Periocular Hemangioma: Clinicopathological Aspects

Abstract

Hemangiomas are pathologically considered to be developmental hamartomatous lesions. In the periocular region, capillary hemangioma is commonly encountered in infants and children, and it is of particular importance because of its critical location if involving the eyelid with obstruction of the visual axis. In this chapter, we aim to briefly discuss the pathogenesis and etiology of such lesions, describe the histopathological features, and the diagnostic immunohistochemical stains used, with differentiating features between infantile hemangioma and capillary hemangioma in adults. In the periocular region, the clinical appearance and manifestations depend on three primary locations of the hemangioma: the superficial, subcutaneous, and deep orbital hemangiomas. Treatment options are similar to hemangioma elsewhere, however, as mentioned above, early treatment may be advocated to avoid developing amblyopia (lazy eye) because of visual deprivation or obstruction. The most used therapy in the periocular region is beta-blockers, either orally or locally. Intralesional steroids and sclerosing agents may also be used. Surgical intervention is reserved for deep orbital-selected lesions.

1. Introduction

Periocular hemangioma is a known benign hamartoma characterized by capillary proliferation and endothelial hyperplasia [1]. Although the exact incidence of periocular hemangioma is unknown, it is one of the most common benign orbital tumors of infants and young children, affecting up to 5% of infants under the age of 1 year [1, 2, 3, 4, 5].

The majority of the time, periocular hemangioma is identified by clinical observation. It can be presented at birth with a precursor sign as telangiectatic patches with a pale halo, erythematous patches, pale patches, and bruise-like macules that rapidly proliferate with the highest growth in the first 3 months of life that slowly involute afterward [6]. Almost all periocular hemangiomas are discovered before the age of 6 months. It manifests as soft, blue lumps under the skin or as strawberry-colored masses that enlarge when the patient cries [1, 7]. Based on the extent of skin involvement, periorbital hemangiomas can be categorized as superficial, deep, or mixed [6].

Although periocular hemangiomas have a regression pattern with age, they can cause serious ocular problems most importantly, amblyopia which is known as “lazy eye.” Infantile hemangioma can cause amblyopia by different mechanisms and one of the main causes is an abnormal visual axis development in the early years of child life. Partial or complete visual axis occlusion also causes imperfection in the curvature of the eye resulting in blurred distance and near vision (astigmatism), asymmetric refractive error between the two eyes (anisometropia), and eye misalignment commonly called strabismus [3, 6, 7, 8, 9].

In this chapter, we aim to briefly discuss the pathogenesis and etiology of such lesions, describe the histopathological findings, and the diagnostic immunohistochemical stains (IHC) used, with a demonstration of the correlating clinical features. Treatment options will be also discussed briefly.

2. Periocular hemangioma etiology and pathogenesis

2.1 Risk factors and etiological theories

Understanding the pathogenesis and risk factors associated with this condition is essential for its early diagnosis and appropriate management.

Certain risk factors such as female gender, prematurity, and history of chorionic-villus sampling or pre-eclampsia during pregnancy have been shown to increase the risk of developing infantile hemangiomas [10]. Infantile hemangioma pathogenesis remains unclear; however, multiple theories have been suggested.

Etiological theories:

1. Embryonic origin: According to this theory, periocular hemangiomas are believed to originate during embryonic development. It suggests that abnormal blood vessels develop due to an error or abnormality in the formation of blood vessels during the early stages of fetal development [11]. This is further supported by the location of facial hemangiomas at areas of mesenchymal and ectodermal fusion [12, 13]. Additionally, the proliferation in hemangiomas exhibits an increased rate of mitosis. This can be induced by certain vasculogenic stem cells like hemangioma-derived stem cells (hemeSCs) [14, 15].

