Table 25.1
Comparison of Hemangiomas and Vascular Malformations
| Hemangiomas | Malformations |
| Absent at birth | Present at birth |
| Independent life cycle | Relentless progression |
| Rapid proliferation (+ mitoses) | Slow expansion (hypertrophy) |
| Slow involution | Never involute |
| Female > male | Female = male |
| More common in white skin | No racial predilection |
| Histology varies with stage | Blood or lymphatic histology consistent over time |
Table 25.2
Immunohistochemical Profile of Infantile Hemangiomas and Vascular Malformations
| Placenta | Hemangioma | Malformation | |
| GLUT-1 | + | + | − |
| Lewis Y | + | + | − |
| Merosin | + | + | − |
| FC-γRII | + | + | − |
The understanding of IH continued to evolve rapidly with the recognition of two distinct subtypes. Discrete hemangiomas that occur along lines of fusion between embryologic facial placodes were called “focal,” and large plaque-like hemangiomas overlying individual or multiple facial placodes were labeled “segmental.”6 These lesions behave differently, associate with systemic disease differently, and require different management approaches. The International Society for the Study of Vascular Anomalies (ISSVA) also revised its classification scheme, categorizing IH among vascular neoplasms.7
Treatment of IH has been controversial for decades, largely because these lesions display the unique characteristic of slow but spontaneous resolution, a process known as “involution.” Patients were advised that hemangiomas would resolve entirely, and popular lore produced a resolution “schedule,” in which hemangiomas resolve by exactly 10% per year of life.8 Despite advances in medications, laser science, and surgical technique, the medical community continued to promote a policy of “watchful waiting.” Multidisciplinary clinics devoted to the management of vascular anomalies arose worldwide after 2000, popularizing a vast array of treatment possibilities for their patients. Ultimately, the serendipitous discovery of the benefits of beta blockers in 2008 revolutionized the modern approach to IH management.9
Fundamental Science
Both angiogenesis and vasculogenesis have proven important in understanding hemangioma science.10 Angiogenesis describes new blood vessels arising from existing vasculature. Typical IH are composed of endothelial cells with multilaminate basement membrane, type IV collagen, pericytes, fibroblasts, mast cells, and macrophages. A number of cellular factors such as the angiogenesis-related receptors E-selectin, integrins αvβ3 and α5β1, and basic fibroblast growth factor (bFGF), a factor found in normal angiogenesis are expressed in both normal and hemangioma endothelial cells. During proliferation, angiogenic growth factors, including vascular endothelial growth factor (VEGF) and insulin-like growth factor 2 (IGF-2), are elevated and thought to promote the growth of IH from existing vessels.11
Vasculogenesis, in contrast, describes derivation from early endothelial structures that typically spawn the endocardium and the great vessels. The cells of these structures originate from mesoderm-derived hemangioblasts, which are believed to function as progenitors to both hematopoietic and endothelial cells. A number of studies have found that endothelial cells from IH coexpress hematopoietic and endothelial cell markers and thus support the vasculogenesis model.12
The proliferation and involution of IH are governed by numerous molecular, cellular, and hormonal regulators. Although the catalyst to involution is unknown, it is associated with an increase in mast cells and a fivefold increase in endothelial apoptosis.
Familial and syndromic associations in IH cases suggest a possible genetic component to their origins. Although most occur sporadically, autosomal dominance is the most common pattern among those with familial inheritance, and the relative risk in siblings is 2.5.13 Atopic disease and hemangiomas appear to be strongly associated. In one study of 2063 patients with hemangioma, the authors found a 36% increased risk of allergies, 67% increased risk of asthma, and 82% increased risk of eczema. Eczema was most strongly associated with hemangioma, with a nearly twofold increased risk.14
Most genetic research on IH has focused on endothelial cells. Endostatin is an angiogenesis inhibitor that normally inhibits endothelial cell activation. However, endostatin paradoxically stimulates the endothelial cells of hemangioma, leading Boye to conclude that hemangiomas constitute clonal expansions of endothelial cells.15 Indeed, these tumors may be caused by somatic mutations in one or more genes modulating endothelial cell proliferation.
