better tolerated with intralesional corticosteroid injection this region.221–223 This complication significantly fewer severe adverse an effective intervention, given its likely results from a combination of effects.207 Rebound growth occurs in effectiveness and the relatively high injection pressures (causing 14% to 37% during dose tapering, low frequency of reported systemic retrograde flow of the drug from the occasionally requiring the resumption adverse effects at low doses (#2–3 eyelid toward the apex of the orbit) of steroid therapy.205 This wide range mg/kg).210–219 and excessive injection volume.224 fl in rebound rates likely re ects the In most studies, patients were injected However, in several large series of varied duration of corticosteroid with either triamcinolone alone or intralesional corticosteroids for therapy reported in the literature. a mixture of triamcinolone and periorbital lesions, this complication Optimal dosing of systemic betamethasone, at total equivalent was not reported. Avoidance of this corticosteroids remains somewhat doses of triamcinolone doses of complication is discussed further in “ ” controversial. However, although ,3 mg/kg, by using a 27- or 30-gauge the subsection Eye and Orbit under “ recommendations for prednisolone needle.218 The interval between IHs With Special Anatomic ” dosing have ranged from 2 to 5 mg/ injections varied from 1 to 6 weeks.208 Concerns. kg per day,132,203,204,208,209 optimal After corticosteroid injection, large Topical Corticosteroids dosing appears to be 2 to 3 mg/kg studies have reported accelerated per day. The duration of therapy regression in 77% to 100% of patients The use of high-potency topical depends on response rate as well as with IH and cessation of growth in corticosteroids in IH is usually limited the age of the patient and phase of IH 16% to 23%.210–219 The effects of the to thin, superficial lesions. In the growth but generally ranges from 4 to steroid last approximately 3 to 4 initial reports in the 1990s, topical 12 weeks at full dose, followed by weeks216 and thus patients may clobetasol propionate was used for tapering over several months and require additional treatments during periocular IHs with good efficacy and completion of treatment by 9 to the proliferating phase for rebound no significant adverse effects.225,226 A 12 months of age.132,205 growth. subsequent retrospective chart review of 34 infants with Local complications of intralesional proliferating IHs who had been Intralesional Corticosteroids corticosteroids include fat and/or treated with high-potency topical dermal atrophy and/or The effectiveness of intralesional steroids found that 35% of the infants hypopigmentation (0%–3%).213–215 corticosteroid therapy for had good response, whereas 38% had problematic IHs was first described in Systemic adverse effects, including 227 – a partial response. A more recent 153 cushingoid features (0%–3%)213 217 1967 by Zarem and Edgerton, in comparison of topical mometasone and adrenal suppression,220 can the same article in which they furoate versus intralesional occur when very large doses of reported their success treating IH triamcinolone acetonide in superficial intralesional steroids are given ($5 with oral corticosteroids. IHs less than 5 cm in diameter mg/kg). A more serious complication Subsequently, numerous studies have showed that 86.5% (50% excellent, of intralesional corticosteroid therapy suggested that intralesional 36.5% good) of patients in the topical corticosteroid injection is a safe and group and 95.7% (63.8% excellent, 210–219 effective treatment of IH. TABLE 6 Potential Adverse Effects of 31.9% good) in the intralesional In general, corticosteroid injection is Systemic Corticosteroids group responded to the therapy.228 reserved for small, bulky, well- HPA axis suppression localized IH lesions. Large or diffuse Cushingoid features Adverse Effects of Corticosteroid IHs are more difficult to manage with Growth deceleration Therapy Weight gain/increased appetite intralesional corticosteroids because Hypertension Potential systemic adverse effects of of the following: (1) a large volume of Gastric irritation corticosteroids used in the treatment injectable steroid is more likely to Irritability of IH are presented in Table 6 and are cause systemic adverse effects220 and Insomnia the most common reason cited for (2) it is difficult to evenly distribute Immune suppression using propranolol as first-line Cardiomyopathy the corticosteroid throughout a large Steroid myopathy therapy. It should be noted, however, tumor. In lesions that are relatively flat Osteopenia that a few physicians have favored the or superficial, intralesional steroid Ocular adverse effects (glaucoma, cataracts) safety profile of corticosteroids over injection carries an increased risk of HPA, hypothalamic-pituitary-adrenal. that of propranolol.229

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1080 FROM THE AMERICAN ACADEMY OF PEDIATRICS Suppression of the hypothalamic- experts.238–240 Furthermore, it has Highlights of This Section pituitary-adrenal axis has been been suggested that infants not observed during therapy with both receive live vaccines during long-term • Despite their efficacy, sys- intralesional215–217,220,230,231 and corticosteroid therapy and that temic corticosteroids are no systemic132,232–236 steroids. clinicians consider checking vaccine longer considered by most However, incidence estimates for titers on completion of corticosteroid clinicians to be first-line hypothalamic-pituitary-adrenal axis therapy to assess the adequacy of therapy for IH due to the suppression vary widely, from response.237 associated risk of adverse 1.7%222 to 87%.234 Furthermore, effects. Ocular adverse effects of long-term although many patients experience • Corticosteroids, adminis- systemic corticosteroid therapy abnormal morning cortisol levels, tered orally at a dose of 2 to include cataracts241,242 and increased nearly all appear to normalize in 3 mg/kg per day, are effica- intraocular pressure,242–245 although afewmonths.220,231 cious in reducing size and neither has been frequently reported discoloration of IH. Temporary growth deceleration has among children in general or among • also been reported with both those being treated for IH in The mechanism of IH growth 218,220,232 intralesional and particular. The most serious ocular inhibition by corticosteroids 132,236,237 systemic steroid therapy of adverse effect is that of vision loss likely involves reduced vas- IHs. Almost all children experience caused by embolic occlusion of the culogenesis and enhanced “ ” catch up growth after completion of central retinal artery after adipogenesis. 236 therapy. Gastric irritation is seen in intralesional injection.221–223 • Corticosteroids adminis- 236 234 21% to 32% of patients taking However, the actual risk is thought to tered intralesionally and oral corticosteroids. This adverse be quite low and is primarily related topically also appear to be effect can be ameliorated by to high injection pressure.224,246,247 effective in certain subsets concomitant use of H2-receptor This complication is discussed in of patients with more local- 132,215,218 antagonists. Mild behavioral greater detail in the subsection “Eye ized IH, but their dosing and fi changes have been seen in up to 29% and Orbit” under “IHs With Special safety pro le are not well of infants receiving systemic Anatomic Concerns.” studied. 