2. Genetic factors: Genetic factors are also thought to play a role in the pathogenesis of periocular hemangiomas. Certain genetic mutations or alterations may contribute to the development of abnormal blood vessels in the eye region. Studies have identified specific gene mutations, such as in the Glucose transporter -1 gene (GLUT-1) that may be associated with the formation of hemangiomas [14, 16]. Other theories suggest a mutation in the genes encoding growth and hormonal factors [13, 17, 18].

3. Hormonal factors: Hormonal factors, particularly estrogen, have been proposed as potential contributors to the development of periocular hemangiomas. It has been observed that these tumors occur more frequently in females than males, and they often exhibit rapid growth during periods of hormonal changes such as infancy and pregnancy. Estrogen is believed to promote the proliferation of endothelial cells, which may contribute to hemangioma formation [19, 20, 21].

4. Placental factors: Some studies suggest that periocular hemangiomas may be influenced by placental factors. It is hypothesized that certain placental trophoblasts or hormones produced by the placenta can stimulate the growth of blood vessels in the eye region, leading to the development of periocular hemangiomas [13, 19]. The placenta produces 2-methoxyestradiol which is an angiogenesis inhibitor and it is believed to be downregulated in cases of infantile hemangioma (IH) [22, 23].

5. Growth factors: Capillary proliferation is enhanced by vascular proliferative angiogenesis markers such as vascular endothelial growth factor (VEGF). VEGF-A is classically elevated in the proliferative phase of the disease and decreased in the involutional phase; thus, suggesting it has a pivotal role in the disease process. Similarly, insulin-like growth factor-2 (IGF-2) also regulates the growth and proliferation of the hemangioma. It is further hypothesized that IGF-2 production is derived by cell hypoxia from low oxygen levels [14, 24] Basic Fibroblast growth factor (bFGF) is also elevated in hemangioma cases [25].

2.2 Pathogenesis

As mentioned, the exact pathogenesis of periocular hemangioma remains unclear to date. As the disease is characterized by a proliferative phase followed by an involutional phase, studies often compare the biomarkers between these phases to better understand the disease process.

The proliferative phase shows active inflammation as it exhibits an increase in the number of T lymphocytes and pro-inflammatory cytokines [26]. Matrix metalloproteinase-9 (MMP-9) regulates the extracellular matrix components and can indirectly regulate the angiogenesis process through the release of VEGF [27].

Interferon beta levels were noted to be decreased in cases of IH in its proliferative phase, suggesting its therapeutic role in the resolution of disease [25].

In the involutional phase, mast cells exhibit an increase in number suggesting a role in the regression of the hemangiomas [28].

Hypoxia a recognized trigger for new blood vessel formation, plays a significant part in the development of hemangiomas. It stimulates the production of hypoxia-inducible factor-1 alpha (HIF-1a), which in turn triggers the activation of VEGF and Stromal-Derived Factor-1 alpha (SDF-1a), thereby encouraging the growth of endothelial cells [19, 29]. VEGF can also be influenced by certain inflammatory cytokines such as Interleukin-6 (IL-6) and Interleukin-8 (IL-8). While both IL-6 and IL-8 were significantly increased in hemangioma cells, only anti-IL-6 resulted in suppression of proliferation [30].

Therefore, comprehending the intricate relationship between the vasculogenic process, angiogenesis, and inflammatory markers sheds light on the underlying mechanisms driving the infantile hemangioma pathogenesis. This is crucial for directing future treatment options for infantile hemangioma and targeting research efforts.

3. Histopathological features and diagnosis

In the periocular region, most ophthalmologists use the term capillary hemangioma for infantile vascular lesions that develop in early infancy while lobular capillary hemangioma is known to occur as acquired lesions in adults [31]. Lobular capillary hemangioma has been described since 1897 followed in 1904 by the evolution of the so called “pyogenic granuloma,” which represents exuberant granulation tissue [32]. In that context, pyogenic granuloma has been added to the category of lobular capillary hemangioma despite the characteristic clinical and morphological features that differentiate the two entities. Histopathologically, all hemangiomas exhibit microscopic features characterized by varying-sized lobules of proliferating capillary-like blood vessels lined by plump endothelial cells with intervening variable amounts of fibrous stroma [31, 32].

