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    Infantile Hemangioma

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    Apr.14.2022

    Infantile Hemangioma

    Synopsis

    Key Points

    • Infantile hemangioma is a common, benign vascular neoplasm of infancy composed of proliferating endothelial cells. Lesions follow a characteristic life cycle of proliferation and regression; duration and rate are variable
    • Diagnosis of cutaneous hemangioma is typically confirmed by history, physical examination, and observation of clinical course
      • Superficial lesions become apparent weeks after birth; often begin with bright red papule or plaque
      • Deep lesions often become apparent by age 2 to 3 months; can present with subcutaneous swelling with an associated blue hue
      • Lesions involved in specific distributions (eg, periorbital lesions, some segmental facial and perineal lesions, midline lumbar lesions, presence of 5 or more focal cutaneous lesions) require specialized work-up
    • Active observation is required for most lesions; treatment is indicated for ulceration, impairment of vital structures, and potential for disfigurement
    • When indicated, treatment modalities include pharmacologic, laser, and surgical options; often multimodal
      • Propranolol is typically the first choice for pharmacotherapyr1; initiation of outpatient treatment requires special monitoring and may require inpatient hospitalization in young infants
    • Complications of cutaneous hemangiomas are largely dependent on size of lesion, location, and morphology; they include ulceration, cosmetic disfigurement, and functional problems (eg, ocular complications; airway obstruction; feeding difficulties; impaired mobility; and, rarely, heart failure)
    • Overall, prognosis is good for most lesions; approximately 12% to 33% of infantile hemangiomas require some form of intervention r2r3
      • Minor residual skin changes often remain after involution of lesions; laser treatment and surgery may be required

    Urgent Action

    • Emergent treatment is indicated for potentially life-threatening lesions (eg, airway lesions with significant obstruction, abdominal compartment syndrome, hypothyroidism, heart failure associated with hepatic lesions) in consultation with appropriate subspecialist
    • Urgent referral to ophthalmologist is indicated for periorbital lesions (high risk for serious visual complications)
    • Urgent treatment is indicated for existing or imminent functional impairment, pain, or bleeding in consultation with appropriate subspecialist

    Pitfalls

    • Failure to consult ophthalmologist for periorbital lesions can lead to increased morbidity; formal ophthalmic examination is indicated for all patients with periorbital hemangioma
    • Obtain liver ultrasonogram in infants presenting with 5 or more cutaneous hemangiomas; patients with 5 or more lesions are at high risk for liver hemangiomas
    • Prompt thyroid function evaluation required for hepatic lesions owing to risk for consumptive hypothyroidism
    • Obtain screening bronchoscopy for patients with segmental hemangiomas in a lower face (beardlike) distribution and multiple hemangiomas in cervical cutaneous distribution; hemangiomas in these cutaneous distribution patterns signal high risk for airway hemangioma
    • Obtain evaluation to assess for PHACE syndrome in children with large segmental hemangiomas involving head-neck-face region and LUMBAR syndrome in children with lumbosacral segmental lesions; facilitates proper treatment of hemangioma and other associated underlying abnormalities
      • Assess for underlying abnormalities in children with lower midline lumbar lesions; occult underling spinal and urogenital lesions are associated with significant low-lying midline lumbar lesions
    • Remind caregivers at each visit that discontinuation of propranolol is indicated during any intercurrent illness or prolonged period of fasting to prevent hypoglycemia

    Terminology

    Clinical Clarification

    • Infantile hemangioma is a benign vascular neoplasm of infancy composed of proliferating endothelial cells; lesions commonly manifest as superficial and/or deep subcutaneous masses r4
      • Most common tumor of infancy r2
    • Lesions follow characteristic life cycle of growth and regression; duration and rate are variable
      • Proliferative phase: occurs during early infancy
      • Latent or plateau phase: dramatic slowing of overall growth of lesion by mid-to-late infancy r2
        • Likely represents a period of temporarily balanced cell proliferation and apoptosis within the same lesion r2
      • Involution phase: spontaneous shrinking of lesion often begins by age 1 year;r2usually complete by age 4 yearsr2, but may not be complete in some children before the age of 10 yearsr5
      • Involuted phase: involution is complete and no further changes occur r5

    Classification

    • Based on depth of tissue involvement r4r6
      • Superficial
        • Involves superficial dermis r5
      • Deep
        • Involves deep dermis and subcutaneous tissue r5
      • Mixed or compound or combined
        • Lesion composed of both superficial and deep components
      • Reticular/abortive /minimal growth r6
    • Based on pattern of distribution r4r6
      • Focal (localized)
        • Solitary discrete lesion that appears to arise from a single focal point
        • Accounts for approximately 80% of lesions r7
      • Multifocal
        • Lesions that occur at more than 1 anatomic site r2
        • 5 or more discrete lesions are associated with increased incidence of liver hemangioma r2
      • Segmental
        • Large lesions that cover a territory that loosely corresponds to a neuroectodermal placode r2
        • Segmental lesions on the face are subclassified into 4 distinct zones: r2r8
          • Zone 1: frontotemporal
          • Zone 2: maxillary
          • Zone 3: mandibular
          • Zone 4: frontonasal
        • Associated with increased risk for complications r9
        • Often the most difficult type of lesion to treat; associated with worse outcome
        • May be associated with other vascular and nonvascular anomalies, including: r6r9
          • PHACE syndrome: posterior fossa brain malformations, hemangiomas of the face, arterial anomalies, cardiac anomalies, eye abnormalities, sternal clefting, and/or supraumbilical raphe
          • LUMBAR syndrome: lower body hemangioma and other cutaneous defects, urogenital anomalies, ulceration, myelopathy, bony deformities, anorectal malformations, arterial anomalies, and renal anomalies
          • Airway lesions when distribution involves lower face (ie, beard area), which includes some or all of the following cutaneous areas: preauricular, mandibular, lower lip, chin, and anterior neck
      • Indeterminate r6

    Diagnosis

    Clinical Presentation

    History

    • Lesions typically follow a natural pattern of growth and involution; however, exact timing of clinical course may be somewhat variable
      • Typical cycle of growth and regression
        • Birth
          • Mature lesions are not visible at birth r4
            • Premonitory mark may be visible (eg, pale macule, fine telangiectasia, subtle ecchymotic patch) in up to 50% of cases r5r7
              • Often accompanied by surrounding pallor from local vasoconstriction c1c2c3c4
        • Age 1 to 4 weeks r4
          • Most lesions become clinically apparent
        • Age 5 to 8 weeks c5
          • Rapid proliferation occurs r8
        • Age 3 to 6 months r4
          • Growth to approximately 80% of final size is generally reached at age 3 to 5 months r8
          • Many lesions complete growth by age 5 to 9 months r2r8
        • Late infancy (by 12 months) r4
          • Growth has ceased by age 12 monthsr8 in most patients and tumors are latent or involuting
          • Size begins to drastically shrink and lesion flattens
        • Childhood c6
          • Involution completes by age 4 years in most children r2
          • Skin may return to normal color and contour or leave behind some residual changes
      • Most patients present a single focal lesion r2c7
    • Airway lesions (eg, nasal, subglottic, laryngeal) c8c9c10c11c12
      • Most are in the subglottic region and present with progressive biphasic stridor and barky cough; hoarseness may be present r5
      • Symptoms often begin between 4 and 12 weeks of life r5
      • Can occur in presence or absence of skin findings r2
        • Up to 50% of infants with a subglottic lesion have concomitant cervical skin involvement, often in a beardlike distribution r5c13
    • Hepatic lesions c14c15c16
      • Suggested by symptoms consistent with high-output heart failure (eg, poor feeding, difficulty breathing, abdominal distention)
      • Presence of 5 or more cutaneous lesions is associated with risk for hepatic lesion(s) c17