236 corticosteroid for IH therapy. These • Periodic reexamination of Cutaneous adverse effects of steroids include irritability, fussiness, insomnia, children receiving cortico- 230,234,236,237 are most often associated with and personality changes. steroid therapy for IH has intralesional and topical therapy. The Osteopenia is a known adverse effect been suggested for monitor- most common risks are atrophy and of long-term systemic corticosteroid ing of growth and blood hypopigmentation, although the therapy but is rarely observed in pressure as well as changes children with IH, which presumably is former is often attributable to the IH in the lesion(s) being related to the relatively short duration itself, whereas the latter is usually treated. and nonrepetitive nature of therapy transient.227,233 Other potential but typically used for the treatment of IHs. unusual risks include acne, Hypertension is also a risk of systemic periorificial dermatitis, striae corticosteroid therapy, but the distensae, and hypertrichosis. In Other Medical Therapies percentage of affected individuals is treating bulky IHs with intralesional therapy, cutaneous complications can Before the discovery of the therapeutic unknown and is likely dose dependent. fi be avoided by keeping the injection ef cacy of propranolol for IH, several Immunosuppressive effects of well below the dermis. otheragentswereusedinanattempt systemic corticosteroid therapy are to optimize efficacy and safety. This well known. These include increased Given the many potential adverse section will focus on 3 agents that have infection risk, reduced B- and effects of glucocorticoid therapy, many documented utility in the treatment of T-lymphocyte counts, and poor physicians will periodically reevaluate IH: vincristine, interferon-a,and response to vaccines.132,218,236,237 those infants receiving systemic imiquimod. Unfortunately, the adverse Rare cases of pneumonia attributable corticosteroids (oral or intralesional), effect profiles of these agents limit to Pneumocystis carinii infection have with specific attention to growth their usefulness, and they are generally been reported in infants taking variables and blood pressure. Some reserved as treatments only for corticosteroids for IH, and physicians will also reassess adrenal recalcitrant lesions. In addition, the prophylaxis of these patients with function at the end of therapy and potential usefulness of newer trimethoprim-sulfamethoxazole has determine the need for stress doses of angiogenesis inhibitors will be been advocated by some steroids on cessation of therapy. discussed.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1081 Vincristine neutropenia, and spastic diplegia. The drug was used 3 times weekly in Vincristine is a plant-derived vinca Although some have reported 10 patients and 5 times weekly in 8 alkaloid that impairs mitosis via response rates of up to 90% in patients, with a mean duration of fi microtubule formation. It has steroid-resistant lesions, the effect is therapy of 17 weeks. All super cial traditionally been used as gradual in onset, and rebound can IHs improved, but little or no change 254 a chemotherapeutic agent and occur on discontinuation. occurred in mixed and deep IHs. possesses multiple antiangiogenic Up to 20% of children treated with Irritation and crusting were the qualities. It induces endothelial cell interferon-a appear to develop most common adverse effects. This apoptosis and is also a potent spastic diplegia.255 This complication study was criticized because of the 263 inhibitor of endothelial cell growth, tends to occur later in the treatment lack of a control group. migration, and in vitro capillary-like course and may be irreversible.256 A subsequent phase II, open-label tube formation.248 Given that Some practitioners initially theorized study followed 16 children with 264 endothelial cells also possess a high that only interferon-a 2a, or perhaps mixed results. tubulin content, a biological rationale the preservative or vehicle, were the Although some proponents of for IH sensitivity to vincristine cause of these symptoms; however, imiquimod continue to use it for the exists.249 Most reports on the efficacy similar toxicities have also been treatment of superficial IH, irritation, of vincristine address the treatment reported with interferon-a 2b.257 crusting, and occasionally significant of patients with vascular lesions that Given these concerns, interferon-a is ulceration noted with treatment were not true IHs but rather KHE or generally considered a “last resort” seriously limit its utility. Imiquimod TAs associated with KMP.250 treatment, and most physicians prefer does not have a role in the treatment However, vincristine has also been to use propranolol, systemic of deep IHs. used successfully in the management corticosteroids, or vincristine before of function-threatening or life- treating with this agent. Antiangiogenic Agents threatening IHs (airway, orbital, or Although all of the above treatments hepatic).251,252 The drug is Imiquimod (Imidazoquinoline 5%) have antiangiogenic effects, a few administered weekly through newer therapies have specific a central catheter because of its This topical immune-response antiangiogenic mechanisms of action fi extreme vesicant and irritative modi er stimulates the innate that make them theoretically attractive potential. Adverse effects include immune system by augmenting the therapeutic options. Antagonists to irritation, neurotoxicity, loss of deep production of cytokines, including vascular growth factors or receptors, tendon reflexes, constipation, cranial interferons (a, b, and g); IL-10, IL-12, such as inhibitors of VEGF or bFGF, nerve palsies, and bone pain. and IL-18; and tumor necrosis factor. have been successfully used to blunt Alopecia, rash, and myelosuppression These agents enhance cell-mediated angiogenesis in tumor models and as are also possible. Reported adverse immunity and induce apoptosis. therapies for advanced neoplasms; effects were transient.253 This drug However, it may well be that however, the simultaneous ’ appears to be particularly useful in imiquimod s therapeutic effect on IH administration of cytotoxic agents patients with corticosteroid-resistant results from the inhibition of appears to be required to achieve KMP, but it is not a first-line therapy angiogenesis by these cytokines. In significant response rates.265 An for IH. addition, imiquimod downregulates incidental decrease in the size of proangiogenic factors such as bFGF a liver IH was noted in a patient Interferon-a and MMP-9 and upregulates other treated with bevacizumab, a VEGF Interferon-a 2a and 2b have both endogenous angiogenesis inhibitors, inhibitor.266 Most recently, the been used successfully for IH in including interferon-inducible protein antivasculogenic effect of rapamycin children.156,157 Interferon-a is given 10, tissue inhibitor of MMPs, and has been shown in a mouse 258 subcutaneously with an initial dose of thrombospondins. Topical hemangioma model; the drug 1 million IU/m2, increasing to 3 application of imiquimod has been diminished the self-renewal capacity million U daily over the first month of shown to markedly inhibit tumor of the IH stem cells while – therapy while monitoring neurologic cell induced angiogenesis in a human simultaneously inducing other 259,260 status, white blood cell count, and keratinocyte model. antiangiogenic effects on IH liver function status.206 Most patients In 2002, the successful use of endothelial cells.267 Rapamycin is have required between 2 and imiquimod was reported in the a macrolide known to have both 12 months of therapy. Adverse effects treatment of scalp IHs.261 immunosuppressant and are significant and include flulike Subsequently, a retrospective study antiangiogenic actions, and therefore reactions, rash, gastrointestinal reported the efficacy of topical the risk-benefit ratio of this agent will symptoms, transaminitis, imiquimod in 18 children with IH.262 need to be clearly established before it

