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Infantile Hemangiomas and Vascular Malformations


  • Vascular anomalies, which often present at birth or during early infancy, are classified into two groups based on their biologic and clinical behavior:

    • –

      Vascular tumors , most commonly the infantile hemangioma (IH), that are characterized by endothelial cell proliferation

    • –

      Vascular malformations that result from abnormal vascular morphogenesis

  • Features that distinguish IHs from vascular malformations are presented in Table 85.1 , and differences in their natural histories are depicted in Fig. 85.1 .

    Table 85.1
    Comparison of infantile hemangiomas with vascular malformations.
    CVS, chorionic villus sampling; GLUT1, glucose transporter protein-1 (expressed by the placenta as well as infantile hemangiomas, but no diffuse expression in other vascular tumors).
    Characteristic Infantile hemangiomas Vascular malformations
    Epidemiology More common in:

    • Girls (female:male ratio 3–5:1)

    • Premature and/or low-birth-weight infants

    • Infants whose mothers are older or underwent CVS

    • Equal sex ratio

    • No predilection based on gestational history

    • Certain variants have autosomal dominant inheritance (see text)

    Appearance at birth

    • Often absent

    • ∼50% with a subtle precursor lesion, e.g. telangiectatic, vasoconstricted, pink or bluish bruise-like macules or patches ( Fig. 85.2 )

    • Typically present and already demonstrate characteristic clinical findings

    Natural history

    • Postnatal proliferation for 6–9 months, followed by slow involution over several years

    • Lifelong persistence , with commensurate growth during childhood and often gradual worsening (e.g. thickening of capillary malformations) over time

    Radiology

    • Well-defined mass with high-flow vessels

    • Varies depending on the type (see text)

    Pathology In the proliferative phase:

    • Dense lobules of hyperplastic endothelial cells forming capillaries with tiny lumens

    • Increased cellular turnover demonstrated by markers of proliferation (e.g. Ki-67)

    • Ectatic or distorted vascular channels

    • Typically no increase in cellular turnover

    Immunophenotype

    • GLUT1-positive

    • GLUT1-negative

    Fig. 85.1, Natural history of infantile hemangiomas and vascular malformations.

  • Additional vascular neoplasms are discussed in Chapter 94 ; other vascular ectasias, such as telangiectasias and angiokeratomas, are covered in Chapter 87 .

Infantile Hemangioma (IH)

  • Benign vascular neoplasm that represents the most common tumor of infancy.

    • –

      Affects ∼5% of infants, with a predilection for girls and premature neonates (see Table 85.1 )

  • IHs appear during the first few weeks of life, with a characteristic course:

    • –

      Proliferation for 5–9 months, tending to “mark out their territory” early on and then grow primarily in volume; overall, ∼80% of growth is in the first 5 months of life, with the most rapid growth in the first 2–3 months

    • –

      Subsequent involution gradually over several years (completed at a median age of 3 years), with development of a duller, lighter red to gray color and softening followed by flattening ( Fig. 85.3 )

      Fig. 85.2, Hemangioma precursors.

      Fig. 85.3, Involuting infantile hemangioma.

    • –

      Some IHs involute with little or no visible sequelae, whereas others (especially pedunculated or exophytic lesions) leave atrophic, fibrofatty, or telangiectatic residua in addition to scars at sites of previous ulceration (discussed later; Fig. 85.4 )

      Fig. 85.4, Residua of infantile hemangiomas.

  • Divided into three clinical subtypes based on the depth of cutaneous involvement:

    • –

      Superficial lesions (∼50%; upper dermis) are bright red with a finely lobulated surface (“strawberry” hemangiomas) during proliferation, changing to a mixture of purple-red and gray during involution ( Fig. 85.5 )

      Fig. 85.5, Superficial infantile hemangiomas.

    • –

      Deep lesions (∼15%; lower dermis and subcutis) present as warm, ill-defined, light blue-purple, rubbery nodules or masses ( Fig. 85.6A ); often become evident later and proliferate ∼1 month longer than superficial lesions

      Fig. 85.6, Deep and mixed infantile hemangiomas.

    • –

      Mixed lesions (∼35%) have superficial and deep components – e.g. a well-defined red plaque overlying a poorly circumscribed bluish nodule ( Fig. 85.6B )

  • IHs have two major distribution patterns:

    • –

      Focal lesions arise from a localized nidus (see Fig. 85.5A,B )

    • –

      Segmental lesions cover a broader area or developmental unit and are more likely to be associated with regional extracutaneous abnormalities – e.g. PHACE(S) and LUMBAR syndromes (discussed later) ( Fig. 85.7 ; see Fig. 85.5C )

      Fig. 85.7, Segmental infantile hemangiomas.