    Physical examination

    • Cutaneous distribution
      • Focal hemangioma
      • Segmental
        • Facial location is most common r9c23
    • Cutaneous appearance based on depth of lesion r10
      • Superficial lesions
        • Bright red, slightly elevated, lobulated papule or plaque r4c24c25c26c27
          • Historically, described as strawberry or capillary r2
        • Thin, delicate surface epithelium covers lesion r5c28
        • Often active proliferative changes are appreciated within weeks after birth r5
      • Deep lesions
        • Bluish, soft, warm, nontender soft tissue nodule or mass deep to skin surface r4c29c30c31c32
          • Historically, referred to as cavernousr2
        • Epidermis retains normal thickness r5
        • Often appreciated somewhat later than superficial lesions (around age 2-3 months) r11
      • Compound (combined) lesions c33
        • Exhibit signs of both superficial and deep components r4
    • Appearance based on pattern of distribution
      • Focal lesion c34
        • Single localized lesion r4
      • Multifocal lesions c35
        • Multiple, distinct, localized lesions r4
      • Segmental lesion c36c37
        • Assume a pattern roughly conforming to developmental segments r4
        • Solitary, confluent plaque or small individual papules clustered in a patterned distribution
    • Appearance based on pattern of growth
      • Clinical differentiation of an individual lesion into a single distinct growth phase may be difficult, especially during transition between phases r5
        • Processes of proliferation, latency, and involution often occur simultaneously within the same lesion
      • Proliferative phase c38c39c40c41c42c43
        • Growth is rapid; lesion becomes elevated
          • Increased risk for complications such as ulceration occur during this phase r5
        • Lesion may be surrounded by pallor and dilated veins r2
        • Rubbery consistency develops r2
      • Latent (plateau) phase c44c45c46c47c48
        • Growth arrests
        • Tense, rubbery, noncompressible mass with visible draining veins at the periphery r5
      • Involution phase
        • Size diminishes at a slower rate than growth during proliferative phase r5
        • Most lesions flatten and shrink from the center toward the periphery r2
        • Color typically fades from bright red to gray, then finally to a more neutral skin color r5
        • Lesion becomes softer and less rubbery to palpation r5
        • Residual skin changes are common (eg, dyspigmentation, redundant skin, telangiectasias, fibrofatty tissue, scarring) r2c49c50c51c52c53c54c55c56c57c58
      • Involuted phase
        • Skin returns to normal or near normal in up to 50% of cases r5
        • Remaining 50% demonstrate residual skin changes r5
          • Minor residual skin changes include focal telangiectasias, atrophic wrinkling, hypopigmentation, and refined textural changes
          • Major residual skin deformity includes anetoderma (crepelike laxity scarring), fibrofatty residuum, and significant swelling of the redundant skin
    • Signs of clinically significant airway lesions are suggested by:
      • Biphasic stridor and difficulty breathing c59c60
    • Signs of clinically significant hepatic lesions are suggested by:
      • Hepatomegaly c61
      • Signs of high-output heart failure (eg, bounding pulses, midsystolic murmur, gallop cardiac rhythm, tachycardia, wide pulse pressure, tachypnea) c62c63c64c65c66c67

    Causes and Risk Factors

    Causes

    • Cause is not completely understood, but may develop from intrinsic endothelial progenitor cells or from angioblasts of placental origin r2c68c69

    Risk factors and/or associations

    Age
    • Infants
      • Occurs in up to 4.5% of all infants by age 3 months and up to 12% by age 1 year r4c70c71
    Sex
    • More common in female infants (female to male ratios ranging from 1.4:1 to 3:1) r2c72c73
    Genetics
    • While most cases are sporadic, familial clustering has been reported r2
      • In one study, family history of infantile hemangioma was present in up to one-third of patients; definitive inheritance model is uncertain r12c74
    Ethnicity/race
    • More common in White populations; rare in dark-skinned populations r7c75c76
    Other risk factors/associations
    • Risk factors
      • Major risk factors
        • Preterm infants r4
          • Low birth weight is the major contributor to risk r2c77
            • Occurs in 22% to 30% of infants weighing less than 1 kg r2
      • Minor risk factors
        • Child of a multiple gestation pregnancy r4c78
        • Children of mothers with advanced maternal age r4c79
        • Firstborn infants r2c80
        • Prenatal and perinatal complications (eg, placenta previa, preeclampsia, breech presentation) r13c81c82c83c84c85
      • Possible risk factors
        • Children born to mothers requiring transcervical chorionic villus sampling r5c86
        • Use of fertility drugs or erythropoietin during pregnancy r2c87c88
    • Associations
      • 5 or more cutaneous lesions r14c89
        • Increased risk for concomitant visceral hemangiomatosis (of central nervous system, eye, pancreas, gastrointestinal tract, or lungs), particularly liver involvement
      • Zone 3 (lower face or beardlike distribution) of segmental lesion or multiple hemangiomas in cervical distribution r2r5r14c90c91
        • Increased risk for concomitant airway lesions
      • Lower midline back lesions c92c93c94
        • Associated with underlying spinal dysraphism, and anal/urogenital anomalies r11
      • Segmental hemangiomas c95
        • May be associated with increased risk for visceral hemangiomatosis; underlying lesions are often located adjacent to cutaneous region involved r15
      • Large regional (head-neck-face and lumbosacral) segmental hemangiomas are hallmark signs of:
        • PHACE syndromer16r2(OMIM 606519)r17
          • Minority of infants with large segmental hemangiomas on the head, neck, face, or scalp have PHACE syndrome (posterior fossa brain malformations), a sporadic neurocutaneous syndrome r16
          • Cerebrovascular anomalies are present in 90% of patients, cardiac anomalies in 67%, and structural brain anomalies in 52% r2c96c97c98c99c100c101c102c103
            • Acute ischemic stroke is a risk from underlying vascular anomalies;r48% of children experience stroke in infancy r7
          • Common associated abnormalities are variable and may include: r2r17
            • Posterior fossa malformations (eg, Dandy-Walker malformation, cerebellar hypoplasia) c104c105
            • Hemangioma
              • Associated hemangiomas are often segmental or large complex facial lesions; common facial segments affected are zone 1 and/or 3r2
            • Arterial cerebrovascular anomalies (eg, aneurysms, arterial stenosis) c106c107c108
              • Most common noncutaneous manifestations of disease are arterial anomalies of the head and neck
            • Cardiovascular anomalies (eg, coarctation of the aorta) c109c110
            • Eye anomalies (eg, optic nerve hypoplasia, retinal vascular anomalies, cataracts) c111c112c113c114
            • Sternal clefting/pits and supraumbilical abdominal raphe (ventral midline developmental defects) c115c116c117
        • LUMBAR syndrome r2r18
          • Defined by hemangioma or multiple hemangiomas on the lower body, in association with other congenital anomalies
          • Lower body cutaneous defects c118c119c120
            • Hemangiomas are usually segmental lumbosacral or anogenital lesions
            • Other cutaneous defects include lipomas, hair tufts, skin tags, and nevi
          • Urogenital anomalies and ulceration c121c122
          • Myelopathy (eg, spinal dysraphism, tethered cord, lipomyelocele, lipomyelomeningocele) c123c124c125c126c127
          • Bony deformities (eg, foot deformity, extremity atrophy, hip dysplasia, scoliosis) c128c129c130c131c132
          • Anorectal malformations (eg, imperforate anus, rectal fistulas, complex cloacal anomalies) and arterial anomalies c133c134c135c136c137
          • Renal anomalies (eg, single kidney, pelvic kidney, hypoplastic kidney, hydronephrosis) c138c139c140c141c142