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1082 FROM THE AMERICAN ACADEMY OF PEDIATRICS can be considered a safe alternative to for absorption by hemoglobin and of treated and observation groups.280 the agents currently available for the an appropriate exposure time to Although these findings have been treatment of IH. avoid the generation of excess disputed,281 another article authored thermal energy in adjacent tissues. by leading laser authorities suggested As indicated in these reports, PDL that infants were particularly Highlights of This Section achieves these parameters and has susceptible to complications from “ ” 151 • Medications other than become the workhorse laser in the PDL treatment. The controversy fi b-blockers and cortico- treatment of super cial vascular over laser use was recently rekindled steroids may have efficacy in lesions. by a study that showed an advantage 282 treating IH, but their utility is PDL was developed primarily for the to early laser management. limited by their safety profile. treatment of port wine stains. IHs Although small IHs may be treated • Vincristine is used for differ greatly in many respects. without sedation, children with larger lesions associated with KMP; Although port wine stains are lesions often require general however, such lesions are malformations made up of low-flow, anesthesia. Recent data suggest that KHEs and TAs rather than thin-walled ectatic postcapillary early exposure to general anesthesia IHs and are associated with venules, IHs are tumors made up of may have a negative effect on potential risks of irritation small capillaries lined with plump learning and behavior.283 As a result, and neurotoxicity. endothelial cells and have a higher repeated anesthetics required to treat rate of blood flow. IHs are also of such lesions may be less desirable • Interferon-a and imiquimod, more varied thickness. As a result, when the likelihood of improvement although effective in IH improvement in IH with the use of is low and other available treatment treatment, are associated PDL is somewhat less predictable options are available. with an undesirable rate of than that for port wine stains. The complications. Proposed uses for PDL in IH mechanism for laser destruction of management include the following: IHs has not been completely (1) early superficial facial IHs, (2) elucidated. treatment of compound IHs in which PDL has undergone multiple sacrifice of the overlying skin is LASER THERAPY FOR IH improvements since it was first undesirable, (3) refractory ulceration, fi Before the discovery of the efficacy introduced. Current models use and (4) signi cant residual fl of propranolol in the treatment of IH, a wavelength of 595 nm and larger telangiectasia or at IH persisting PDL therapy was frequently spot sizes (up to 10 mm) with higher after involution. a component of the treatment fluences, allowing the laser to strategy for IHs.268–277 However, penetrate deeper.279 Longer pulse Early Superficial IHs given their limited depth of durations facilitate the treatment of Although not all superficial lesions 279 penetration of less than 2 mm, these larger vessels. In addition, the warrant intervention, early treatment lasers proved useful primarily for introduction of dynamic cooling in cosmetically critical areas can superficial lesions and for deep and delivered to the skin before the laser reduce or eradicate a superficial compound lesions in which salvage pulse has made treatment safer and dermal IH, allowing the return of of the superficial skin was desired. less painful. normal dermis and preventing the Although many such lesions are now In the 1990s, many laser proponents atrophic scarring commonly observed – treated medically, laser therapy may embraced the theory that early laser after involution.268 277 Although stillhavearoleinIHmanagement, treatment could eradicate superficial topical b-blocker therapy is also an particularly when used as a part of proliferating lesions and, at the very option in managing small superficial multimodal therapy or in ulcerating least, reduce the discoloration of the IHs, there may be greater lesions refractory to other therapies. superficial component of a mixed IH. bioavailability of the drug when In the 1980s, technological advances As a result, children often received treating infants, particularly those imparted to lasers the capability of multiple laser treatments during their with IHs that have ulcerated or are selective photothermolysis, a process first year of life. However, a 2002 located near mucous membranes.189 by which blood vessels are selectively study in 120 children randomly PDL is a treatment option in such destroyed while causing minimal assigned to laser treatment or cases. collateral damage to surrounding observation found that the complete tissue.278 For laser light to be clearance or presence of minimum Treatment of Critical Skin optimized for this purpose, it needed residual IH at 1 year was not In certain anatomic locations, the to be of an appropriate wavelength significantly different in the PDL- sacrifice of skin that is atrophic or

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1083 still contains IH tissue is undesirable. During the involution phase of IH, Highlights of This Section The face, and the nasal tip in children are reevaluated periodically if particular, are areas in which the • Laser treatment of IHs may it is likely they might require excision removal of affected skin may leave be useful in early, non- of residual fibrofatty tissue, resection of undesirable scars or a poor color proliferating, superficial scarred/excess skin, or reconstruction match with grafted skin. In such lesions; management of of damaged structures. A residual scar cases, early laser treatment may critical skin; treatment of will always be present after ulceration preserve the overlying skin, allowing ulcerating lesions; “multi- of an IH and may therefore lower the it to be later lifted as a flap to modal” therapy; and man- threshold for surgery in some cases. provide access for excision of the agement of persisting Similarly, those lesions likely to leave deeperIH(demonstratedinFig17 postinvolution large fibrofatty residua may be later in report). telangiectasia. addressed early. Surgery is rarely an • Pulsed dye laser (PDL) is option for extensive IHs from which the Treatment of Ulcerated IH used most commonly be- resulting defect is too large to close The potential benefitof,and cause its light is preferentially primarily or for those cases in which evidence for, laser treatment of absorbed by hemoglobin. surgery will result in significant functional impairment or an ulcerated IH has previously been • Use of laser on proliferating unacceptable scar. Conversely, discussed (see the previous section and superficial IHs may lead “ resection of small, complicated IHs in entitled Management of Ulcerated to ulceration. IHs”).96,148–150 In most cases, such cosmetically favorable locations may • Atrophic scarring and hypo- intervention is a consideration only occasionally be preferable to months of pigmentation are also po- after medical management has observation and/or medical therapy. tential complications of laser failed. use in IH. As discussed earlier, the timing of intervention is based on the age of Persisting Telangiectasia or IH After Involution the patient, the degree of deformity, and whether the tumor is still After treatment or involution of IH, SURGICAL THERAPY FOR IH regressing. If a child has a minor superficial vascular ectasias deformity, postponing intervention frequently remain. These are Timing of Intervention until maximal involution has effectively treated with PDL.284 PDL ElectiveresectionofanIHduringthe occurred may obviate the need for may also be used to treat flat areas of proliferative phase is usually not a procedure. Following the patient residual IH tissue. necessary and occasionally ill advised. for as long as possible may also be Given their young age and the indicated for lesions in problematic Complications of Laser Therapy vascularity of the tumor, affected locations (eg, lip or nasal tip), Complications of laser treatment patients are at greater risk of anesthetic because maximal involution may include atrophic scarring and morbidity, blood loss, and iatrogenic facilitate reconstruction and reduce hypopigmentation, particularly in injury.287,288 In addition, in many the number of required individuals of darker complexion.151 locations such as the lip and nasal tip, interventions. fi Lasers are also capable of inducing the nal cosmetic result is superior Once it is obvious that a child will ulceration, although this is rare and when growth of the lesion has ceased require operative intervention, surgery seen more commonly in rapidly and the number of surgical is usually preferable in early childhood proliferating IHs and segmental IHs, interventions can be kept to (#4 years of age), before the child has which, if left untreated, also have a minimum. However, certain factors much awareness of the a higher risk of ulcerating lower the threshold for resection of lesion.287,288,290–292 However, by 81,84,151 spontaneously. Scarring is a cosmetically or functionally postponing intervention until at least 3 seen when the dermis between the problematic lesion during early infancy, years of age, the tumor has had time to 285 vessels is coagulated. In IHs in including the following: (1) involute, often facilitating the procedure which the dermis is largely replaced contraindication to pharmacotherapy, and improving the final cosmetic fi by vessels, ef cient (2) failure of pharmacotherapy to result.287,288 photocoagulation of these vessels ameliorate the problem, (3) focal will lead to scarring. Although the involvement in an anatomically complication rate of PDL use for IH favorable area, and (4) a high likelihood Location Considerations has not been studied, it is less than that resection will be necessary in the For an IH that causes a deformity that 1% in the treatment of port wine future (due to bulk or ulceration) and cannot be easily concealed (eg, on the stains.286 the scar will be the same.287–289 face), surgical intervention may be