Another paradox is an unexpected reduction in vascular endothelial growth factor receptor-1 (VEGF-R1) in the endothelial cells of hemangioma. Normal activity of the VEGF-R2 signaling pathways in these cells suggests that local therapy with these agents may have a role in the management of hemangiomas in the future.16
Studies of the “Notch” signaling pathway have offered additional insight into endothelial differentiation seen in IH. The Notch receptor is a single-pass transmembrane receptor protein. Notch family members are known to play a role in vascular development during embryogenesis and postnatal tumor angiogenesis.17 RNA from resected hemangioma tissue reveal Notch expression patterns different from normal human endothelial cells. Thus, the pattern of Notch gene expression reflects the progression from immature cells to endothelial-lined vascular channels (i.e., endothelial differentiation) that characterizes the growth and involution of IH.18
Genetic studies on IH have also examined the role of pericyte differentiation. IH-derived stem cells that contact endothelial cells create pericyte-like cells. When pericyte differentiation is blocked, blood vessel formation is reduced, confirming the importance of pericytes in blood vessel development. Further studies investigating the genes involved in angiogenesis in HemSCs have suggested potential therapeutic targets for hemangiomas. Corticosteroids, for example, suppress expression of at least three important proangiogenic factors.19
Infantile Hemangioma
Infantile hemangiomas are the most common tumors of infancy, affecting 1.1% to 2.6% of all neonates and 10% of white infants by their first year.20,21 This statistic was determined when “hemangioma” was more loosely defined and likely represents a pool of several vascular conditions.22 Nevertheless, the incidence among Asian and black children is much lower.23 Premature infants weighing less than 1000 g have an incidence of up to 22%, and children subjected to chorionic villus sampling are said to have a 10-fold higher risk.24 The female/male ratio ranges from 3 : 2 to 5 : 1.25
Pathogenesis/Etiology
Placenta Theory
Considerable evidence associates IH with the placenta. For example, the increased risk after chorionic villus sampling is thought to result from trophoblast embolization caused by placental microtrauma.26 The natural progression of IH also mimics the placenta, which develops after conception, proliferates in early gestation, and stabilizes thereafter. During placental development, angiogenesis occurs at an extraordinary rate and is controlled by inhibitory factors that prevent inappropriate blood vessel growth into normal maternal and fetal tissues. After birth, the source of sFLt-1 is removed, allowing unopposed proliferation of cells responsive to angiogenic growth factors. This mirrors the natural progression of IH but also coincides chronologically with the appearance of IH in the postnatal period.27 In 2000, IH were found to express GLUT-1, a glucose transporter protein expressed by placental and barrier endothelial tissue, supporting the hypothesis that IH cells are related to placental tissue.4 Placenta and IH tissue also share a number of other markers (Table 25.3),5 which led to the hypothesis that placental tissue shears off during gestation and embolizes to fetal cutaneous vessels. Transcriptomes of human placenta and IH have also been shown to be similar. Genes preferentially expressed in both placenta and hemangiomas were identified, including 17-β hydroxy-steroid dehydrogenase type 2 and tissue factor pathway inhibitor 2.28
Table 25.3
ISSVA Classification
| Vascular Neoplasms (Ch. 25) | Vascular Malformations (Ch. 24) | Vascular Shunts and Fistulae (Ch. 26) |
| Infantile hemangioma | Arteriovenous | Carotid–cavernous sinus (high flow) |
| Hemangiopericytoma | Venous | Dural shunts (low flow) |
| Kaposiform hemangioendothelioma | Venular (port-wine stain) | |
| Rapidly involuting congenital hemangioma | Capillary | |
| Noninvoluting congenital hemangioma | Lymphatic | |
| Tufted angioma | Mixed (e.g., venolymphatic) | |
| Angiosarcoma | ||
| Hemangioblastoma | ||
| Pyogenic granuloma |
Contradicting this theory is the absence of maternal–fetal chimerism, which one might expect if embolization of placental tissue to the fetus had occurred.29 Second, the endothelial cells seem to originate from the fetus and not from the mother.30
Metastatic Theory
Additional support for the idea of placental emboli lies in a different theory based on the work by Massague et al. on malignant tumor metastasis.31
According to their work, the fetal portion of the placenta might produce “secretagogues,” which prepare a site for the precursor cells of hemangioma, similar to the site prepared in the metastatic niche.32 An interesting consideration in this theory is that the mesenchyme of the head and neck is the neuromesenchyme. Embryologically, hemangioblasts migrate through mesenchyme to provide the vasculature of the nerves. Thus, this neuromesenchyme favors hemangioblast migration, which would also support the preference for hemangioblast to lodge at this site.