    Diagnostic Procedures

    Primary diagnostic tools c143

    • History, physical examination, and observation of clinical course confirm diagnosis of cutaneous hemangiomas in most patients
      • Approximately 93% of infantile hemangiomas are diagnosed solely on a clinical basis r5
      • Consider baseline photographic documentation at time of diagnosis to aid in monitoring progression of lesion during follow-up r5
    • Imaging is rarely necessary and only indicated in select patients r2
      • General indications r5
        • Evaluate for visceral involvement (eg, 5 or more cutaneous hemangiomas)
        • Evaluate for additional associated anomalies (eg, perirectal lesions, lower midline back lesions, large segmental facial lesions)
        • Define extent of lesion (eg, periocular lesions, select deep lesions)
        • Assess treatment efficacy, particularly with deep lesions
        • Exclude alternate diagnosis if lesion is indeterminate based on clinical characteristics
        • Plan for surgical excision
      • Preferred modalities include MRI and ultrasonography r5
        • Ultrasonography is a reasonable initial imaging modality and preferred for initial diagnosis r2
        • MRI provides greater detail and is preferred to assess extent of lesion r2
    • Biopsy and pathologic diagnosis is only rarely necessary when definitive diagnosis remains in question after thorough history, physical examination, and indeterminate imaging studies or when malignancy is suspected r7
    • Evaluations in special clinical lesions
      • Lesions with high risk for airway involvement
        • Refer to otolaryngologist for further evaluation in infants with: r2
          • Multiple hemangiomas in cervical distribution and/or lower face (beardlike) distribution r5
          • Progressive symptoms concerning for airway mass (eg, progressive biphasic stridor between ages 4 and 12 weeks) r5
        • Bronchoscopy with direct airway visualization is preferred modality to confirm presence of airway hemangioma r14
        • Screening radiograph of the airway to evaluate for subglottic abnormality may be appropriate for mildly symptomatic infants r2
      • Periorbital lesions
        • Requires consultation with specialist experienced in treating periocular lesions (eg, plastic surgeon, ophthalmologist) for further diagnostic recommendations; most often imaging is required
      • Deep lesions
        • May require imaging to assess for extent of lesion or evaluate for alternate diagnosis
      • 5 or more focal cutaneous lesions r14
        • Obtain hepatic ultrasonogram; ultrasonography is preferred modality to assess for hepatic parenchymal lesions r14
          • Up to 16% of infants with 5 or more cutaneous lesions are found to have hepatic lesions r2
        • Further laboratory and formal cardiac evaluation is indicated if hepatic hemangiomas are identified r14
          • Patients with diffuse or multifocal hepatic lesions require prompt thyroid function evaluation owing to risk for consumptive hypothyroidism associated with lesions r14
        • Suggested algorithm for work-up of infantile hepatic hemangioma is available r19
        • Obtain MRI to assess for suspected gastrointestinal, brain, and lung lesions if symptoms are suggestive r7
      • Large segmental or regional hemangiomas on the face, scalp, or neck (to assess for PHACE syndrome) r16
        • Obtain comprehensive ophthalmologic and dermatologic evaluation r4
        • Magnetic resonance angiography of the head, neck, and aortic arch to evaluate for common vascular anomalies r16
        • MRI of the head and neck to evaluate for common structural abnormalities r16
        • Echocardiography to assess for cardiac and aortic arch abnormalities r16
        • Cardiologist and neurologist consultation for patients found to have underlying cardiac and vascular anomalies for further diagnostic and therapeutic decisions r4
        • Some experts advocate screening thyroid functionr14 and endocrine evaluation r7
      • Lower midline lumbosacral or segmental perineal lesions
        • Imaging is required to assess for occult spinal dysraphism and anal/urogenital anomalies r14
          • Up to 50% of infants with a midline lesion have an associated intraspinal abnormality r11
          • Obtain regional ultrasonogram in infants younger than 4 months; MRI is indicated in older infants or when ultrasonography is equivocal to assess for associated anomalies r7
        • Suggested diagnostic approach algorithm is available to assist with evaluation r14
      • Lesions with associated bruit or thrill on examination
        • Carefully assess cardiac history and perform physical examination to evaluate for findings associated with a high-output state necessitating treatment r14
        • Echocardiogram may be necessary to exclude diastolic reversal of aortic flow r14

    Imaging

    • Doppler ultrasonography c144c145c146c147c148c149
      • Noninvasive but operator-dependent study that renders less information than MRI r5
      • Characteristic findings
        • Nonspecific, echogenic, well-defined, parenchymal mass with increased color flow, high vessel density, and high Doppler shift during proliferative phase r5
        • Appears as high-flow lesion during proliferative phase; high-flow component gradually diminishes during involution r5
        • Areas of increased echogenicity (fat replacement) can be seen during involution phase r2
        • Absent arteriovenous shunting is characteristic for most cutaneous lesions r8
    • MRI c150c151c152c153c154c155c156c157c158c159c160c161c162c163c164c165c166c167c168c169
      • Best imaging technique to diagnose vascular anomalies r5
        • Delineates lesion and evaluates adjacent or visceral anomalies
      • Characteristic findings during proliferative phase r5
        • Well-circumscribed, densely lobulated, parenchymal mass with dilated high-flow feeding and draining vessels r5
        • Intense, uniform contrast enhancement with IV gadolinium is typical r5
        • Lesion is usually isointense or hypointense to muscle on T1-weighted images and hyperintense on T2-weighted images r5
      • Findings during involution phase
        • Foci of increased signal on T1-weighted images (fat) becomes apparent and postcontrast images reveal less avid enhancement r2

