Despite the considerable advances in our understanding of the pathogenesis of hemangiomas, many unanswered questions remain and the precise mechanisms dictating both proliferation and involution are not clearly understood.³,¹³ Most cases are sporadic and are not inherited; however, families with a Mendelian pattern of inheritance have provided some insight into the genes that may one day prove to have a causal link or at least may be partially involved in the pathogenesis of IH through the proteins these genes encode.⁹ These associations are mostly weak; however, candidate genes have been mapped to some specific locations including 2p13, 2q23, 4q12, 5q31, 7q33, and 15q26.⁹,¹⁴,¹⁵

However, it appears that somatic mutations may play a far more important role in the pathogenesis of congenital hemangioma (CH), which is the rarer variant of IH. Mutations in both GNAQ and GNA11 loci have been demonstrated recently in both variants of CH: the rapidly involuting type (RICH) and the noninvoluting type (NICH).¹⁶

The exact pathogenetic events leading to the development of hemangioma are unknown. It is hypothesized that vascular stem cells, the so-called hemangioma stem cells (HemSCs) that are normally present in the fetus, occasionally persist and become dysregulated leading to hemangioma formation, but it is not clear whether they originate from the placenta or the bone marrow.¹⁷,¹⁸ A placental origin of IH has been proposed repeatedly over the years. Recent evidence is more in favor of a placental embolic origin during early fetal life, in addition to a postnatal favorable environment that supports proliferation and differentiation of those embolized primitive cells.¹⁹,²⁰ Embolization usually occurs in the first trimester coinciding with the migration of neural crest cells, which leads to the integration of these cells along the neural crest migratory routes, thereby manifesting as segmental lesions. If embolization occurs later during fetal life, it usually results in discrete lesions which are the more frequently observed pattern in the periorbital region.¹⁹,²⁰ This placental origin of IH is supported by the expression of glucose transporter 1 (GLUT1) protein on the endothelium of hemangiomas and is also supported by the increased incidence of IH in infants born following amniocentesis and chorionic villus sampling.¹⁹,²⁰

It is also not entirely clear whether the initial or proliferative phase of IH involves angiogenesis (formation of new blood vessels from existing ones through sprouting of endothelial cells) or vasculogenesis (de novo formation of vessels from
progenitor cells). The former theory is supported by the detection of angiogenic factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF-A) within the tumor. The vasculogenesis theory is supported by the presence of immature multipotent progenitor stem cells, which are capable of de novo blood vessel formation as well as adipogenesis.¹,²¹ It is not implausible that both mechanisms may play a role, with vasculogenesis as the initiating event, followed by angiogenesis, which amplifies the size of the lesion to become an irregular mass full of blood vessels.²¹ The involution of IH is attributed to the gradual depletion of HemSCs.¹⁷

Recently, it has been shown that hemangioma patients have significantly increased serum levels of renin and angiotensinogen II. This discovery of a potential role for the renin-angiotensin system in the pathogenesis of IH provides a credible explanation for the programmed biologic behavior of IH and the accelerated involution that occurs with the use of β-blockers.¹³,²⁰ The insulin-like growth factor system and the TRAIL-osteoprotegerin antiapoptotic pathway are also possibly involved in the evolution of IH.²⁰

Historically, vascular anomalies were classified according to the size of the lumen (capillary vs cavernous), or according to the nature of their fluid content (hemangiomas vs lymphangioma). This classification is no longer accepted and currently vascular anomalies are classified according to the proliferative potential of the vascular endothelium.¹² A distinction should thus be made between hemangiomas, which are true tumors that grow by endothelial cell hyperplasia or proliferation, are not present at birth, do not grow indefinitely, and have a regression phase, and vascular malformations, which occur as a result of a structural defect in vascular morphogenesis, are present at birth, grow in size with growth of the individual, do not possess a regression phase, and have a normal rate of endothelial turnover.¹⁴,²² Because of their clinical diversity, the classification of hemangioma itself is difficult. While IH elsewhere in the body is usually classified morphologically into (1) localized, (2) segmental, (3) indeterminate, or (4) multifocal, the majority of periocular IHs are small and localized, and even if they are large or display a geographic pattern, they are not consistently associated with a particular segmental distribution.¹⁰,¹² Although periocular IH still can be classified zonally into the aforementioned groups, which may indeed be of useful prognostic value, larger periocular lesions may not follow a specific dermatomal distribution,¹¹ which may hinder a strict classification. From a clinical standpoint, it may be better to classify periocular lesions according to their depth into superficial, deep, or mixed lesions where the lesions acquire characteristics of both subtypes.⁴,⁵,¹²

IHs represent the most common vascular tumors in infancy. It most frequently involves the head and neck region, followed by the trunk, and the extremities. IH is found in greater frequency in girls (3:1-5: 1 ratio), whites, premature infants, and twins, and more commonly develops when the mother is of higher maternal age.¹,²,¹⁴ Obtaining an accurate natural history as regard the age of onset, ethnicity, and rate of progression/regression is extremely important in patients with hemangiomas to differentiate IH from closely related lesions but less common ones like CHs where the lesion is fully developed at birth, does not show a proliferative phase, and may either rapidly involute by 12 to 18 months (RICH) or may never regress at all, but instead grows with the growth of the child (NICH).²,⁹ An intermediate form exists where partial regression may be observed (partially involuting congenital hemangioma, PICH).¹²

The classic dictum that IHs are not present at birth may not entirely be accurate.¹ Not infrequently, there is a precursor lesion, usually a small area of pallor or a slightly purplish hue that gradually brightens and expands in size. In actual clinical practice, those lesions become more apparent in the first few weeks of life as a flat macular area of telangiectatic vessels that usually blanches on compression.¹,⁴,⁵ This is followed by a rapid proliferative phase for 6 to 12 months, in which the tumor grows exponentially. Subsequently, this is followed by a phase of gradual involution or spontaneous regression.²,⁴

In superficial lesions that involve the skin, the infant usually presents with a flat to slightly elevated bright red tumor with a smooth or irregular outer surface (Figure 73.1). The surface may resemble a strawberry, and hence the old name strawberry nevus. During the proliferative phase, lesions enlarge rapidly, often resulting in aesthetic and functional disability (Figure 73.2). Deep lesions may be located subcutaneously where the eyelid assumes a deep bluish hue or may be located deep within the orbit where it causes a mass effect in the eyelid without any discoloration (Figure 73.3).⁴,⁵,¹² Deeper orbital lesions may displace the globe, causing axial or nonaxial proptosis, optic neuropathy, or bony deformities.⁴,¹³ Mixed lesions may involve both the skin and the deeper tissues. Rapidly growing superficial lesions may cause deprivation amblyopia in as little as 1 week during the proliferative phase because of occlusion of the visual axis.⁴ IH is considered a relative oculoplastic emergency in the first year of life as the prevalence of amblyopia may be as high as 63%.⁴,²³ Deeper lesions are also potentially amblyogenic due to anisometropia or strabismus.⁴,²³