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1084 FROM THE AMERICAN ACADEMY OF PEDIATRICS considered in early childhood to diameter of the original IH.293 This IHS WITH SPECIAL ANATOMIC prevent psychosocial morbidity. If the technique can also be used to alter CONCERNS tumor is hidden by clothing and is not a vertical forehead scar to a Eye and Orbit bothersome to the child, waiting for horizontal orientation. In the maximal involution to occur is scalp, lenticular excision and linear IHs of the orbit, eyelid, and acceptable. When considering closure is preferred to circular conjunctiva, also known as periocular resection, it is important to weigh the excision/purse-string closure because IHs, have the potential to cause postoperative scar after removal of a long linear scar is camouflaged a unique set of vision-related the IH against the preoperative by hair, whereas a circular scar may complications because of their appearance of the lesion. Linear scars leave an area of visible alopecia.288 anatomic location. Compression of are ideally placed along the relaxed Fibrofatty residuum from the the globe, obstruction of the visual skin tension lines in the anatomic deep component of an IH can axis, and extension into the area where the IH is located to be removed by using suction-assisted retrobulbar space have the potential facilitate the best possible cosmetic lipectomy; similar lesions on the to cause refractive errors, strabismus, outcome. cheek can occasionally be approached and amblyopia. Although evaluation Certain anatomic locations present intraorally to avoid a major and management follow principles specific challenges to the surgeon. cutaneous scar. common to all IHs, additional IHs of the auricular helix and nasal considerations in these cases strongly fl tip involve skin that does not move in uence clinical decision-making. well over the underlying cartilage Highlights of This Section The importance of early and is difficult to replace. Lesions ophthalmologic assessment of • Indications for surgery for of the lip that extend outside patients with periocular IH cannot be IH during infancy are limited the vermilion may require overemphasized. Ophthalmologic to the following: reestablishment of the vermilion- consultation is often necessary to 1. failure of, or contraindi- cutaneousborderaswellasthe determine the urgency of naturallabialcontours.Surgery cation to, pharmacotherapy; intervention. In addition, the full involving the eyelids, oral depth of these lesions within the orbit 2. focal involvement in an commissure, and genitalia also is often underappreciated on routine area anatomically favor- carries a risk of functional physical examination, as are visual able for resection; and impairment from the procedure field cuts and changes in refraction or itself. 3. a high likelihood that re- extraocular motion. section will ultimately be Technical Considerations necessary and the scar Amblyopia is the most common and Because an IH itself acts as a tissue will be the same regard- most serious ophthalmic expander, there is usually adequate less of timing. complication of periocular IHs. This disorder results when, because of skin to allow primary, linear closure of • During involution, surgery fl improper stimulation of the involved the wound; skin grafts and local aps may be indicated for excision eye, the portion of the brain serving are rarely needed. Because the tumor of residual fibrofatty tissue, that eye does not develop properly. is benign, the entire lesion does not resection of scarred/excess Amblyopia occurs in 43% to 60% of need to be removed; the goal is to skin, and/or reconstruction improve the appearance of the child of damaged structures. and subtotal excision is often • performed. For circular lesions Timing of surgery is based located in visible areas, the length of on the age of the patient, the the scar and distortion of location and degree of de- surrounding structures can be formity, and whether the minimized by circular excision and tumor is still regressing. purse-string closure.293 Although • Elective surgical intervention lenticular excision of such a lesion will for IH is reasonable after age result in a scar 2 to 3 times the 4 years because, by this age, diameter of the lesion, purse-string self-esteem and long-term closure, followed by second-stage memory begin to form and FIGURE 14 fi lenticular excision several the tumor has completed IH of the left eye causing visual eld cut and astigmatism. Untreated, the lesion could pro- months later, will leave a scar most of its involution. liferate, potentially resulting in deprivation approximately the same length as the amblyopia.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1085 children with untreated periocular involvement is common in typical the region all influence the treatment IHs, usually as a result of visual superonasal eyelid and orbit cases, method selected. deprivation or refractive but the strabismus is subtle and As with most IHs, treatment with 294–296 requires forced ductions or other errors. propranolol has become the mainstay testing to diagnose. Deprivation amblyopia occurs when of systemic therapy for periocular a bulky IH, usually in the upper Permanent eyelid deformity results lesions. Numerous case series eyelid, completely obstructs visual from direct invasion, vascular steal, or suggest success not only in input into the involved eye. The lack prolonged pressure of adjacent controlling the growth and size of the of input causes a maldevelopment of structures, including the levator lesion but also in improvement of visual pathways and may result in palpebrae superioris, tarsus, eyelash astigmatism.302–304 Unfortunately, irreversible loss of vision.297 follicles, and lamina papyracea. The perceived successes with propranolol Refractive errors are due to levator muscle can be salvaged with therapy may, in some cases, lead to astigmatism or anisometropia. early treatment, but prolonged delayed ophthalmologic referral for Astigmatism is the production of invasion produces a fatty, atrophic more subtle sequelae, resulting in a blurred image on the retina due to muscle akin to true congenital ptosis. irreversible changes and limiting altered curvature of the cornea and Tarsus, lash follicles, and the bones of treatment alternatives, underscoring occurs in 20% to 46% of patients the orbit also respond well to early the need for early ophthalmologic with periocular IHs.298 IHs causing intervention because the ongoing evaluation. this disorder usually involve the anatomic destruction or deformity Before the advent of propranolol, upper lid294 (Fig 14) but may occur in can be arrested at a very early stage. intralesional steroid injection was the lower lid as well. The astigmatism Preservation of the tarsus ensures a popular intervention for the can be reversed with early eyelid margin stability, whereas management of bulky periocular intervention, preferably before 9 maintenance of the bony socket IHs.299 With the use of a combination months of age. Beyond 13 months of prevents enophthalmos and facial of triamcinolone and betamethasone, age, astigmatism typically persists asymmetry. a response within 2 weeks could be despite involution of the IH;295,296 anticipated in 60% to 80% of Proptosis is the forward displacement however, some cases of improvement patients.305 However, intralesional of the globe from an intraorbital IH. during involution have also been steroids have been associated with – Occurring in approximately one-third reported.299 301 Anisometropia is a number of complications. Most a difference in refractive error of children with