    Procedures

    Biopsy of lesion c170c171c172c173c174c175
    General explanation
    • Biopsy for histopathologic diagnosis is generally not necessary in the vast majority of cases
    • Procedure is often preceded by imaging to assess extent of lesion, evaluate for risk of bleeding with procedure, and evaluate for likelihood of alternate diagnosis necessitating a different diagnostic and/or therapeutic approach
    Indication
    • Unclear diagnosis after thorough history, physical examination, and imaging (when indicated)
    • Indications may include: r14
      • Lesions that do not follow typical clinical course of hemangiomas
      • Firm lesions
      • Lesions with unusual appearance
      • Lesions found to have radiologic features of concern
    Interpretation of results
    • Histologic findings during proliferative phase
      • Well-circumscribed mass lacking a capsule r2
      • Proliferating, plump, mitotically active endothelial cells and pericytes forming packed sinusoidal capillaries with small, rounded lamina r5
      • Prominent mast cell infiltration r5
      • Small blood vessels that are difficult to identify r5
      • Marked cellularity forms a jigsawlike appearance with normal-appearing dermal stromal elements r5
    • Histologic findings during involution phase
      • Less well-defined mass than is apparent in proliferative phase r2
      • Dense cellularity is replaced by loose fibroadipose tissue r2
      • Residual endothelial cells are mitotically inactive r2
    • Immunohistochemical analysis findings diagnostic of infantile hemangioma
      • Endothelial cell GLUT1 (glucose transporter protein type 1) staining is nearly pathognomonic for infantile hemangioma
        • Infantile hemangiomas are the only vascular anomaly that express GLUT1 r5
        • Placental capillaries and blood tissue barrier endothelial cells (eg, brain, retina) are the only other known tissue to express GLUT1

    Other diagnostic tools

    • Risk stratification r10c176
      • Considered high risk if evidence of or potential for any of the following:
        • Life-threatening complications
        • Functional impairment
        • Ulceration
        • Structural anomalies (eg, in PHACE syndrome)
        • Permanent disfigurement

    Differential Diagnosis

    Most common

    • Congenital hemangioma c177
      • Benign vascular tumors present and fully grown at birth; cutaneous lesions appear similar to infantile hemangiomas, but are biologically and behaviorally different r2
        • Includes 2 subtypes: r14
          • RICH (rapidly involuting congenital hemangioma) is characterized by lesions that spontaneously improve c178
          • NICH (noninvoluting congenital hemangioma) is characterized by lesions that do not change over time c179
      • Differentiate by history and clinical course: congenital hemangiomas are fully grown at birth; infantile hemangioma lesions are not obvious at birth and grow postnatally r14
        • In some infantile hemangiomas, premonitory mark may be visible at birth (eg, pale macule, fine telangiectasia) and grow postnatally
      • Definitive diagnosis can be made by biopsy if unclear; congenital hematomas will have negative stain results for GLUT1 r14
    • Lobular capillary hemangioma (pyogenic granuloma) c180
      • Common, benign, acquired, cutaneous vascular tumor presenting at any age, but often in infants and children; frequently misdiagnosed as hemangiomar2
      • Presents with rapidly growing, bright red papules measuring a few millimeters to 2 cm;r5lesions often occur in an area of skin trauma (scratch) or underlying cutaneous condition (ie, capillary malformation), can be pedunculated, and characteristically bleed repeatedly and profuselyr7
      • Differentiate by history and clinical course; in contrast with pyogenic granuloma, hemangiomas do not often bleed unless there is associated ulceration
      • Definitive diagnosis can be made by biopsy if diagnosis is unclear; lobular capillary hemangioma stain results will be negative for GLUT1 and have distinct differences in histologic findings compared with hemangiomas r5
    • Kaposiform hemangioendothelioma c181
      • Rare, locally aggressive, cutaneous tumor of infancy that can be present at birth or develop after birth; most occur by age 2 years r5
        • Often associated with Kasabach-Merritt syndrome (severe thrombocytopenia and consumptive coagulopathy); hemangiomas are not associated with Kasabach-Merritt syndrome
      • Presents as a deep-seated, bulging, deep red-purple, indurated, warm, edematous soft tissue mass; ecchymosis is visible over the tumor and around surrounding skin. Lesion is often larger than most typical hemangiomas (larger than 5 cm in diameter) and painfulr7
      • Natural history of lesion is somewhat unpredictabler3 (some expand in size slowly, others rapidly; some lesions involute while others persistr2)
      • Differentiate by history and clinical course; definitive diagnosis can be made by biopsy if diagnosis is unclear
        • Kaposiform hemangioendothelioma has a distinct histologic appearance and immunohistochemical profile; lesion stain results will be negative for GLUT1 r5
    • Tufted angioma c182
      • Rare, benign vascular malformation occurring in infants, children, and young adults; often occurs on neck or upper thorax r2
        • Can be associated with Kasabach-Merritt syndrome (severe thrombocytopenia and consumptive coagulopathy); hemangiomas are not associated with Kasabach-Merritt syndrome r6
      • Presents similar to hemangioma with an erythematous to violaceous patch, plaque, or nodule; overlying hypertrichosis is common r2
      • Differentiate by history and clinical course; definitive diagnosis can be made by biopsy if diagnosis is unclear
        • Lesions often proliferate slower than hemangiomas; however, natural history is somewhat unpredictable
        • Tufted angioma has a distinct histologic appearance and immunohistochemical profile; lesion stain results will be negative for GLUT1
    • Capillary malformation (port wine stain, salmon patch, macular stain, nevus flammeus) c183c184c185c186
      • Present at birth as pink to red macules and generally persist throughout life; composed of dilated capillaries and/or postcapillary venules
        • Port wine stains slowly become thicker and darker with time; may be associated with soft tissue or bone overgrowth and other underlying vascular and nonvascular anomalies
        • Salmon patches commonly occur above the neck and lighten or disappear with time; not typically associated with other anomalies
      • Differentiate by history and clinical course; capillary malformations do not proliferate at a rapid rate, as is typical for a hemangioma
      • Definitive diagnosis can be made by biopsy if diagnosis is unclear
    • Venous malformation c187
      • May be focal, multifocal, or diffuse, affecting an entire limb; most lesions that are not deep-seated are diagnosed at birth
        • Can affect any tissue or viscera; slow flow in lesion is prone to thrombosis, resulting in pain and formation of phleboliths
      • Similar to deep infantile hemangiomas, can present with subcutaneous mass with overlying blue skin discoloration; mass is characteristically soft, compressible, and may increase in volume with increase in venous pressure (eg, Valsalva) or exercise
      • Unlike hemangiomas, venous malformations do not involute and are compressible on examination; growth may be influenced by other factors (eg, trauma, hormonal changes) r2
      • Differentiate by clinical presentation and clinical course; definitive diagnosis can be made by imaging (ie, ultrasonography, MRI) and/or biopsy if diagnosis is unclear
    • Other tumors including malignant tumors c188
      • Cutaneous involvement of a variety of malignant tumors (eg, rhabdomyosarcoma, metastatic neuroblastoma, chloroma [cutaneous leukemia], angiosarcoma, fibrosarcoma, glioma) rarely mimic hemangioma at presentation r14d1
      • Malignant tumors often present with more firmness and fixation to surrounding tissue on palpation and systemic signs of illness (eg, weight loss, failure to thrive, pallor, petechiae)
      • Hepatic hemangioma can mimic a variety of liver tumors including hepatoblastoma, metastatic neuroblastoma, mesenchymal hamartoma, hepatic cysts, and arteriovenous malformations r20
      • Differentiate by clinical presentation and distinct imaging characteristics; definitive diagnosis can be made by biopsy if diagnosis remains unclearr21