In summary, the metastasis hypothesis compares the metastatic niche of malignant tumors to a possible niche in IH. It more clearly explains focal hemangiomas but may also explain segmental hemangiomas; if the niche were prepared early in placode formation, placode migration could theoretically stretch the niche along the migration course, thereby creating a segmental lesion.6
Progenitor Cell Theory
The link between hemangiomas and placenta might be based on a common origin. If IH results from a mutation in a primitive or precursor stem cell, that would tilt further development of these cells toward placental characteristics. Cultured blood endothelial progenitor cells isolated from controls and patients with IH express placenta-specific markers such as GLUT-1, Lewis Y, Fc-γ RII, and merosin. This supports the idea that hemangiomas arise from somatic mutation and clonal expansion of progenitor cells. More recently, pluripotential stem cells have been isolated from human IH tissue that give rise to hemangioma-like lesions in immunodeficient mice. Since hemangiomas mimic the natural life cycle of the placenta, perhaps hormonal or oxygen tension levels play important roles in progression and subsequent involution.
Extrinsic Factor Theory
The finding of two distinct patterns of tissue involvement in facial IH suggests that the environment or an extrinsic factor may have a role in the timing of hemangioma precursor cells deposition, with earlier events resulting in segmental hemangiomas and later events resulting in focal lesions near lines of mesenchymal fusion.33 Hypoxia may contribute to the pathogenesis of IH, a hypothesis supported by the cutaneous blanch that often precedes vascular proliferation (Fig. 25.2). Mihm et al. suggested that local ischemia may create hypoxic conditions leading to an upregulation of hypoxia-inducible factor 1α (HIF-1α), responsive chemokines such as stromal cell–derived factor 1α (SDF-1α), and vascular endothelial growth factor (VEGF). Newer in vivo murine models promise better understanding of the pathogenesis and potential therapies for IH.34
Classification
The revised classification of the ISSVA recognizes two major vascular lesion divisions: tumors and malformations. The tumor division is subdivided into benign, borderline, and malignant lesions. Hemangiomas are the most common of the vascular neoplasms, appearing in the benign subdivision (Table 25.3).
Differential Diagnosis
Because of the great variety in the presentation of IH, a comprehensive differential diagnosis is quite long. Early in presentation, IH may be confused with benign venular midline malformation, also known as “nevus flammeus neonatorum,” “stork bite,” “angel kiss,” or “salmon patch” that occurs in up to 40% of newborns and that most often disappears by the first year of life (Fig. 25.3).
Focal hemangiomas with cutaneous components may mimic venous malformations, particularly when mucosal surfaces are involved. In cases of focal, deep (subcutaneous or orbital) hemangiomas, rhabdomyosarcoma, metastatic neuroblastoma, hemangiopericytoma, mucocele, meningocele, and other childhood mass lesions must be considered. On the eyelids, small focal hemangiomas may appear to be pyogenic granulomas (PGs). Segmental hemangiomas are easily confused with port-wine stain (cutaneous venular malformations) or rarer cutaneous vascular malformations that also tend to follow dermatomal patterns. The involuted cutaneous hemangioma may appear as a fatty subcutaneous deposit (lipoma) or may leave scarring that appears as the residuum of trauma or chemical or thermal burns (Table 25.4).
Table 25.4
Differential Diagnosis of Infantile Hemangioma
| Clinical Characteristic | Differential Diagnoses |
| Early | Stork bite |
| Mucosal | Venous malformation |
| Focal, deep, orbital | Metastatic neuroblastoma, rhabdomyosarcoma, hemangiopericytoma |
| Eyelids | Pyogenic granuloma |
| Segmental | Port-wine stain (cutaneous venular malformation) |
| Involuted | Lipoma, trauma, burn |
Clinical Features
IH are often absent or small at birth and generally grow rapidly in the first months of life followed by a variable period of involution spanning months to years. More than 75% of hemangiomas are detected by 4 weeks of life, and 5% to 30% show some clinical evidence at birth, often with a paradoxically hypovascular blanch, pale halo, area of erythema, or cluster of telangiectatic vessels (Fig. 25.4).