orbital IHs, proptosis feared is embolism of the central between the eyes that results in can result in impaired approximation retinal artery.221–223 This a relatively clear retinal image in the of the eyelids and corneal exposure. complication is thought to result eye with the smaller refractive error Optic neuropathy may also result from several factors, including high and a relatively blurred retinal image from compression or stretching of the injection pressures (causing in the eye with the larger refractive optic nerve.294 retrograde flow of the drug from error. Although children with Patients with PHACE syndrome may the eyelid toward the apex of the refractive errors attributable to IH present with a unique set of orbit), excessive injection volumes, can be treated with contralateral ophthalmologic abnormalities, and direct intravascular patching regimens, many still develop 224,246,247 including increased retinal injection. Although it has permanent spectacle dependence; in vascularity, microphthalmia, optic been argued that high pressures can many cases, the brain may ignore the nerve hypoplasia, exophthalmos, be avoided by using a large-capacity blurry image in the involved eye, 306 choroidal hemangiomas, strabismus, syringe and small bore cannula, resulting in amblyopia. colobomas, cataracts, and glaucoma. studies suggest that even these precautions may be insufficient in Strabismus, or misalignment of the Twenty percent of affected patients preventing embolization.224 Other eyes, occurs in approximately one- will have at least 1 of these findings, reported complications include third of children with untreated often on the side contralateral to the periocular IHs.294 Strabismus may hypopigmentation, atrophy of IH.118 result from deprivation amblyopia, subcutaneous fat, and full-thickness mechanical obstruction of extraocular Alternatives available to treat eyelid necrosis.307–310 With muscle movements, or direct periocular IHs mirror general improvements in systemic extraocular muscle invasion. Medial treatment options, but special medications and surgical techniques, rectus involvement is most common regional factors may influence the many now believe that there are and most obvious, producing final treatment plan. Urgency, laser better options for the management of esotropia. Superior oblique safety, and the luxuriant vascularity of periocular IHs.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1086 FROM THE AMERICAN ACADEMY OF PEDIATRICS Airway IHs can involve any part of the airway.314 The exact incidence of airway IH is unknown; however, over a 4-year period, 33 freestanding US children’s hospitals discharged an average of 2.5 patients with this diagnosis who had undergone an airway procedure.315 Symptoms of airway IH usually manifest during the period of rapid growth during the first few months of life. A total of 80% to 90% of affected infants will present within the first 6 months of life, with ameanageof3.6monthsat diagnosis.316,317 Most develop biphasic stridor and barky cough as the IH enlarges in the subglottis, the narrowest portion of the pediatric FIGURE 15 airway (Fig 15). Voice and Airway IH extending from the vocal folds inferiorly into the subglottic space, the narrowest region of swallowing are generally normal. the pediatric airway. (Photo courtesy of Jonathan Perkins, DO.) Often, the symptoms are mistaken for those of infectious or inflammatory croup or reactive Topical use of timolol has shown eyelid, and orbit preservation.312,313 airway disease, especially when the efficacy in the management of For periocular IHs that are symptoms worsen in the presence of superficial periocular IHs, as well as considered for surgical resection, upper respiratory illness. As IHs involving the conjunctiva and preoperative imaging aids in a result, symptoms are often present fi iris.194,311 This drug has replaced establishing the extent of the lesion. for several weeks before a de nitive Those that are best suited for surgery other topical therapies such as diagnosis is made. are located outside the bony orbit and imiquimod, which causes significant Approximately half of infants in well circumscribed and irritation of the skin, conjunctiva, whom an airway IH is diagnosed noninfiltrative on MRI.313 and cornea, and topical steroids, also will have a cutaneous IH, but which carry the risk of glaucoma only 1% to 2% of children with and cataract formation. Laser cutaneous IHs also have airway treatment (PDL) can also be very IHs.318,319 Symptomatic airway IHs effective in treating superficial Highlights of This Section can be associated with lower facial periocular IHs but usually requires • IHs of the periocular area have cutaneous or oral/pharyngeal mucosal corneal protection and general the potential to cause com- IHs in approximately 50% of anesthesia. pression of the globe, obstruc- cases.106,107 Periocular IHs are often diffuse and tion of the visual axis, and Most infants suspected of having an are therefore difficult to excise. extension into the retrobulbar airway IH on the basis of historical Surgery can also cause hemorrhage space, resulting in refractive and clinical presentation undergo that complicates the surgery and can errors, strabismus, and ambly- operative endoscopy.320 Imaging of cause postsurgical changes, such as opia, leading to vision loss. the head and neck may be useful in ptosis and ectropion, which may be • The permanence of ophthal- some cases to confirm the diagnosis of difficult to correct. However, early mic complications due to IH IH, to define the extent of the airway surgical removal, in selected lesions, is often related to their se- lesion, or to detect any associated eliminates the risk of amblyopia, verity and duration, under- vascular, brain, or chest anomalies that decreases amblyopia treatment times, scoring the need for early could affect treatment.321,322 Because and dramatically improves the ophthalmologic evaluation. these airway lesions have chances for extraocular muscle, a characteristic clinical and endoscopic

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1087 appearance, biopsy of airway IH is not initial management of all airway in patients with bilateral or usually necessary, but when IHs.338 circumferential lesions who may be at performed, the histologic appearance Corticosteroids may be helpful in risk of postoperative stenosis or and cellular markers are the same as refractory cases. Initial doses of require tracheotomy. However, open those of cutaneous IH.323,324 As in prednisolone at 2 to 4 mg/kg per day surgical excision may be more difficult cutaneous IH, airway IH can be are generally necessary to control in cases involving significant extension localized (focal) or extensive growth. Maintenance doses of outside the larynx, and the procedure (segmental), and many subglottic approximately 1 to 2 mg/kg per day may potentially result in some degree lesions show transglottic or are often considered before weaning paratracheal extension.108,314 The of dysphonia. the medication, and treatment more extensive the lesion, the more duration is based on clinical response. significant the airway compromise, Highlights of This Section Response rates reported in the and aggressive therapy is usually literature vary between 30% and • Most patients with IHs of the necessary to prevent airway 93%, although there is little airway have subglottic in- obstruction. consistency among dosing volvement causing biphasic The need for and type of intervention regimens.339 stridor and barky cough, of- for airway IH is determined by ten mistaken as croup. Voice Intralesional steroids are several factors, including the degree and swallowing are gener- a consideration for patients whose ally normal. of airway obstruction, the extent of IHs have necessitated endoscopy or • extralaryngeal IH, the location of the endoscopic resection. Although Diagnosis of airway IHs is patient at the time of diagnosis, the repeated injections are usually usually made by endoscopy experience of the treating physician, necessary as single-modality in the operating room. and the preferences of the parents/ therapy,327 these medications may be • In most cases, IHs of the caregivers. Because involution is the effective adjuvant therapy for airway may be managed ultimate fate of virtually all IHs, patients whose lesions