  • Some superficial IHs have minimal or arrested growth (IH-MAG) , presenting as patches of reticulated erythema with telangiectasias, often on a vasoconstricted background, and variable development of small red papules involving <25% of the surface area ( Fig. 85.8 ).

    Fig. 85.8, Infantile hemangiomas with minimal or arrested growth (IH-MAG).

  • DDx: precursors and early lesions : capillary malformation, telangiectasias; well-developed lesions : pyogenic granuloma, other vascular tumors (e.g. kaposiform hemangioendothelioma, which can lead to Kasabach–Merritt phenomenon, see Ch. 94 and Fig. 85.15D ), venous/lymphatic malformation, and rare entities such as nasal glioma and soft tissue sarcomas (see Table 53.1 ); multiple lesions: glomuvenous malformations, blue rubber bleb nevus syndrome, multifocal lymphangioendotheliomatosis with thrombocytopenia, “blueberry muffin baby” (see Ch. 99 ).

  • When an atypical clinical appearance or natural history leads to consideration of entities in the DDx of an IH, additional evaluation may include ultrasonography, other imaging, and biopsy.

Complications of IHs

  • Ulceration : occurs in ∼10% of lesions, especially those on the lip and in the anogenital region or other skin folds, at a median age of 4 months ( Fig. 85.9 ); whitish discoloration of an IH in an infant <3 months of age may signal impending ulceration; results in pain, a risk of infection (relatively uncommon), and eventual scarring (see Fig. 85.4A,B ).

    Fig. 85.9, Ulcerated infantile hemangiomas.

  • Disfigurement and interference with function due to the IH’s location and/or large size.

    • –

      Periocular IH – risk of astigmatism if puts pressure on globe, amblyopia if obstructs the visual axis, and strabismus if affects orbital musculature (see Fig. 85.7A,C ); requires ophthalmologic evaluation

    • –

      IH on nasal tip , columella, or lip (especially if crosses the vermilion border) – high risk of distortion of facial structures (as well as ulceration if on the lip) (see Fig. 85.7B )

    • –

      IH on breast (in girls) – may affect underlying breast bud, so early surgery should be avoided

  • Associated extracutaneous abnormalities.

    • –

      IHs in “beard” area of the lower face – often associated with airway IHs , which may present with noisy breathing or biphasic stridor; otolaryngologic evaluation is needed for infants with symptoms or when the IH is likely to be actively proliferating (i.e. <5 months of age) ( Fig. 85.10 )

      Fig. 85.10, Infantile hemangiomas in a “beard” distribution.

    • –

      Large facial IHs, particularly segmental lesions – risk of PHACE(S) syndrome: P , p osterior fossa malformations; H , h emangioma; A , a rterial abnormalities (cervical, cerebral); C , c ardiac defects, especially c oarctation of the aorta; E , e ye anomalies; S , s ternal defects and s upraumbilical raphe ( Table 85.2 ; Figs 85.11 and 85.12 ; see Fig. 85.7A,C )

      Table 85.2
      Diagnostic criteria for PHACE(S) syndrome.
      Definite PHACE(S):

      • Hemangioma >5 cm in diameter of the head including scalp PLUS 1 major criterion or 2 minor criteria

      • Hemangioma of the neck, upper trunk, or trunk and proximal upper extremity PLUS 2 major criteria

      Possible PHACE(S):

      • Hemangioma >5 cm in diameter of the head including scalp PLUS 1 minor criterion

      • Hemangioma of the neck, upper trunk, or trunk and proximal upper extremity PLUS 1 major criterion or 2 minor criteria

      • No hemangioma PLUS 2 major criteria

      Organ system Major criteria Minor criteria
      Arterial

      • Anomalies of major cerebral or cervical arteries ∗ – dysplasia ∗∗ , hypoplasia, stenosis/occlusion, aberrant origin/course

      • Persistent carotid–vertebrobasilar anastomosis (e.g. proatlantal segmental, hypoglossal, otic, trigeminal arteries)

      • Aneurysm of cerebral arteries

      Structural brain

      • Posterior fossa anomalies – Dandy–Walker complex, other hypoplasia/dysplasia of the mid or hind brain

      • Midline anomalies

      • Malformation of cortical development

      Cardiovascular

      • Aortic arch anomalies

      • Aberrant origin of subclavian artery ± vascular ring

      • Ventricular septal defect

      • Right/double aortic arch

      • Systemic venous anomalies

      Ocular

      • Posterior segment anomalies – persistent hyperplastic primary vitreous/persistent fetal vasculature, retinal vascular anomalies, optic nerve hypoplasia, morning glory disc anomaly

      • Anterior segment anomalies, e.g. sclerocornea, cataract, coloboma, microphthalmia

      Ventral or midline

      • Sternal defect/pit/cleft

      • Supraumbilical raphe

      • Hypopituitarism

      • Ectopic thyroid

      • Midline sternal papule/hamartoma

      ∗ Includes internal carotid artery; middle, anterior, or posterior cerebral artery; and vertebrobasilar system.