    Treatment

    Goals

    • Early consultation with a specialist to assist with treatment plan for lesions likely to result in functional impairment or permanent disfigurement r2
    • Minimize associated morbidity and complications r4
    • Maximize functional and cosmetic result r4

    Disposition

    Admission criteria

    Propranolol induction for select patients

    Criteria for ICU admission
    • Infants with severe airway compromise or hypoxia from airway hemangioma or deep, soft tissue neck hemangioma
    • Infants with congestive heart failure and abdominal compartment syndrome

    Recommendations for specialist referral

    • Refer patients with high-risk infantile hemangiomas to a hemangioma specialist for evaluation and early treatment, ideally by 1 month of age r10r22
      • Team of experts with experience treating hemangioma (eg, vascular anomalies team) may be needed when multimodality approach is likely necessary for significantly complex hemangioma
    • Consult a specialist with experience treating hemangioma (eg, pediatric dermatologist) when systemic treatment is a consideration for hemangiomas r3
    • Consult cardiologist for patients with relative risks before propranolol treatment for further diagnostic and treatment recommendations r2
    • Consult otolaryngologist early for any infants with concern for airway hemangioma (eg, zone 3 lesion distribution, early-onset progressive stridor) for diagnostic and treatment recommendations r2r7
    • Consult ophthalmologist early for all infants with periorbital hemangioma for diagnostic and treatment recommendations r7
    • Consult cardiologist, neurologist, and ophthalmologist for infants in whom PHACE syndrome is of concern for diagnostic and treatment recommendations

    Treatment Options

    Decide whether treatment intervention is indicated or if initial observation is reasonable r2

    • Most infantile hemangiomas follow benign course without need for therapeutic intervention; approximately 12% of lesions are complex, requiring referral for specialist evaluation r8
      • Indications for intervention r2
        • Emergency treatment of potentially life-threatening complications (eg, obstructing airway lesions, liver lesions associated with high-output heart failure and severe hypothyroidism)
        • Urgent treatment of existing or imminent functional impairment, pain, or bleeding (eg, due to ulceration, ocular complications, impaired feeding from perioral lesions, or reduced mobility)
        • Elective treatment to reduce likelihood of long-term or permanent disfigurement (eg, scarring from severe ulceration; certain anatomic areas including eyelid, nasal tip, lip, breast, and genitalia)
        • Evaluation to identify associated structural anomalies (eg, spinal malformations associated with lumbosacral lesions, anomalies related to PHACE syndrome)

    Therapeutic interventions are individualized; appropriate therapy and timing of intervention depends on various factors: r2

    • Age of patient
    • Location, size, and growth phase of lesion(s)
    • Degree of skin involvement
    • Intervention urgency and complication severity
    • Potential for adverse psychosocial consequences
    • Physician experience
      • Initiate systemic therapy in consultation with a clinician with expertise in managing infants with hemangioma (eg, pediatric dermatologist) r3
      • Multidisciplinary team composed of experts in treating significantly complicated hemangiomas may be key to obtaining optimal results in complex cases r5
    • Parental preference (especially in elective cases)