Congenital hemangiomas manifest in two types: the non-involuting type and the rapidly involuting type, each displaying distinct characteristics [31, 33]. Non-involuting congenital hemangiomas present large vascular channels with features of arteriovenous malformations, whereas rapidly involuting congenital hemangiomas showcase prominent fibrosis accompanied by calcification, intralesional hemorrhage, hemosiderin deposition, and atrophic dermis or epidermis [31, 33].

Infantile hemangiomas are different in terms of natural history, presentation, histopathological characteristics, and treatment. Infantile hemangiomas exhibit microscopic variations depending on their phase [31]. The growth phase manifests large, mitotically active endothelial cells with discrete capillary lumina, while the maturation phase displays flattened endothelial cells with widened capillary lumina [31]. Involuted infantile hemangiomas demonstrate progressive fibrosis and fatty replacement. Lobular capillary hemangiomas reveal characteristic hyperplastic clusters of capillaries separated by fibrosis [31].

Immunohistochemical (IHC) staining reveals that endothelial cells in all tumors uniformly test positive for CD-34 [31]. However, when stained with GLUT-1, different types of hemangiomas exhibit varied results. Congenital hemangiomas and Lobular Adult hemangiomas test negative for GLUT-1, whereas infantile hemangiomas yield a positive staining for GLUT-1 [16, 31].

The histopathological features and the IHC staining of the capillary-like proliferation are shown below (Figures 1–3).

Figure 1.

Lower power histopathological appearance of an infantile lobular capillary hemangioma of the upper eyelid (Original magnification X50 Hematoxylin & Eosin).

Figure 2.

Higher power histopathological appearance of the proliferating capillary blood vessels (black arrows) within fibro-collagenous stroma in an infantile hemangioma (Original magnification X400 Hematoxylin & Eosin).

Figure 3.

The proliferating capillary blood vessels in an infantile hemangioma outlined using endothelial cells immunohistochemical marker, some of which are marked with red arrowheads (Original magnification X200 CD34).

4. Clinicopathological correlation

Periocular capillary hemangiomas typically manifest within the initial months of an infant’s life, with nearly half of cases apparent at birth [7]. They commonly undergo a phase of rapid proliferation within 3–6 months of onset, followed by a stabilization period and subsequent regression. This involution phase typically occurs between the ages of 2–5 years [7, 34].

Haik et al. classified periocular capillary hemangiomas into three distinct clinical presentations: the superficial strawberry nevus, the subcutaneous hemangioma, and the deep orbital tumor [4]. This classification is based on the depth of the lesion and the subsequent resultant color variations. The more superficial lesions are bright red (strawberry-like) in appearance while the deeper lesions give a more purple/blue appearance. In some cases, the lesion is very deep resulting in normal skin color making the diagnosis more difficult with the need for orbital imaging [35]. Superficial hemangiomas tend to appear and regress sooner than deeper hemangiomas [36]. Superficial lesions typically emerge a few months after birth as reddish papules or nodules that may exhibit a flat or uneven surface (Figure 4). Therefore, applying pressure to these lesions to assess blanching can aid in distinguishing them from a port-wine stain in individuals with Sturge–Weber syndrome [37].

Figure 4.

External photo of a 9-month-old girl with mixed deep and superficial periocular hemangioma inducing mechanical right medial upper eyelid ptosis. Kindly note the clear visual axis, which is not obstructed by the lesion.

Another classification of infantile hemangioma is based on their anatomic distribution ranging from focal localized lesion, segmental involving a larger embryonic territory, or multifocal extending to different anatomical areas. Focal hemangiomas are most common, with unilateral upper eyelid involvement being the most frequent location [34, 36, 37]. Segmented hemangiomas were reported in 13% of cases and they usually follow a distinct pattern on the face similar to the dermatomal distribution like frontal, maxillary, or mandibular configuration. Multifocal involvement can be seen in 3.6% and is often associated with hemangioma syndromes [36].

