4.1 Introduction

The natural history of a “typical” hemangioma of infancy is rapid postnatal growth over several months, followed by spontaneous, gradual extensive involution. Whereas physicians often advocate passiveness, stating that “hemangiomas go away, therefore no need to intervene,” it is important to recognize the features of hemangiomas that should trigger prompt management decisions and realize that timely evaluation with newer treatment modalities can prevent unwanted morbidity, permanent sequelae, and possibly the need for invasive procedures in the future. Additionally, seemingly innocuous hemangiomas, in a noticeable area, trigger negative remarks, often from curious adults and children, affecting the quality of life for the patient and his or her family. ^{1 ,​ 2 ,​ 3} One large study showed that the mean infant age for referral to specialists was 5 months, although most hemangioma growth has occurred by then, underscoring the importance of timely referral to hemangioma specialists, who can determine risk and initiate treatments to prevent unwanted medical and psychosocial morbidity. ⁴

Factors mediating proliferation and involution are ambiguous and likely multifactorial, with potential interactions dependent on hypoxia, estrogen (and other hormones), endothelial progenitor cells, hemangioma stem cells, dendritic cells, pericytes, adipocytes (in late stages), mast cells, transcription factors, growth factors, and intracellular signaling pathways. ^{5 ,​ 6 ,​ 7 ,​ 8 ,​ 9 ,​ 10 ,​ 11 ,​ 12 ,​ 13 ,​ 14 ,​ 15 ,​ 16 ,​ 17 ,​ 18 ,​ 19} Studies measuring the levels of circulating growth factors in infants with hemangiomas have shown inconsistent results. ^{20 ,​ 21 ,​ 22}

Results of the multicenter Hemangioma of Infancy Study of more than 1,000 children with hemangiomas disclosed an increased incidence in white non-Hispanic infants, in multiple gestation, in infants born to older mothers, when placenta previa or pre-eclampsia occurred, and especially in low-birth-weight, premature infants. ^{23 ,​ 24} In a study of 650 children with hemangiomas, Chen et al identified a positive correlation of hemangioma occurrence with early intrapartum progesterone therapy or vaginal bleeding, implicating a possible role of hypoxia-mediated processes or placental damage in hemangioma development. This study also found an association between in vitro fertilization and the occurrence of hemangioma. ²⁵ This study and others demonstrated a high incidence of hemangiomas in twin gestation, especially those with low birth weight. ^{23 ,​ 24 ,​ 25} Initial studies suggesting a correlation between infantile hemangioma incidence and transcervical chorionic villous sampling have since been refuted. ^{26 ,​ 27 ,​ 28} A Dutch report identified a correlation between infantile hemangioma and maternal amniocentesis, although other studies have not corroborated this finding. ²⁹

It is not known why hemangiomas occur more frequently in the cervicofacial location. Waner and colleagues initially recognized a nonrandom distribution of facial hemangiomas, identifying two growth patterns: focal lesions (in 76.3% of 205 patients assessed) and diffuse lesions (in 23.7%). The focal hemangiomas correlated to 22 sites, all proximate to mesenchymal or mesenchymal–ectodermal embryonic fusion lines. The diffuse hemangiomas respected a segmental distribution pattern: frontonasal (27%), maxillary (35%), or mandibular (38%) ( Fig. 4.1 ). ³⁰

Haggstrom et al further defined nonrandom distribution into specific segments, denoted as Seg1, 2, 3, or 4, correlating with a cutaneous hemangioma location ³¹ ( Fig. 4.2 ). Appreciation of the anatomical distribution of and potential problems associated with hemangiomas can be advantageous in directing appropriate evaluation and management. Table 4.1 summarizes these features.

4.2 Which Hemangiomas Require Treatment?

Hemangiomas may cause complications requiring medical therapy or other interventions to prevent further proliferation and catalyze the involution phase. These complications may include obstruction of the upper airway, ophthalmologic disturbances, ulceration or bleeding, anatomical deformity, cerebral vasculopathy, and high-output congestive heart failure. Principles for evaluating a patient include confirming the diagnosis as hemangioma, assessing the degree of existing or impending morbidity based on the location and size of the hemangioma, the patient’s age, and appreciating any comorbidities (e.g., prematurity, other medical issues).