    Treatment modalities include pharmacologic, laser, and surgical options r2

    • Pharmacologic treatment
      • Systemic therapy is usually indicated for patients with lesions that are: r2
        • Large or medically complex
        • At high risk for functional impairment or disfigurement
        • Refractory to other initial therapies
      • β-adrenergic blockers are typically first line medical therapy r1r2
        • Systemic propranolol is the most effective and is associated with the fewest treatment-related complications r1r10r23r24
          • Effective in reducing size and color intensity of lesions; treats both deep and superficial components
            • Reported overall response rates range from 86% to 98%;r1r4r2early response often occurs within 1 to 3 days of treatmentr9
          • Atenolol and nadolol appear to have similar efficacy and fewer adverse events as propanolol but use of these is limited r25r26
          • Contraindications to propranolol therapy r2
            • Cardiogenic shock
            • Heart failure
            • Heart block greater than first degree
            • Hypotension
            • Sinus bradycardia
            • Asthma or reactive airway disease
            • Known hypersensitivity to the drug
            • Caution suggested for patients with PHACE syndrome and significant intracranial vascular anomalies r2
          • Pretreatment risk assessment r2
            • Document complete history and physical examination, with special attention to cardiac and pulmonary systems r2
            • Recommendations for extent of pretreatment assessment are evolving and vary between clinicians r2
              • Some clinicians obtain ECG and/or cardiologist consult before starting propranolol
                • Of uncertain value in patients with unremarkable history or examination
              • Relative risks that require further evaluation (eg, ECG, cardiologist consultation) before propranolol initiation include: r3
                • Heart rate below reference range for age
                • Family history of congenital heart conditions or arrhythmias (eg, heart block, long QT syndrome, sudden death)
                • Maternal history of connective tissue disease
                • History of or auscultation of an arrhythmia
                • PHACE syndrome diagnosis r4
          • Initiation of treatment
            • Recommendations for optimal setting may vary between clinicians
            • Inpatient initiation of treatment is suggested for patients who: r2
              • Are aged 8 weeks or younger
              • Are preterm infants younger than 48 weeks of postconceptional age
              • Have inadequate social support
              • Have significant comorbidity (eg, cardiac or pulmonary risk factors)
            • Outpatient clinic treatment recommendations (for infants older than 8 weeks)
              • Assess heart rate and blood pressure at 1 and 2 hours after first dose and with any new dose increase of more than 0.5 mg/kg/day r2
          • Adverse effects r2
            • Serious adverse effects are rare
              • Bradycardia and hypotension (typically asymptomatic)
              • Bronchospasm
              • Hypoglycemia/seizures
                • Reduce risk of hypoglycemia by giving medication after feeding, avoiding prolonged intervals between feedings, and holding doses when oral intake is decreased (eg, illness, vomiting, fasting) r2r10
            • Common adverse effects include sleep disturbancesr27r28, acrocyanosis, diarrhea, and bronchial hyperreactivity
          • Duration of treatment r2
            • Varies with age of initiation and clinical response
              • Typically continues for at least 6 months, often up to age 12 months (some experts recommend extending treatment until patient is aged 15 months) r10r29
            • Discontinue medication by gradual tapering over 1 to 3 weeks to prevent rebound sinus tachycardia
            • Rebound growth of hemangioma
              • Observed in 6% to 25% of cases (notably in those with long proliferative phase and large subcutaneous component)
              • Consider tapering propranolol over weeks to months
              • May require reinitiation of therapy for variable periods
        • Topical β-adrenergic blockers
          • Consider topical timolol for treatment of small, thin, uncomplicated, superficial lesions r2r10
            • Topical propranolol and topical timolol were as effective as oral propranolol in treating superficial infantile hemangiomas, and topical timolol was associated with fewer adverse effects r30
            • Useful when treatment is desired but risks are considered too high to justify systemic β-blocker therapy
            • Use of topical timolol after oral propanolol may allow reduced duration of systemic beta blocker therapy and minimize the potential adverse effects r31
            • Available in extended-release gel-forming solution with less systemic absorption than regular solution
              • Concerns remain regarding bioavailability in neonates and infants, especially with large or ulcerated lesions and those involving mucous membranes
        • Intralesional propranolol administration is reported but efficacy data are limited r4
      • Corticosteroids
        • Alternative therapy if propranolol cannot be used or is ineffective r2
        • Systemic (oral) corticosteroids r10
          • Overall response rate (43%-84%) is inferior to propranolol and rate of relapse is higher with corticosteroids r2r4r32
          • More adverse effects are associated with oral administration of corticosteroids (23%) than with propranolol (9.6%) r4
          • Potential adverse effects include hypothalamic-pituitary-adrenal axis suppression, growth deceleration, hypertension, gastric irritation, mild behavioral changes, cushingoid facies, and immunosuppression r2
            • Periodic monitoring of infants with attention to growth and blood pressure is suggested r2
          • Duration of therapy r2
            • Varies with clinical response, patient age, and growth phase of lesion
              • Generally ranges 4 to 12 weeks at full dose and tapers over weeks to months r2
                • Typically completed by age 9 to 12 months;r2 some experts aim to discontinue by age 11 months in effort to avoid interference with 12-month immunization schedule
        • Intralesional corticosteroids r2
          • Consider intralesional injection of triamcinolone and/or betamethasone to treat focal, bulky lesions during proliferation phase or in certain critical anatomic locations (eg, lip) r10
          • Often requires multiple injections, typically at 4- to 6-week intervals
          • Complications include local hypopigmentation, fat and/or dermal atrophy, and systemic effects at large doses
            • Use in lesions of upper eyelid may cause retinal embolization
        • Topical corticosteroids
          • Consider use of high-potency topical formulations for small (less than 5 cm), thin, superficial lesions
      • Other medical therapies r2
        • Typically reserved for recalcitrant lesions owing to limited safety profiles
        • Sirolimus has potent antiangiogenic activity but is not well studied for infantile hemangiomas r22
        • Vincristine and interferon-alfa are rarely used owing to adverse effects r22
    • Laser treatment
      • Pulsed dye laser therapy provides selective photothermolysis of vascular tumor while sparing normal surrounding tissue r4
      • Primary use is to treat residual skin changes (eg. telangiectasia and refractory ulceration) after involution r22
      • Other uses may include: r2
        • As a component in multimodal therapy
        • To treat early, nonproliferating superficial lesions and areas of critical skin (eg, nasal tip, facial lesion)
          • Controversial; use of laser on early proliferating and superficial lesions may lead to ulceration r2
    • Surgical treatment
      • Surgical resection may be necessary for up to 40% of patients requiring treatment overall r4
      • Suggested criteria for intervention are somewhat vague owing to difficulty in predicting some final tumor manifestations r4
        • Base timing of surgery on patient age, location and degree of deformity, and stage of tumor growth r2
          • Elective resection during proliferative phase is not usually indicated r2
            • Vascularity of tumor can place infant at greater risk of anesthetic morbidity, blood loss, and iatrogenic injury; cosmetic result is usually superior with fewer interventions after growth of lesion has stopped r2
            • Early surgical intervention may be indicated for certain patients with significant, recalcitrant complications or functional impairment
          • Preferred timing for repair for most lesions requiring surgical intervention is during the involution stage between the ages of 3 and 4 years r5

    Treatment is often multimodal r4

    • Combining various treatment methods to optimize different components of individual lesions is common
      • For example, a common treatment approach for compound lesions includes systemic propranolol to address deep component and laser therapy to treat superficial component; surgery and/or additional laser therapy may be used for any unacceptable, residual cosmetic issues r4
    • Aggressive early multimodal therapy is often used for lesions in sensitive anatomic areas prone to significant complications, such as: r5
      • Periorbital, tip of nose, and lip lesions
      • Airway lesions
      • Large segmental or nodular lesions in trauma-prone areas at high risk for ulceration

    Management for lesions in specific anatomic locations

    • Periorbital
      • Early consultation with ophthalmologist is essential; extent and depth of periorbital lesions intruding into the orbit is often unappreciated on routine physical examination r2
        • Manage aggressively with multimodal therapy; early systemic pharmacotherapy is imperative for most lesions, even when surgical therapy is unavoidable r5
    • Tip of nose
      • Tissue in this area is difficult to excise without considerable cosmetic consequence; lesions are prone to injure underlying cartilage and may obstruct nasal airway
      • Aggressive multimodal therapy with early initiation of systemic pharmacotherapy is recommended to avoid poor outcome r2
    • Lip
      • Distortion of lip contour is common and difficult to reconstruct; lesions are highly prone to complications such as ulceration, scarring, and disfigurement
      • Aggressive multimodal therapy with early initiation of systemic pharmacotherapy is recommended to avoid poor outcome r2
    • Perineal
      • Early pharmacotherapy may be appropriate given high risk for ulceration and complications associated with ulceration in this region (eg, infection) r2
    • Those obstructing auditory canal
      • Manage aggressively with trial of systemic pharmacotherapy r5
      • Early multimodal approach may be necessary with laser therapy and surgical resection r5
    • Those prone to ulceration
      • Lesions over pressure points (eg, back), near mucosa (eg, lip, perineum), and intertriginous areas are prone to ulceration and require meticulous local care r14
      • Consider early pharmacotherapy and/or multimodal approach to lesions at high risk for ulceration
    • Hepatic
      • Management is based on type of lesion (ie, focal, multifocal, or diffuse), presence and degree of vascular shunting, and presence of complications (eg, high-output heart failure, abdominal compartment syndrome, consumptive hypothyroidism) r19
      • Suggested algorithm for management of infantile hepatic hemangioma is available; multimodal therapy is often used, beginning with pharmacotherapy r19
      • Additional specific surgical management may include embolization, hepatic artery ligation, resection, and even transplant for patients with failure of medical therapy or recalcitrant heart failure r5
      • Associated consumptive hypothyroidism requires thyroid hormone replacement, sometimes intravenously, until hepatic hemangioma has involuted
    • Airway
      • Manage life-threatening lesions with immediate surgical resection; temporary tracheostomy may be required r5
      • Manage lesions causing significant airway obstruction with carbon dioxide laser treatment r5
      • For lesions that are not immediately life-threatening, initial management is systemic pharmacotherapy r5