Hemangiomas demonstrate a predictable life cycle with a proliferative phase characterized by rapid expansion and endothelial hyperplasia within the first year. The proliferative phase can be biphasic, with most of the growth occurring within the first month and a second rapid growth phase at 6 months. Very few hemangiomas continue to proliferate after age 1 year, although segmental hemangiomas have continued up to age 18 months in some cases. The subsequent involutional phase is characterized by spontaneous, steady regression, with histologic fibrosis and fat deposition spanning months to years.3 There is no reliable method of predicting which hemangiomas will involute, how long the regression will continue, or how completely a given hemangioma will resolve. Finn et al. described two distinct groups of involuters and showed that those lesions whose involution commenced earlier tended to resolve more thoroughly.35
Nearly 60% of hemangiomas occur in the head-and-neck region, with clear sites of predilection36 (Fig. 25.5). These include the scalp, medial upper eyelid and superomedial orbit, nasojugal sulcus, nasal tip, and upper and lower lips. Segmental hemangiomas tend to follow a beard distribution or superotemporal hemiface, including the upper eyelid33 (Fig. 25.6).
Focal periocular IH can cause significant functional and cosmetic deformity, with 43% to 60% of patients being affected by amblyopia.37 Visual development is commonly affected when IH of the eyelids exert pressure on cornea and sclera to cause astigmatism with subsequent amblyopia.38 The corneal astigmatism induced by hemangiomas is reversible in patients who undergo surgical resection of the hemangioma before 9 months of age. Patients who were treated after 13 months of age showed little improvement in astigmatism. Tumor growth within the eyelid can lead to ptosis with obstruction of the visual axis resulting in deprivational amblyopia.39 With orbital involvement, IH can produce rapidly evolving proptosis, exposure keratopathy, compressive optic neuropathy, displacement of the globe, and strabismic amblyopia.40,41
Hemangiomas can infiltrate soft tissue and cause significant tissue destruction. Nasal and ear cartilage, as well as eyelid tissues, can be destroyed (Fig. 25.7). The very common medial, superior eyelid hemangiomas can distort tarsus and displace levator muscle laterally. Commonly, these hemangiomas invade the superomedial orbit, passing medial to the levator muscle and superior to the medial horn (Fig. 25.8). In other cases, hemangiomas can invade levator muscle directly. In these cases, the entire width of levator can become infiltrated with fatty tissue, demonstrating loss of contractile muscle fibers. In other cases, only the medial portion of levator is affected (Fig. 25.9).
Orbital hemangiomas can distort bone as well. A large intraorbital hemangioma, left untreated, can produce orbit expansion with considerable increase in orbital volume and subsequent enophthalmos or inferior displacement of the eye within the cavernous orbit. Similarly, periorbital hemangiomas may produce hyperostosis with anterior growth of the frontal or maxillary bones (Fig. 25.10).
Soft tissue ulceration of hemangiomas is exceedingly painful, raises the risk of infection, and uniformly results in cutaneous scarring. Ulceration is seen more frequently in segmental hemangiomas. In the periocular region, the nasojugal and V2 distributions tend to be at highest risk for ulceration (Fig. 25.11).
Systemic Associations
PHACE (Posterior fossa malformations, segmental infantile Hemangioma of the head, neck, or face, and anomalies of cerebral Arteries, Cardiac, and Eye) syndrome is a neurocutaneous syndrome of unknown etiology. It may be associated with a 7q33 deletion error.42 Patients with segmental facial hemangiomas at risk for PHACE syndrome should undergo retinal and optic nerve examination, as well as echocardiography, to evaluate aortic coarctation (Fig. 25.12).
In Kasabach-Merritt syndrome (KMS), platelets become sequestered in large vascular lesions, resulting in thrombocytopenia and consumptive coagulopathy. Clotting factors can also be reduced.43 KMS has reportedly been seen in children with large infantile hemangiomas. Following recognition of IH as a unique entity, KMS is felt to be associated with Kaposiform hemangioendothelioma (KHE), a vascular lesion distinct from IH. KHE arises later in infancy and demonstrates different histologic and clinical features. Children with IH are no longer felt to be at risk for KMS.44,45
Investigations
Ancillary testing for suspected IH is limited to ultrasonographic, radiographic, and nuclear magnetic imaging, as well as surgical biopsy. There are currently no laboratory investigations in clinical use. On magnetic resonance imaging (MRI), IH are characterized by intermediate T1 and T2 signals and are vividly enhanced following contrast administration. Typically, septations are visible within the hemangiomas, and prominent vascular structures are often visible within and adjacent to the tumors, particularly the larger ones. Differentiation from venous malformations is based on uniform enhancement, presence of vascular structures associated with the lesion, and T2 signal that is usually less than that of venous malformations. The radiation exposure associated with computed tomography (CT) is avoided in this infant population whenever possible.