      ∗∗ Includes kinking, looping, tortuosity, and/or dolichoectasia.

      Fig. 85.11, PHACE(S) syndrome.

      Fig. 85.12, Evaluation of a child with infantile hemangiomas for possible systemic involvement.

    • –

      Large IHs on the lower body, particularly segmental lesions (often IH-MAG) – risk of LUMBAR syndrome: L , l ower body/ l umbosacral IH and l ipomas; U , u rogenital anomalies and u lceration; M , m yelopathy (spinal dysraphism); B , b ony deformities; A , a norectal and a rterial anomalies; R , r enal anomalies ( Fig. 85.13 ; see Figs 85.7D and 85.12 )

      Fig. 85.13, LUMBAR syndrome.

    • –

      Midline lumbosacral IHs – risk of spinal dysraphism (see Ch. 53 )

    • –

      Multifocal IHs (≥5) – may be associated with extracutaneous hemangiomas , most often hepatic; the cutaneous IHs are usually relatively small and superficial, but hepatic involvement can be associated with complications such as high-output cardiac failure and hypothyroidism (due to iodothyronine deiodinase production by the IH) ( Fig. 85.14 ; see Fig. 85.12 )

      Fig. 85.14, Multifocal infantile hemangiomas with extracutaneous hemangiomas.

Treatment of IHs

  • “Active non-intervention,” including education of parents and observation with periodic photography, is sufficient for most small IHs expected to have a good cosmetic outcome.

  • Patients with a potentially problematic IH should be referred for systemic therapy by 4–6 weeks of age.

  • Local Rx: topical timolol, e.g. one drop (0.25 mg) of 0.5% gel-forming ophthalmic solution applied BID (systemic absorption possible, especially if ulcerated or involving mucous membranes; limit to <0.25 mg/kg/day), or superpotent CS for thin superficial lesions; intralesional CS for thicker lesions (avoiding the periocular area); pulsed dye laser for residual telangiectasias and possibly for thin superficial lesions.

  • Systemic Rx: indications are listed in Table 85.3 ; oral propranolol ( Table 85.4 ) has replaced prednisolone as the first-line systemic therapy.

    Table 85.3
    Reasons to consider systemic therapy for infantile hemangiomas.
    Threatened vital functions

    • Vision

    • Airway

    Potential for disfigurement

    • Nasal tip or columella

    • Lip, especially if crosses the vermilion border

    • Large or rapidly growing lesion, especially if on the face

    Severe/recalcitrant ulceration
    High-output cardiac failure

    Table 85.4
    Administration of propranolol for infantile hemangiomas (IHs): pretreatment evaluation, dosing, and monitoring.
    Propranolol, a nonselective β-blocker, binds to β 2 -adrenergic receptors on hemangioma endothelial cells, with effects including vasoconstriction (leading to softening and dulling of color within 24 hours), decreased expression of pro-angiogenic growth factors, and induction of apoptosis. Practices vary, and the patient’s age, hemangioma-related issues, and medical comorbidities also affect management.
    Pretreatment evaluation

    • If history of bronchospasm/reactive airway disease (a relative contraindication to propranolol therapy): consult with a pulmonologist or consider alternate therapy

    • If at risk for PHACE(S) syndrome ∗ : MRI/MRA of head/neck and echocardiogram to exclude arterial and cardiovascular anomalies (see Fig. 85.12 ); if abnormal, consult with a neuroradiologist, neurologist, and/or cardiologist as indicated

    • Cardiac examination, heart rate, and manual blood pressure; also consider an electrocardiogram (ECG); bradycardia (<80 beats per minute), greater than first degree heart block, blood pressure <50/30 mmHg, and decompensated heart failure are considered to be contraindications

    Dosing and course

    • Initial: usually ∼1 mg/kg/day divided into 2 (or 3) doses ∗∗

    • Goal: 2–3 mg/kg/day divided into 2 (or 3) doses ∗∗ ; the target dose for the FDA-approved formulation (Hemangeol™) is as high as 3.4 mg/kg/day, whereas doses ≤1 mg/kg/day may lead to shorter healing times for ulcerated hemangiomas