Diagnostic confirmation rarely requires a biopsy. If the lesion is following the age-appropriate growth curve (i.e., minimally if at all evident at birth followed by rapid growth, then stabilization and gradual improvement), most physicians can be reassured that the diagnosis is a hemangioma. If atypical (i.e., rapid growth, unusual clinical and radiologic appearance, and firmness), histologic confirmation must be considered. Hemangioma tissue is distinguished by positive staining for the glucose transporter 1 protein in any growth stage. ³²

Once the clinical history and physical examination support the diagnosis of hemangioma of infancy, important features to consider when approaching a patient with a hemangioma include the following:

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  Anatomical location, size, and configuration of the hemangioma

  
  
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  Number of hemangiomas

  
  
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  Age of the patient when first seen (i.e., early versus late)

  
  
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  Associated morbidities: upper airway obstruction, ophthalmologic sequelae, ulceration, bleeding, feeding difficulties, pain, functional impairment, anatomical deformity, high-output state

  
  
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  Underlying morbidities: other medical issues that might influence treatment decisions

  
  
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  Location and type, which may affect the risk of morbidity or quality of life

Luu and Frieden provide practical evidence-based guidelines to help determine which patients with hemangiomas necessitate further evaluation and treatment. ³³ Higher-risk features include segmental hemangiomas larger than 5 cm in diameter on the face (risk of PHACE syndrome); ophthalmologic or otolaryngolic sequelae; hemangiomas over the lumbosacral or perianal areas (risk of SACRAL [spinal dysraphism and anogenital, cutaneous, renal, and urologic anomalies associated with an angioma of lumbrosacral localization, ulceration]) syndrome; bulky lesions; central facial and regional (periobital, perianal, or perioral) lesions with a concomitant higher risk of anatomical deformity. Intermediate-risk hemangiomas occur on the peripheral facial areas, scalp, hands, feet, skin folds (e.g., neck, perineum, axilla), and segmental lesions of the trunk and extremities larger than 5 cm in diameter. Lowest-risk lesions occur on nonvisible areas of the trunk and extremities. ³³

Segmental hemangiomas are more likely to require medical intervention and may be associated with a higher incidence of PHACE(S) ( Fig. 4.3 ), visceral hemangiomas, underlying lumbosacral anomalies (e.g., occult spinal dysraphism, including lipomyelomeningocele with tethered cord). ^{34 ,​ 35 ,​ 36}

PHACE(S) syndrome (Online Mendelian Inheritance in Man, OMIM no. 606519) is an acronym for posterior fossa structural malformations, hemangiomas (segmental), arterial anomalies, cardiac defects, eye abnormalities (and sternal and other midline deformities). ³⁷ Major and minor diagnostic criteria for PHACE (or possible PHACE) syndrome are described in a Consensus Statement. ³⁸ PHACE necessitates a facial or scalp segmental hemangioma larger than 5 cm in diameter and one major criterion or two minor criteria. Possible PHACE is defined as having a facial or scalp hemangioma larger than 5 cm in diameter and one minor criterion. About a third of patients with facial segmental hemangiomas had PHACES syndrome according to the preceding criteria; those at higher risk had frontonasal or frontotemporal or large (i.e., more than one segment) hemangiomas. Central nervous system (CNS) arteriopathy or cardiac anomalies were the most commonly observed extracutaneous findings. ³⁹ “Beard distribution” hemangiomas (seg3) may be associated with symptomatic airway hemangiomas. ⁴⁰ Cutaneous hemangioma in the S1 and S3 segments may be at risk for auditory area intracranial hemangiomas with ipsilateral conductive or sensorineural hearing loss. ⁴¹ Neurodevelopmental language-speech, gross, and fine motor delays were more prevalent in patients who had nonposterior fossa CNS structural anomalies. ⁴² Further details regarding this syndrome are included later in this book (Chapter 5).

Segmental perianal or lower midline back hemangiomas should alert the physician to screen for congenital renal, sacral, lower spine, or genitourinary anomalies. LUMBAR and PELVIS syndromes are acronyms for lower-body hemangioma and other cutaneous defects, urogenital anomalies, ulceration, myelopathy, bony deformities, anorectal malformations, arterial anomalies, and renal anomalies and for perineal hemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag). ^{35 ,​ 43 ,​ 44 ,​ 45}