are being medically; in cases of severe “watchful waiting” is reasonable in observed, treated pharmacologically, obstruction, surgical re- cases involving minimal or partially resected. Successful duction or excision may be symptomatology. In rare symptomatic management has been achieved in entertained. cases for which observation is still 77% to 87% of cases with the use of preferred or pediatric airway intralesional steroids.317,327 expertise is not readily available, Airway IHs causing focal obstruction Nose tracheotomy is occasionally may be addressed surgically by necessary.325 However, in most cases, Nasal IHs deserve special attention for a subtotal endoscopic approach by some alternative intervention for the several reasons. First, the prominence using a microscope or telescope or IH is more desirable. and central location of the nose make by total excision through an open it a critical facial feature. As a result, Before the advent of propranolol approach. Subtotal approaches even a small IH of the nose can have 317 therapy, endoscopic laser ablation generally use a laser or rotary- a greater effect on appearance than 340 or surgical excision was often powered instrument. However, a lesion of the same size located recommended in the management subtotal resection carries the risk of elsewhere. In addition, damaged nasal of airway IH, because the only growth of the residual lesion during tip skin is exceedingly difficult to medical therapy was long-term the proliferative phase, and laser excise or replace without considerable corticosteroids.317,326–330 However, treatment carries a 5% to 25% risk of cosmetic consequence. Functionally, many clinicians have now reported subglottic stenosis that is greatest a nasal IH may also cause collapse of success and low complication rates with deeper resections and in cases of the nasal introitus and intranasal using propranolol in the management bilateral or circumferential obstruction. 326,331–336 disease.326,341,342 of airway IHs. Although Focal nasal IHs account for 15% to the optimal dose and appropriate Open surgical excision of a focally 20% of all focal IHs of the face; of duration of therapy remain uncertain, obstructing airway IH became popular these, approximately one-third most clinicians are dosing the drug in the 1990s, after complications of involve the nasal tip.81 These lesions as they would for cutaneous IH.337 laser therapy became increasingly appear to have their origin in the Some authors have suggested apparent.329,343–345 The procedure is intercartilaginous ligament of the that treatment with propranolol useful in cases refractory to medical lower lateral nasal cartilages.346 As should become the standard for therapy and may be preferable to laser the IH grows, it displaces the

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1088 FROM THE AMERICAN ACADEMY OF PEDIATRICS playwright known as much for his prodigious proboscis as for his dramatic works.290,347 Segmental IHs involving the nose typically affect more nasal subunits than their focal counterparts, and they are more likely to ulcerate, resulting in destruction of critical areas such as the columella and ala. Conservative management of nasal IHs is associated with a poor outcome in most cases.129,209,348 As a result, early management of nasal IHs has been advocated to avoid complications and improve the likelihood of a favorable outcome,290,346,349,350 although the assumed benefit is yet unproven. The approach to nasal IHs is often multimodal, varying with the location, the stage, and the depth of the IH.290,350,351 Medical therapy may commence once the diagnosis has been made and it is clear that the IH is growing. The duration of treatment will depend on the type of lesion and its response. Focal IHs that respond to propranolol FIGURE 16 are generally treated until at least 9 Open rhinoplasty approach to nasal tip IH. These lesions (H) originate within intercartilaginous to 10 months of age, at which time ligament of the lower lateral nasal cartilages (arrows), rotating them outward. growth of these lesions is likely to cease. Rebound growth may be cartilages outward, rotating them in involution of the IH, will remain addressed by restarting the an “open book” fashion (Fig 16). The disfigured. The deformity has been medication for a month at a time until net effect is a bulbous, distorted nasal referred to as the “Cyrano” nose, after there is no further growth. Because tip, which, even with complete Cyrano de Bergerac, the French segmental IHs may proliferate for longer periods of time, weaning is often delayed until 18 months of age; rebound may be addressed with additional treatment in 3-month intervals. Propranolol-treated IHs of the nasal tip are less likely than untreated lesions to undergo surgery or laser therapy, but many lesions still require such interventions.352 Extensive skin involvement in focal lesions may respond to topical b-blockers or judicious use of laser (PDL) during proliferation (Fig 17). This treatment will salvage the skin FIGURE 17 by reducing the number of A, Compound IH of the nasal tip with significant surface involvement. B, Nasal tip after treatment intracutaneous vessels and will also with PDL to salvage tip skin before surgical resection. diminish the risk of venous stasis in

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1089 the deep component after surgical resection. It also helps to maintain more normal collagen and skin after proliferation has ceased. Similarly, for nasal lesions within segmental IHs that have failed to respond to medical therapy, it may be best to delay surgery until the overlying skin has been adequately treated.350 It is generally preferable to delay surgical intervention for such lesions until there is no further proliferation. PDL may also be used to treat residual involvement of the overlying skin after surgery. Nasal IHs that fail to respond to FIGURE 18 propranolol or leave significant Ulcerated IH of the lower lip has resulted in distortion of the soft tissue and obliteration of the vermilion-cutaneous border. residual tissue after treatment are usually addressed surgically. Although some authors have occurs, some infants will have advocated surgery for focal IHs as Highlights of This Section difficulty latching on to a breast or 346 earlyas10to12monthsofage, • Early management of nasal bottle nipple without discomfort, most physicians will operate at 1 to tip IH reduces the likelihood occasionally leading to failure to 353 3 years of age. This approach of poor cosmesis resulting thrive. Furthermore, the vermilion of allows for complete cessation of from skin excision and/or the lip is a unique tissue that cannot growth and adequate time for replacement and effects on be replaced if permanently damaged involution of small lesions that may the underlying cartilage. by ulceration,358 and reconstruction fi ultimately cause no signi cant • Goals of surgery for nasal tip of the normal lip contours after distortion of the tip. IHs include complete IH ex- ulceration can be challenging. Several publications have dealt with cision, reconstruction of the Proactive management of IH of the lip, the surgical approach to nasal cartilaginous framework, often systemic, is vital if ulceration is IHs.346,347,350,353–357 All of these and judicious skin excision to be avoided. However, in the lower publications predate the treatment and redraping. lip, some 30% of IH lesions ultimately of IH with propranolol, which has ulcerate.98 Once ulceration has clearly changed the management occurred, occlusive dressings are paradigm. The major issues in impractical, and therapies such as Lips surgery for IHs of the nasal tip relate topical anesthetics and petroleum- to adequate access and the ability to The lips deserve special consideration based products carry the risk of dispose of the excess skin once the in the management of IH due to their accidental oral ingestion. Occasionally, lesion has been removed. In general, critical role in cosmesis and function. children with IHs on the lip benefit smaller lesions may be addressed in Distortion of the lips from IH is from laser treatment of the ulcer, but a single procedure through an common, and restoring normal lip worsening of the ulceration is external rhinoplasty approach, contour is one of the greatest arisk.151 Early surgical resection is leaving a scar only on the columella challenges in reconstructive surgery. a consideration, but only for small of the nose.290,350,353,356 Larger IHs Furthermore, the lips (and the lower ulcers in cosmetically favorable may require external incisions on lip, in particular) are at increased risk areas. Otherwise, attention is best 96,98 the ala, also described as a “modified of ulceration, resulting in pain directed to systemic therapies to subunit approach,” which simplifies and bleeding in the short term and in reduce the likelihood of further fi excision and redraping of the increased scarring and dis gurement ulceration and of excessive lengthening skin.346 Surgery is also useful in in the long term. of the lip. restoring the normal position of the During proliferation, the goals of Reconstruction of a lip that is scarred lower lateral cartilages and other managing IH of the lips are to and disfigured because of IH is best components of the cartilaginous minimize distortion and to control performed only after growth of the framework. ulceration (Fig 18). Once ulceration IH has definitively ceased, because