    Drug therapy

    • β-adrenergic blockers
      • Propranolol oral r3r33c189
        • FDA-approved dosage
          • Propranolol Hydrochloride Oral solution [Hemangioma]; Infants 5 weeks to 5 months at initiation: 0.6 mg/kg/dose PO twice daily given at least 9 hours apart. After 1 week, increase to 1.1 mg/kg/dose PO twice daily. After 2 weeks, increase to 1.7 mg/kg/dose PO twice daily and maintain for 6 months. Readjust periodically based on weight.
        • Alternative dosage recommended in clinical practice guidelines r3
          • Propranolol Hydrochloride Oral solution [Cardiovascular Disease]; Neonates and Infants: 1 mg/kg/DAY PO initially, titrated to a target dose of 2 to 3 mg/kg/DAY, unless there are comorbidities or adverse reactions that require a lower dose. Administer in 2 to 3 divided doses. Consensus guideline initiation protocols are based on age, social support status, and patient comorbidities affecting cardiovascular/respiratory systems and/or blood glucose maintenance. Inpatient initiation (neonates and infants younger than 8 weeks, inadequate social support, or comorbidities): 0.33 mg/kg/dose PO every 8 hours. If tolerated, increase to 0.66 mg/kg/dose PO every 8 hours and prepare for discharge. If dose not tolerated at any point, reduce dosage and gradually increase to target dose; discharge on tolerated dose of 1 mg/kg/DAY or more. Outpatient initiation (infants older than 8 weeks, adequate social support): 0.33 mg/kg/dose PO 3 times daily, at least 6 hours apart. If tolerated for 3 to 7 days, increase to 0.5 mg/kg/dose PO 3 times daily. If once again tolerated for 3 to 7 days, increase to 0.66 mg/kg/dose PO 3 times daily. If dose is not tolerated at any point, reduce dosage and gradually increase to target dose; consider target dose of 1 mg/kg/DAY.
          • Any dose escalation over 0.5 mg/kg/day requires in-office observation with a 1- and 2-hour heart rate and blood pressure check r4
      • Timolol topical gel-forming solution r2r33c190
        • Available in concentrations of 0.25% and 0.5%
        • Best responses using 0.5% gel applied 2 times daily r2
        • Timolol Maleate Ophthalmic 0.5% gel-forming solution; Infants: Apply 1 drop to affected area twice daily. r34
      • Propranolol 1% topical (not commercially available in the United States) r4r35
        • Alternative for patients who experience adverse effects from oral propranolol administration r36
        • Propranolol 1% Topical cream; Infants: Apply a thin film to the affected areas twice daily. r36
    • Corticosteroids r2r34
      • Oral
        • Prednisolone Oral solution; Infants: 2 to 3 mg/kg/day PO divided twice daily. r34c191
      • Intralesional
        • Triamcinolone Acetonide Solution for injection; Infants: 1 to 2 mg/kg (Max: 3 mg/kg) intralesional injection every 30 days; typically 2 to 3 injections are required. r2r37c192
      • Topical
        • Mometasone Furoate 0.1% Topical cream; Infants: Apply a thin film to the affected areas twice daily. r38c193

    Nondrug and supportive care

    Active observation c194

    • Majority of lesions do not require medical or surgical treatment r4
      • Small, focal, nonfacial lesions without ulceration are safely managed with active observation alone r5
      • Allowing lesions to follow natural course of involution often results in the best cosmetic outcome r5
    • Manage with parental reassurance, close follow-up with photographic documentation, and routine clinical monitoring for changes requiring treatment r4r5

    Wound care of ulcerated infantile hemangiomas c195

    • Barrier dressings can prevent drying, control pain, reduce chance of trauma and bleeding, and reduce risk of bacterial colonization or infection r2
      • Dressing choices include hydrocolloid dressings, silver impregnated dressings, and petroleum gauze
    • Topical agents may include barrier creams or ointments (eg, petroleum, zinc oxide) and antibiotics (eg, mupirocin, bacitracin ointment)
    Procedures
    Pulsed dye laser therapy c196c197c198c199c200
    General explanation
    • Emission of short pulses of light between 585 and 595 nm are absorbed by oxyhemoglobin, resulting in destruction of vascular tumor component while sparing unaffected surrounding tissue r4
      • Standard pulsed dye laser is capable of only 1.2 mm depth penetration r4
    • Requires a series of treatment at 2- to 6-week intervals until desired response is achieved r9
    • Larger lesions or lesions in sensitive anatomic areas often require general anesthesia r2
    Indication
    • Removal of telangiectasias, treatment of residual flat components of lesions, or smoothing contour irregularities after involution r2r14
    • Treatment of ulceration refractory to other therapies r2r4
    • Treatment of early, nonproliferating superficial lesions or superficial component of compound lesion r2
      • Controversial; use of laser on proliferating and superficial lesions may lead to ulceration
    • Treatment of critical skin regions (eg, nasal tip, face) in effort to preserve overlying skin r2
    Complications
    • Temporary local swelling r4
    • Hyper- or hypopigmentation r4
    • Scarring, ulceration, or hemorrhage are rare r4
    Interpretation of results
    • When applied to proliferating lesion, results in reduced redness and limitation in overall growth (size) r4
      • Excellent or good results are expected in up to 86% of superficial lesions r4
      • Deep components of mixed hemangiomas are not amenable to treatment r4
    • When applied to ulcerating lesion, results in improved healing and diminished pain r4
    Surgical resection c201c202c203c204c205c206
    General explanation
    • Some lesions are amenable to single resection; lesions involving lips, glabella, cheek, and scalp often require a staged approach r5
    Indication
    • Limited to the following during infancy (proliferative phase): r2
      • Failure of or contraindication to pharmacotherapy
      • Focal involvement in an area anatomically favorable for resection
      • High likelihood that resection will be ultimately needed and scar will be the same, regardless of timing
    • During involution, may be indicated for: r2
      • Reconstruction of damaged structures
      • Resection of scarring or excess skin
      • Excision of residual fibrofatty tissue

    Comorbidities

    • PHACE syndrome c207
      • Treat in close consultation with cardiologist and/or neurologist owing to prevalence of underlying vascular malformations and potential risk for ischemic stroke with use of propranolol r16
      • Propranolol use is controversial r16
        • May be contraindicated in the presence of severe cerebrovascular and/or cardiovascular arterial abnormalities r2
      • Alterations in propranolol treatment, when indicated, are recommended and may include:
        • Lowest possible dosing r4
        • Slow up-titration of dosing on inpatient unit r4
        • Strict 3-times-daily dosing with meals to minimize blood pressure effects r4