In cases with deep orbital hemangiomas, anterior displacement of the eye may induce proptosis and expose the cornea to potential damage, and in severe cases, optic nerve impairment may occur from external mass compression [7, 34]. Approximately 60% of patients with eyelid involvement in superficial hemangiomas develop amblyopia [34]. This occurs via two mechanisms: (1) the mass-induced deformation of the highly flexible infantile sclera and cornea leads to anisometropia from resultant astigmatism, and (2) the enlarging eyelid mass obstructs the visual axis, depriving the infant of clear vision [4].

It is important to note that periocular hemangiomas can also be a component of systemic diseases. One of the prominent hematological abnormalities associated with extensive capillary hemangiomas is Kasabach–Merrit syndrome (KMS). This syndrome is characterized by the entrapment and consumption of platelets and/or fibrinogen, resulting in coagulopathy that can lead to sudden and substantial hemorrhages [4, 7]. KMS may even be fatal when significant hemorrhage results in heart failure and secondary multiorgan failure with a mortality rate ranging from 12 to 30%. These patients may require blood transfusions in the form of fresh frozen plasma with the addition of high-dose steroids, antifibrinolytics, and antithrombotic [38]. Another significant systemic condition is PHACE syndrome. PHACE is an abbreviation that stands for:

P = posterior fossa anomalies of the brain and cerebellum.

H = Hemangioma both cutaneous and visceral.

A = Arterial anomalies affecting the arteries of brain neck or chest.

C = Cardiac anomalies from major heart defects or large vessel abnormalities.

E = Eyes including anatomical irregularities and visual disturbances.

In infants with substantial segmental facial hemangiomas, the estimated incidence of PHACE syndrome is around 20% [37, 39]. PHACES should be considered in infants with large segmental hemangiomas over the head, neck, and chest areas. A distinct feature of PHACE syndrome is the ulceration of the hemangiomas from the rapid proliferation. Certain life-threatening complications are associated with PHACE syndrome such as arterial ischemic stroke (AIS), cerebral infarction, and aortic changes like aortic coarctation and aneurysms. Infants with PHACE syndrome may suffer from significant hypothyroidism in the early years of life which may threaten their neurological development.

Extensive hemangiomas may form in the respiratory tract such as subglottic hemangiomas where special care needs to be taken to maintain the airway and prevent respiratory failure in such cases [40].

It is therefore important to diagnose any underlying systemic conditions associated with infantile hemangiomas to ensure early and adequate intervention and management.

5. Periocular hemangioma management considerations

5.1 Treatment options and indications

Periocular hemangiomas are self-limiting disorders that undergo natural spontaneous resolution with age. This phenomenon supports the general practice of observation without treatment, especially when the hemangioma is of small size and does not result in disfiguration [40].

There are certain indications that warrant the initiating of treatment in periocular hemangioma. Indications to treat include life-threatening or vision-threatening sequalae in addition to psychological distress from cosmetic disfigurement or dissatisfaction. Periocular hemangiomas may be associated with serious life-threatening complications like high cardiac output failure or bleeding disorder from consumptive coagulopathies. In such cases, treatment is considered mandatory and lifesaving. Furthermore, vision-threatening complications can lead to occlusive or refractive amblyopia, either through direct mechanical ptosis obstructing the visual axis or mechanical distortion of the cornea resulting in unilateral refractive changes. In such scenarios, treatment is also imperative. Although there is controversy on whether treatment of periocular hemangioma reverses the astigmatism or refractive error; it is often done to limit the progression of these corneal changes. Studies did document successful refractive error reduction and improvement in visual acuity after treatment of hemangiomas as well as amblyopia treatment with spectacles and occlusion [41]. Other nonfunctional causes such as major facial disfigurement is another indication for treatment as it may psychologically impact the child and family.