    • For a proliferating IH, treatment is typically continued for 6–12 months, depending on the clinical setting and course

      • – The dose should be adjusted to account for weight gain and maintain the goal dose/kg, especially during the proliferative phase

    • Taper over 2–4+ weeks before discontinuing, primarily to assess for rebound growth

    Monitoring

    • Risks of propranolol include bradycardia, hypotension, hypoglycemia, sleep disturbances, and bronchospasm

    • Consider a brief inpatient stay (e.g. 1–2 days) with telemetry for initiation of treatment if <5 weeks of age (using corrected age for premature infants) and/or complications such as cardiovascular or cerebrovascular anomalies

    • Outpatient initiation of therapy

      • –

        Monitor heart rate and blood pressure for 2 hours after the initial dose or a significant dose increase

      • –

        Measure heart rate and blood pressure every 4–8 weeks while on a stable dose

      • –

        Normal ranges for pediatric vital signs are available at: www.emedicinehealth.com/pediatric_vital_signs/article_em.htm

    • Educate parents about signs of hypoglycemia – early (may be masked by β-blockade): sweating, rapid heart rate, shakiness, fussiness; late : lethargy, poor feeding, hypothermia, seizures

    • Administer during or immediately after a feeding; twice daily doses should be ≥9 hours apart

      • –

        Dose should be lowered or therapy suspended during intercurrent illnesses with decreased oral intake or vomiting

    ∗ Segmental hemangioma ≥5 cm in diameter on the head or upper body (see Table 85.2 ).

    ∗∗ The dose is typically increased in increments of 1 mg/kg/day weekly in an outpatient setting or after 1–3 doses in an inpatient setting, until reaching the goal dose. A lower starting dose and slower escalation may be required for patients at higher risk of complications or when treatment is initiated without in-office monitoring (e.g. starting with 0.5 mg/kg/d and increasing by 0.5 mg/kg/d every 3-4 days). The FDA-approved Hemangeol™ 4.28 mg/ml solution has a dosing chart in the package insert; the concentration differs slightly from generic propranolol 20 mg/5 ml (4 mg/ml) solution.

    A longer duration of treatment may be required for IHs with prolonged growth or rebound growth after reduction/discontinuation of propranolol.

  • Management of an ulcerated IH includes wound care (e.g. hydrocolloid dressings), pain management, monitoring for infection, and specific therapies directed at the ulcer (e.g. pulsed-dye laser) or IH (e.g. β-blockers; faster healing with propranolol dose ≤1 mg/kg/d).

  • Surgical excision is useful to remove fibrofatty tissue and redundant skin in involuted or partially involuted IHs; often done in preschool-aged children with cosmetically significant lesions (e.g. on the lip), and earlier resection may be considered when eventual surgery is inevitable (e.g. for some pedunculated lesions).

Hemangioma Variants

  • Congenital hemangiomas are fully developed at birth, typically presenting as a warm, pink to blue-violet mass or plaque with overlying coarse telangiectasias, surrounded by a vasoconstricted rim and/or radiating veins; unlike IHs, congenital hemangiomas are GLUT1-negative and often have an underlying somatic mutation in GNAQ or GNA11 that activates G protein α-subunits.

    • –

      Rapidly involuting congenital hemangioma (RICH) – rapid involution during the first year of life ( Fig. 85.15A,B )

      Fig. 85.15, Congenital hemangiomas and other vascular tumors.

    • –

      Partially involuting congenital hemangioma (PICH) – incomplete involution early in life

    • –

      Non-involuting congenital hemangioma (NICH) – postnatal growth in proportion to the child, without involution ( Fig. 85.15C ); tardive expansion occasionally occurs during childhood

Vascular Malformations

  • Categorized based on the predominant type(s) of vascular channels, which are divided into slow- and fast-flow groups:

    • –

      Slow-flow : capillary (port-wine stain), venous, microcystic lymphatic (“lymphangioma”), and macrocystic lymphatic (“cystic hygroma”)

    • –

      Fast-flow : arteriovenous (arterial anomalies + arteriovenous shunting)

  • Vascular malformations may contain only one type of vessel or an arteriovenous malformation ( simple ) or ≥2 types of vessels ( combined ; e.g. capillary–lymphatic–venous malformation).

  • Although they can affect any organ, vascular malformations are most easily identified in the skin and mucous membranes, where they may extend into deeper structures or be associated with other extracutaneous abnormalities.

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