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1090 FROM THE AMERICAN ACADEMY OF PEDIATRICS recurrence is certain to interfere be fraught with complications, failure, hepatomegaly, or abdominal with recontouring. Furthermore, management strategies generally distension.84,91,92 Hepatic IHs have the mucosa of the mandibular oral focus on those topical and systemic been characterized as occurring in 3 vestibule is most useful for medical remedies previously patterns: focal, multifocal, and reconstruction of the vermilion when discussed (see “Management of Acute diffuse.362 Focal singular lesions are it is free of the IH. IH Ulceration”). In rare cases, usually detected on antenatal Lesions located exclusively on the colostomy has been performed to imaging or as an abdominal mass in 361 vermilion can be removed by using facilitate wound care. the newborn infant. It is now clear a transverse mucosal incision to hide that these lesions are not true IHs; the scar at the junction of the rather, they are the hepatic vermilion and vestibular mucosa358; Highlights of This Section manifestation of a RICH, which explains why they are fully grown at lesions traversing both tissues may • IHs involving the lips and birth.362,363 They spontaneously require a vertical incision. Bulkier perineum have a tendency to involute 90% volumetrically by 13 lesions that cause lengthening of the ulcerate, and these regions months of age, and involution is not lip and those that cross the vermilion- are difficult to reconstruct. likely to be hastened by cutaneous border are best addressed Such lesions are appropri- pharmacologic agents.362 Diagnosis by using a wedge excision,359 with ately managed aggressively may be made by ultrasonography on some authors advocating a 2-stage with medical therapy. procedure to improve scar the basis of the presence of camouflage.358 In such cases, arteriovenous shunting or on CT or incisions may be placed along the MRI, which reveal hyperintense mucocutaneous junction or philtral Liver peripheral contrast enhancement columns. Debulking lip IH while and central sparing. Some hepatic The liver is the most common location RICHs have associated preserving vermilion can be for visceral IH. Research from the past performed through a mucosal macrovascular shunts (usually decade has contributed greatly to the hepatic artery to hepatic vein) that incision; however, it is often classification of hepatic tumors and to fi can cause high-output cardiac exceedingly dif cult to separate IH clarify their natural history.91,362 359 failure. If shunts are absent, a hepatic from orbicularis oris muscle. Previously viewed homogenously, and Eversion of the lower lip can be RICH can be observed with serial often treated inappropriately, it is now ultrasonography to determine corrected by excision of a mucosal becoming clear which patients are at strip, and correction of inversion may whether its behavior is typical. risk and what treatment options are Differential diagnosis can include require a lyophilized dermal implant sensible. or dermal graft.359 Setting the “white hepatoblastoma and mesenchymal roll” (ridge at the vermilion- Patients at risk of hepatic and other hamartoma. If imaging and cutaneous border) of the lower lip extracutaneous IHs are those with involution are not diagnostic, and restoring normal sublabial multiple or multifocal cutaneous IHs. percutaneous biopsy may be concavity may be particularly Because studies have documented indicated. If shunts are present and challenging.360 that infants with multiple cutaneous causing high-output failure, selective IHs are at increased risk of having embolization can ameliorate cardiac hepatic involvement, screening for failure, and the lesion can be allowed Perineum hepatic lesions with abdominal to involute. There is a very small risk Although perineal area IHs occur in ultrasonography has been suggested of rupture and hemorrhage with a nonconspicuous area, they are highly for infants with 5 or more cutaneous extremely large tumors. Surgical prone to ulceration. In case series from IHs.89,92,93 Other nonhepatic visceral resection or transplantation is rarely tertiary care dermatology practices, organ involvement is relatively rare in necessary. perineal IHs account for approximately infants with multiple cutaneous IHs; Multifocal and diffuse hepatic IHs one-third of all ulcerating lesions, and however, performing a thorough exist on a spectrum. They are true approximately 50% of IHs occurring in review of systems and physical IHs and often coexist with cutaneous 96,98 this area ultimately ulcerate. examination on any infant with lesions. In a prospective study in 151 Perineal ulceration can, at least multiple cutaneous hemangiomas is infants, 16% of infants with 5 or fi transiently, result in signi cant pain advisable. more cutaneous IHs were found to during defecation and urination and Infants with hepatic IHs may remain have hepatic lesions on screening during diaper changes. clinically asymptomatic or can ultrasonography.364 Multifocal Because surgical intervention present with life-threatening lesions have ample normal hepatic involving structures in this area may symptoms of congestive heart parenchyma between them.362 They

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1091 are often asymptomatic; however, with massive hepatomegaly and CONCLUSIONS some patients will have macrovascular abdominal compartment syndrome The management of IHs has evolved fl shunting causing high- ow and occasionally has disease that cannot considerably in the past decade. The possible high-output cardiac failure. wait for drug-induced involution; in serendipitous discovery of the These patients are best treated rare cases, such a child may be response of IH to systemic b-blockers pharmacologically with propranolol or a candidate for hepatic has expanded therapeutic options corticosteroids. Shunts will usually transplantation. for these tumors. Timolol, a topical close with involution of the IH. b-blocker, has shown promise as Selective shunt embolization is a potential therapy for superficial a consideration in those rare instances lesions. A greater understanding of in which rapid cardiac failure does not Highlights of This Section the indications and limitations of allow sufficient time for response to laser therapy also has emerged. • Hepatic IHs have been char- pharmacotherapy. Concurrently, bench research has acterized as occurring in 3 provided a deeper understanding of Diffuselesionshavelittlehepatic patterns: focal, multifocal, the origins of IH and patterns of IH parenchyma apparent between and diffuse. densely packed nodular IHs growth. It is anticipated that • Focal hepatic IHs are the throughout the liver.362 Patients continued research will further clarify hepatic manifestation of present with hepatomegaly, which can the etiology of IH, hopefully leading to RICH; they are fully grown at become massive. They may develop pathogenesis-directed therapeutic birth, and involution is al- abdominal compartment syndrome options. most complete by 1 year of with compromised ventilation, renal age. Although many IHs can be observed failure attributable to renal vein without