5.2 Medical management and expected outcomes

There are different treatment options available including local and systemic medical management as well as surgical options [16]. Observation remains the most common management plan for patients with periocular hemangioma [40].

The most recent and widely accepted medical approach to managing periocular hemangioma is the administration of systemic beta-blockers. This was first introduced in the management of hemangiomas in 2008 as an incidental finding in children receiving oral propranolol for cardiac disease. Due to its rapid efficacy in promoting hemangioma regression and the favorable safety profile associated with beta-blockers, this treatment approach has gained significant traction and is now regarded as the primary treatment of choice.

The chemical structure of propranolol has a similarity to catecholamines and, thus, competes with B-adrenergic receptors. While the precise mechanisms underlying the action of propranolol in hemangioma regression remain unclear, it is proposed that propranolol’s blockade of catecholamines leads to suppression of angiogenesis via the downregulation of key factors such as HIF-I alpha, VEGF-A, MMPs, and IL-6, potentially contributing to hemangioma regression [37, 42]. Propranolol has a membrane-stabilizing action with blockage of sodium and calcium channels in high dosages. The main effect on infantile hemangioma is believed to be through the regulation of the renin-angiotensin system (RAS) via a biological effect since angiotensin is known to promote the proliferation of capillaries [36]. Additionally, beta-blockers are known to decrease nitric oxide levels, resulting in vasoconstriction, particularly during the early stages of treatment.

Propranolol is administered 1–3 mg/kg/day in a titration regimen starting from 0.5 mg/kg/day in three doses. This requires a multidisciplinary approach as it is strongly recommended that patients undergo regular follow-ups with their general pediatrician and cardiologist to monitor for possible side effects such as bradycardia, hypotension, hypoglycemia, hyperkalemia, and other sleep disturbances. Admission and close observation during the initiation of treatment have also been strongly recommended [43, 44]. However, infants who develop adverse effects that necessitate cessation of propranolol treatment may reach only 4%, therefore, it is still considered to be safe and effective [42].

Another method for beta-blocker administration is topical application, typically reserved for superficial hemangiomas, although successful outcomes in deeper lesions have been reported [45]. Timolol maleate usually in a 0.5% solution or gel form is administered twice daily on the lesion and is continued until complete regression is achieved. Results are often visible after 4–8 weeks of treatment [37, 46]. Topical Timolol can be started in the first few months of life and can prevent hemangioma growth and prevent the future need for oral therapy from disease sequalae [47].

Propranolol cream 5% twice daily for 24 weeks showed an efficacy of up to 68.8%. Potential side effects reported include mild elevation in liver enzymes, eczema, urticaria, and infectious dermatitis [48].

Furthermore, the local form of beta-blocker treatment is Intralesional Propranolol injection. With this modality, regression is noted within the first 24 hours and continues for 3 weeks post-administration. The recommended dose is 0.2 ml up to 1 ml (1 mg/ml) depending on the lesion size [49].

Prior to the emergence of beta-blockers as a primary therapeutic approach in the management of periocular hemangioma, corticosteroids were considered the cornerstone of therapy. Corticosteroids also work by inhibiting VEGF-A production as well as suppression of MMP-1 and IL-6 thereby mitigating the vasculogenic process [50]. The recommended effective dose for systemic corticosteroid therapy is 2–3 mg/kg/day for 2 weeks. However, the use of corticosteroids in the treatment of periocular hemangiomas declined in popularity due to the undesirable side effects associated with their administration, including growth retardation, adrenal insufficiency, hypertension, hyperglycemia, weight gain, gastritis, and immune suppression [37, 51].

Intralesional steroids continue to be a viable option in managing periocular hemangiomas. The recommended dosage typically involves a 1–5 ml injection of Triamcinolone (40 mg/ml), with or without Betamethasone (4 mg/ml). It is essential to exercise caution and administer the injection slowly as this may adversely result in central retinal artery or vein occlusion. Other less serious side effects include localized fat atrophy and skin necrosis [51].