    Monitoring

    • Monitoring for lesions that do not require immediate treatment
      • Monitor clinical examination in office weekly to monthlyr7 during proliferative phase if lesion has potential for causing obstruction, destruction, or ulceration requiring intervention r2c208
      • Observe annually after lesion stabilizes during involution phase to assess need for repair of excess skin, intervention for residual fibrofatty tissue, or reconstruction of damaged structures r7c209
    • Monitoring for infants requiring systemic propranolol
      • Adjust dose for growth based on weight gain at each visit and continue to monitor lesion for clinical response and development of complications c210
      • Monitor clinically for serious adverse effects of therapy (eg, bradycardia, hypotension, bronchospasm, hyperkalemia, hypoglycemia) c211c212c213c214c215
    • Monitoring for patients requiring systemic corticosteroids c216c217
      • Observe clinically for adverse effects of medication with specific focus on growth parameters and blood pressure r2
        • Adjust dose for growth based on weight gain at each visit and continue to monitor lesion for clinical response and development of complications
      • Consider checking vaccine titers after completion of treatment to assess adequacy of response r2c218
      • Consider assessing adrenal function at the end of therapy to determine need for stress dose steroid requirement on cessation of therapy r2c219
    • Monitoring for hepatic hemangiomas
      • Varies depending on type of lesion (ie, focal, multifocal, diffuse), presence of shunts, risk for complications, clinical course, and response to treatment r19
      • Management algorithm is available; in general, monitoring ultrasonography is suggested every 2 to 8 weeks after initial diagnosis r19c220
    • Monitoring for infants with segmental hemangiomas
      • Observe for symptomatic visceral involvement (eg, central nervous system, eye, pancreas, gastrointestinal tract, lungs) if early evaluation is otherwise not indicated for assessment of other associations (eg, PHACE syndrome, LUMBAR syndrome, airway lesions)
      • Regional imaging is indicated if infant becomes symptomatic c221

    Complications and Prognosis

    Complications

    • Disease-related complications
      • General risk for complications include: r4
        • Lesion in rapid proliferation phase of growth
        • Facial location
          • Risk is increased for obstruction of vital function and cosmetic disfigurement
        • Segmental morphology
          • Associated with up to 8-fold increased risk for complications r8
        • Larger size
          • 5% increase in the likelihood of developing a complication occurs for every 10 cm² increase in size r4
      • Ulceration c222c223
        • Reported to occur at highest frequency during proliferative phase;r39most ulceration occurs during the first 4 months of life r8
        • Lip, periorbital, cheek, scalp, neck, perineal, and anogenital locations are commonly affected r2r8r9
        • Segmental lesions ulcerate (50%) more frequently than focal lesions (10%-15%); mixed lesions ulcerate more frequently than superficial lesions r9
        • Early, central blanching of proliferating lesion is a marker for impending ulceration (average age, 2.6 months) r39
        • Requires aggressive local care similar to burn treatment; significant pain common with ulceration and requires treatment r2
          • Occasionally results in secondary infection requiring topical or oral antibiotics r2
        • Self-limited bleeding responsive to local pressure is common; hemostatic agents are occasionally necessary r5r14
          • Severe bleeding is rare (less than 1% of ulcerations) r8
        • Almost all lesions that ulcerate result in residual scarring r8
      • Cosmetic disfigurement c224
        • High-risk lesions include those involving the lip, eyelid, ear, nasal tip, breast, and genitalia r2r7
          • Necrosis to underlying cartilage can occur with lesions in areas supported largely by cartilaginous structures (eg, nose, ear) r2
        • Risk of scarring is increased with pedunculated lesions and lesions with a steep marginal slope (ie, sharp, steep drop of at margins)
      • Ocular complications
        • Periocular lesions can cause globe compression, obstruction of the visual axis, and extension into retrobulbar space, leading to many potential complications (eg, strabismus, proptosis, refractive errors, optic nerve compression, amblyopia) r14c225c226c227c228c229
          • Amblyopia develops in up to 60% of untreated periocular lesions and strabismus develops in up to 33% r2
          • Patients with periocular lesions larger than 1 cm in diameter and diffuse periorbital segmental hemangiomas are at highest risk for associated amblyopia r14
          • Other lesions at high risk for amblyopia include upper eyelid location, nasal location, associated ptosis, eyelid margin change, and displacement of globe r2
        • Lesions in the periorbital region can result in permanent visual loss if left untreated c230
      • Airway obstruction
        • Subglottic or laryngeal obstruction c231
          • Patients with lower face (beardlike) cutaneous distribution of facial hemangioma(s) are at risk for hemangiomas of the airway r14
          • Mean age at diagnosis is 3 to 4 months r2
        • Nasal obstruction c232
      • Bleeding r2c233
        • Common concern among caregivers and providers, but it is rarely a problem
      • Feeding difficulties and failure to thrive r2c234c235c236c237
        • Can occur with perioral or airway lesions
      • Parotid gland dysfunction c238c239
        • Large preauricular segmental lesions often affect parotid gland function and rarely affect facial nerve function r5
      • Auditory canal obstruction c240c241
        • Large periauricular lesions can lead to obstruction and if untreated can result in conductive hearing loss of the affected canal; speech delay is uncommon without bilateral involvement r5
        • Obstruction or partial obstruction leads to increased risk of otitis externa r7
      • Impaired mobility c242
        • Can occur with large extremity lesions r2
      • High-output congestive heart failure (rare) c243
        • Can occur with large cutaneous hemangiomas, owing to arteriovenous shunting of large blood volume through the lesion r2
      • Residual skin changes after involution
        • Occur in up to 40% r9
        • Minor residual skin changes include focal telangiectasias, atrophic wrinkling, hypopigmentation, and refined textural changes r5c244c245c246c247
        • Major residual skin deformity includes anetoderma (a crepelike laxity scarring), a fibrofatty residuum, and significant swelling of the redundant skin r5c248c249c250
      • Complications associated with hepatic hemangioma
        • High-output heart failure c251
          • Can result from very large, diffuse, or multifocal hepatic lesions associated with a large volume of arteriovenous shunting r2
        • Consumptive hypothyroidism c252
          • Multifocal hepatic lesions can lead to hypothyroidism as a result of increased type 3 iodothyronine deiodinase activity in the hepatic hemangioma tissue r2
        • Abdominal compartment syndrome c253
          • Can be caused by diffuse hepatic hemangioma r2

    Prognosis

    • Cutaneous hemangiomas
      • Vast majority of lesions proliferate and involute spontaneously without sequelae and require active observation without further intervention r7
        • Most lesions are small and localized, occurring in aesthetically or functionally unimportant areas r7
        • 50% to 70% of involuted hemangiomas leave residual skin changes such as telangiectasia, fibrofatty tissue, atrophy, scarring, hypopigmentation, or alopecia r22
      • Approximately 12% to 33% of infantile hemangiomas require some form of intervention r2r3
      • 10% to 20% of infantile hemangiomas are associated with complications such as ulceration, infection, bleeding, functional impairment, permanent disfigurement, hypothyroidism, and airway obstruction r22
      • Treatment efficacy is approximately 96% with oral propranolol, 62% with topical timolol, 58% with intralesional triamcinolone, and 43% with oral steroids (compared to 6% a control group) r22r32
      • After successful treatment with propanolol, rebound growth may occur in 10% to 25% of patients; this usually responds to repeat treatment with propranolol r22
    • Hepatic hemangiomas
      • Mortality is high among infants who develop heart failure from hepatic hemangiomas r5
        • Patients are at high risk for persistent heart failure, infection, and bleeding

    Screening and Prevention

    Screening c254

    Prevention c255

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