treatment, others will clearly • Multifocal and diffuse he- compression, or poor inferior vena benefit from medical or surgical patic IHs are true IHs and caval blood return to the heart and intervention. It is important for often coexist with cutaneous may progress to death.92 Virtually all pediatricians to keep abreast of lesions. diffuse hepatic IHs cause acquired advances in IH management, because hypothyroidism attributable to the • Multifocal hepatic IHs have the types of intervention and the inactivation of thyroid hormones by normal hepatic parenchyma threshold for their use are likely to type 3 iodothyronine deiodinase between them. Many evolve. When complications are likely constituent in the lesions.365 patients are asymptomatic; or the threshold for intervention Hypothyroidism can be very profound however, those with high- is uncertain, referral to an fl and can require massive replacement ow and/or high-output experienced specialist or hormone dosing. Multifocal lesions cardiac failure require phar- a multidisciplinary vascular also suggest the need for prompt macologic therapy with pro- anomalies center may be thyroid screening, because they may pranolol or corticosteroids. advantageous. collectively contain enough tumor • Patients with diffuse hepatic mass to overwhelm endogenous IHs present with hepato- LEAD AUTHORS thyroid production.91,92,365 megaly that can lead to David H. Darrow, MD, DDS, FAAP compromised ventilation, Arin K. Greene, MD, FAAP Infants with diffuse hepatic IH, renal failure attributable to Anthony J. Mancini, MD, FAAP particularly those with congestive renal vein compression, poor Amy J. Nopper, MD, FAAP heart failure, are at greatest risk of inferior vena caval blood mortality.363 Aggressive CONTRIBUTING AUTHORS return to the heart, and pharmacologic therapy and thyroid death. Richard J. Antaya, MD, FAAP (Dermatology) hormone replacement are indicated Bernard Cohen, MD, FAAP (Dermatology) • for infants with such lesions. Effective Diffuse hepatic IHs may Beth A. Drolet, MD (Dermatology) IH treatment will result in a gradual cause acquired Aaron Fay, MD (Ophthalmology) Steven J. Fishman, MD, FAAP (Pediatric reduction in the requirement for hypothyroidism. • Surgery) thyroid replacement and eventual Most hepatic IHs are man- Sheila F. Friedlander, MD, FAAP (Dermatology) return to the euthyroid state.366,367 aged medically; rarely, em- Fred E. Ghali, MD, FAAP (Dermatology) High-flow shunts are uncommon in bolization, surgical Kimberly A. Horii, MD, FAAP (Dermatology) diffuse lesions. There is no role for resection, and trans- Manish N. Patel, DO (Radiology, Interventional plantation have been Radiology) embolization in the absence of Denise W. Metry, MD (Dermatology) macrovascular shunts and a high- necessary. Paula E. North, MD (Pediatric Pathology) output state. An infant who presents Teresa M. O, MD (Otolaryngology)

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1092 FROM THE AMERICAN ACADEMY OF PEDIATRICS Jonathan A. Perkins, DO (Otolaryngology) Noninvoluting congenital hemangioma: Michael L. Smith, MD, FAAP (Dermatology) ABBREVIATIONS a rare cutaneous vascular anomaly. Patricia A. Treadwell, MD, FAAP (Dermatology) bFGF: basic fibroblast growth Plast Reconstr Surg. 2001;107(7): Milton Waner, MD (Otolaryngology, Facial Plastic 1647–1654 Surgery) factor Albert C. Yan, MD, FAAP (Dermatology) CT: computed tomography 3. North PE, Waner M, James CA, Mizeracki EPC: endothelial progenitor cell A, Frieden IJ, Mihm MC Jr. Congenital GLUT1: glucose transporter nonprogressive hemangioma: a distinct SECTION ON DERMATOLOGY EXECUTIVE protein isoform 1 clinicopathologic entity unlike infantile COMMITTEE, 2014–2015 HemSC: multipotential stem cell hemangioma. Arch Dermatol. 2001; Bernard A. Cohen, MD, FAAP, Chairperson – derived from IH 137(12):1607 1620 Richard J. Antaya, MD, FAAD, FAAP Anna L. Bruckner, MD, FAAP specimens 4. Boon LM, Enjolras O, Mulliken JB. Kim Horii, MD, FAAP IH: infantile hemangioma Congenital hemangioma: evidence of Nanette B. Silverberg, MD, FAAP IL: interleukin accelerated involution. J Pediatr. 1996; Teresa S. Wright, MD, FAAP KHE: kaposiform 128(3):329–335 Albert C. Yan, MD, FAAD, FAAP, Chairperson-Elect hemangioendothelioma 5. Baselga E, Cordisco MR, Garzon M, Lee Michael L. Smith, MD, FAAP, Ex Officio KMP: Kasabach-Merritt MT, Alomar A, Blei F. Rapidly involuting phenomenon congenital haemangioma associated FORMER SECTION ON DERMATOLOGY LBW: low birth weight with transient thrombocytopenia and EXECUTIVE COMMITTEE MEMBER LUMBAR: Lower body IH and coagulopathy: a case series. Br J – Sheila F. Friedlander, MD, FAAP other cutaneous defects, Dermatol. 2008;158(6):1363 1370 Urogenital anomalies 6. Rangwala S, Wysong A, Tollefson MM, STAFF and ulceration, Khuu P, Benjamin LT, Bruckner AL. Lynn Colegrove, MA Myelopathy, Bony Rapidly involuting congenital deformities, Anorectal hemangioma associated with profound, malformations and transient thrombocytopenia. Pediatr SECTION ON OTOLARYNGOLOGY–HEAD AND Dermatol. 2014;31(3):402–404 NECK SURGERY EXECUTIVE COMMITTEE, arterial anomalies and 2014–2015 Renal anomalies 7. Berenguer B, Mulliken JB, Enjolras O, MMP: matrix metalloprotease et al. Rapidly involuting congenital Charles Bower, MD, FAAP, Chairperson hemangioma: clinical and Christina Baldassari, MD, FAAP PDL: pulsed-dye laser histopathologic features. Pediatr Dev German Paul Digoy, MD, FAAP PHACE: Posterior fossa defects, Pathol. 2003;6(6):495–510 Andrew Hotaling, MD, FAAP Hemangiomas, Stacey Ishman, MD, MPH, FAAP cerebrovascular Arterial 8. Mulliken JB, Enjolras O. Congenital John McClay, MD, FAAP anomalies, Cardiovascular hemangiomas and infantile Diego Preciado, MD, PhD, FAAP hemangioma: missing links. J Am Acad Kristina Rosbe, MD, FAAP anomalies including Dermatol. 2004;50(6):875–882 Scott Schoem, MD, FAAP, Past Chairperson coarctation of the aorta, Jeffrey Simons, MD, FAAP and Eye anomalies 9. North PE, Waner M, Mizeracki A, Mihm Steven Sobol, MD, FAAP MRA: magnetic resonance MC Jr. GLUT1: a newly discovered David Walner, MD, FAAP angiography immunohistochemical marker for NICH: noninvoluting congenital juvenile hemangiomas. Hum Pathol. 2000;31(1):11–22 STAFF hemangioma Vivian Thorne RICH: rapidly involuting congenital 10. Patrice SJ, Wiss K, Mulliken JB. hemangioma Pyogenic granuloma (lobular capillary SECTION ON PLASTIC SURGERY EXECUTIVE TA: tufted angioma hemangioma): a clinicopathologic study COMMITTEE, 2014–2015 VEGF: vascular endothelial growth of 178 cases. Pediatr Dermatol. 1991; 8(4):267–276 Peter J. Taub, MD, FAAP, Chairperson factor Stephen B. Baker, MD, FAAP 11. Enjolras O, Wassef M, Mazoyer E, et al. Arin K. Greene, MD, FAAP Infants with Kasabach-Merritt syndrome Timothy W. King, MD, MPH, FAAP do not have “true” hemangiomas. Donald R. Mackay, MD, FAAP, Immediate Past REFERENCES JPediatr. 1997;130(4):631–640 Chairperson 1. International Society for the Study of 12. Zukerberg LR, Nickoloff BJ, Weiss SW. Delora L. Mount, MD, FAAP, Chairperson-Elect Vascular Anomalies. ISSVA classification Jordon Philip Steinberg, MD, FAAP Kaposiform hemangioendothelioma of Mark M. Urata, MD, DDS, FAAP, of vascular anomalies. 2014. Available infancy and childhood: an aggressive fi Vice Chairperson at: issva.org/classi cation. Accessed neoplasm associated with Kasabach- April 2015 Merritt syndrome and STAFF 2. Enjolras O, Mulliken JB, Boon LM, lymphangiomatosis. Am J Surg Pathol. Kathleen Kuk Ozmeral Wassef M, Kozakewich HP, Burrows PE. 1993;17(4):321–328

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1104 FROM THE AMERICAN ACADEMY OF PEDIATRICS Diagnosis and Management of Infantile Hemangioma David H. Darrow, Arin K. Greene, Anthony J. Mancini, Amy J. Nopper and the SECTION ON DERMATOLOGY, SECTION ON OTOLARYNGOLOGY-HEAD AND NECK SURGERY, and SECTION ON PLASTIC SURGERY Pediatrics 2015;136;e1060 DOI: 10.1542/peds.2015-2485 originally published online September 28, 2015;

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 Diagnosis and Management of Infantile Hemangioma David H. Darrow, Arin K. Greene, Anthony J. Mancini, Amy J. Nopper and the SECTION ON DERMATOLOGY, SECTION ON OTOLARYNGOLOGY-HEAD AND NECK SURGERY, and SECTION ON PLASTIC SURGERY Pediatrics 2015;136;e1060 DOI: 10.1542/peds.2015-2485 originally published online September 28, 2015;

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