For cases where hemangiomas are unresponsive to treatment or when there are contraindications to the aforementioned modalities, Interferon alpha-2a and -2b can be considered. INFa-2a or -2b has antiangiogenic properties decreasing the proliferation of the endothelial cells within the hemangioma vasculature with a success rate of 80–100% in hemangioma reduction [52, 53]. The recommended dose is 1–3 million units/m2 of body surface. This also requires regular follow-ups with a pediatrician. The reported adverse side effects include flu-like symptoms, transient neutropenia, liver toxicity, and neurotoxicity [54]. In cases of severe vision-threatening lesions that are unresponsive, treatment with chemotherapy such as vincristine and alkylating agents like cyclophosphamide under the care of oncologists may be promising. The exact mechanism of these agents in the treatment of infantile hemangiomas is yet to be established [53].

Local injection of the sclerosing agent, bleomycin has been reported to be successful in the treatment of cutaneous hemangiomas. This agent works by creating fibrosis which is believed to induce regression of the lesion. Although there are limited studies on the efficacy and safety of bleomycin in periocular hemangioma, some reported up to 60–100% regression of these lesions [55].

Surgical options can be implored for deep localized lesions. Hemangiomas are vascular in nature and not encapsulated; making them difficult to be excised completely with a high risk of bleeding. When the choice of surgery is made, the procedure must be done under the care of specialized surgeons and should be done with care to avoid significant blood loss and maintain the anatomical integrity of adjacent structures. Such options are usually reserved for sight-threatening lesions that failed to respond to the aforementioned medical management options [40, 56].

Superficial lesions may be treated with a pulse dye laser. This modality has limited penetration when lesions are deeper than 1.2 mm but has a high safety profile and can reduce overall redness as well regression of vascular components when given every 2–4 weeks intervals. Resultant scarring and skin atrophy with hypopigmentation may be encountered [57].

Brauer et al. conducted a study comparing various laser therapies for hemangiomas. According to their findings, pulse dye laser (PDL) is preferred in their practice due to its excellent tolerance and high safety profile, even among individuals with higher Fitzpatrick skin types. Nd: YAG laser can be used for thicker and deeper hemangiomas because of its ability to penetrate deeper tissue layers, although it often leads to more scarring and pigmentation issues [58, 59]. Additionally, a combination of Nd: YAG therapy and systemic corticosteroids has been reported to achieve a high success rate with minimal risk of complications [41].

6. Conclusion

Periocular hemangioma is a prevalent benign hamartoma among infants and young children, characterized by distinct clinical features and natural course. Its pathogenesis is multifactorial, with embryonic, genetic, hormonal, and placental factors contributing to its development. Despite being generally self-limiting with a pattern of regression, periocular hemangiomas necessitate careful clinical attention due to potential complications such as amblyopia and systemic associations like Kasabach–Merritt and PHACES syndrome.

Clinically, periocular hemangiomas are categorized based on their depth and presentation, each with unique diagnostic and management challenges. The management of periocular hemangioma has evolved significantly, with systemic beta-blockers, particularly propranolol, emerging as a first-line treatment. This shift is due to their efficacy, safety profile, and ability to address both functional and cosmetic outcomes effectively.

Additionally, other treatment modalities like topical beta-blockers, corticosteroids, intralesional injections, and surgical interventions remain relevant in specific contexts. The management of these lesions necessitates a multidisciplinary approach involving pediatricians, ophthalmologists, dermatologists, and other specialists to ensure comprehensive care.

Ongoing research into their pathogenesis and treatment will continue to refine strategies, improving outcomes for affected infants and children.

Acknowledgments

This work was supported by the College of Medicine Research Center, Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia.

Conflict of interest

Authors do not have conflict of interest or any financial disclosures related to the above work or any of the listed items in this chapter.