Pathology
Histopathologic evaluation of hemangioma tissue reveals characteristic findings in each phase of the life cycle. In the proliferative phase, lesions show well-defined, unencapsulated masses of plump, proliferating endothelial cells and attendant pericytes that focally form small, rounded lumens containing red blood cells. The organizing endothelial tubes are invested by closely associated pericytes within a periodic-acid Schiff (PAS)–positive multilaminate basement membrane, without associated smooth muscle cells. Endothelial and pericytic cells in this phase show abundant, clear cytoplasm and variably enlarged and hyperchromatic nuclei. Mitotic figures may be numerous, but apoptotic bodies with nuclear fragmentation are also present (Fig. 25.13).
Involution can be detected microscopically before the lesion begins to regress clinically. Apoptotic bodies and increased numbers of mast cells remain, whereas mitotic figures diminish. The endothelium begins to flatten, accompanied by lumen enlargement. As involution proceeds, the once-proliferating vessels decrease in number, and loose fibrous or fibroadipose tissue begins to separate vessels both within and between lobules. At the latest involutive stage, the light microscopic appearance can approximate that of encapsulated cavernous malformation of the orbit. In end-stage lesions, all that remains is a fibrofatty background with a mast cell count comparable with that of normal skin, studded by a few residual vessels similar to normal capillaries or venules and scattered larger vessels with fibrotic walls that serviced the original lesion. No endothelial or pericytic mitotic activity remains.33
Mast cell numbers increase naturally during involution and can be artificially elevated after steroid treatment. Some now believe that mast cells have a role in endothelial apoptosis observed during involution. CD8+ T cells, as well as the leukocyte-recruiting molecules ICAM-1 and VCAM-1, are also present in hemangiomas. Along with these molecules, upregulation of indoleamine 2,3 dioxygenase, an enzyme found at high levels in the placenta and thought to protect hemangioma cells initially from immune surveillance, is seen.46 (These findings suggest an immune response as one of the mechanisms for hemangioma involution.)
In studying both mitotically active and inactive endothelial cells, Tan et al. found that the endothelial cells comprising hemangiomas possess components of a basement membrane such as type IV collagen, as well as associated pericytes, fibroblasts, and aggregates of mast cells and macrophages.11 More recent studies suggest that immune and immune-mediated inflammatory events may contribute to the progression of hemangioma; allograft inflammatory factor 1 (AIF-1) is a modulator of immune response through macrophage activation that is exclusively expressed by endothelial cells of hemangiomas. AIF-1, therefore, can be used as a biomarker for IH.
Electron microscopy of IH demonstrates endothelial cells and pericytes bound by a common basement membrane. The endothelial cells are arranged in single layers and connected by tight junctions. Each group of cells exhibits a capillary-type structure except that the lumens are compressed. Each back-to-back unit of endothelial cells and pericytes is separated from another by a thin interstitial tissue, composed mainly of multilaminar basement membrane. The septal connective tissue that subdivides the tumor into lobules contains fibroblasts, thickly textured collagen, and larger-caliber arteries and veins (Fig. 25.14).
The earliest immunohistochemical marker for hemangiomas (GLUT-1) was introduced in 2000. Among immunohistochemical biomarkers, CD31 is a transmembrane glycoprotein present in endothelial cells that is considered to be the most specific marker for vascular tumors. CD34 is another hematopoietic progenitor cell antigen that is present in endothelial cells. However, it has been also detected in normal mesenchymal tissues and tumors (e.g., solitary fibrous tumors). Some lymphatic channels have shown sporadic labeling with CD34. Given its wide spectrum of positivity, CD34 should, therefore, be complemented by other markers such as CD31 for the diagnosis of vascular tumors.47 The erythrocyte glucose transporter (GLUT-1) is a reliable immunohistochemical marker for IH endothelial cells that enables the distinction of this entity from other vascular conditions at all stages of its evolution.47 This protein is found in endothelia with a barrier function such as in the brain,48 retina,49 and placenta.50 They also stain for Lewis Y antigen, merosin, and FC-γ RII, thereby establishing an immunohistochemical profile that is virtually unique among vascular conditions and shared only with placental tissues. Use of the GLUT-1 marker has improved diagnostic accuracy, especially when the solid areas of IH undergo transformation into ectatic channels during involution and yet immunoreact with GLUT-1.51
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