Capillary Hemangioma (Infantile Hemangioma)

Key Points at a Glance

1. What is capillary hemangioma (infantile hemangioma)?

Capillary hemangioma is a benign tumor (hamartoma) caused by abnormal proliferation of vascular endothelial cells and is the most common benign orbital tumor in childhood. It occurs in up to 5% of infants, with a female predominance (female-to-male ratio of 3:1). In recent years, the term “infantile hemangioma” has become more common.

30% are present from birth, and over 90% develop by 6 months of age. Proliferation typically begins around 2 weeks after birth, peaks at 1–2 months, and stops around 1 year of age. Regression then begins at 3–4 years, with 70% resolving spontaneously by school age, and about 90% disappearing by 7–9 years. Complete regression occurs in 40% by age 4 and 80% by age 8.

Histologically, it is a hamartoma due to abnormal proliferation of normal vascular endothelium, and GLUT-1 (glucose transporter 1) positivity is a specific marker for infantile hemangioma¹⁾. This is an important distinguishing point from vascular malformations (congenital lesions without proliferation).

It is classified into superficial and deep types based on morphology. Superficial lesions, also called strawberry hemangiomas, appear as bright red, well-demarcated, hemispherical elevated masses. Atypical cases may have minimal color change and slight elevation. Deep (cavernous) hemangiomas have a bluish-purple skin surface color with indistinct borders and usually do not regress spontaneously.

Q Does infantile hemangioma resolve on its own?

In many cases, it regresses spontaneously. Shrinkage begins at 3–4 years of age, and about 90% disappear naturally by 7–9 years. However, if there is a risk of amblyopia, treatment intervention is necessary without waiting for spontaneous regression. For details, refer to the “Standard Treatment” section.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Infantile hemangioma is not painful. The main symptoms are as follows.

Eyelid swelling: Tends to worsen during crying, upon waking, or with colds.
Vision loss: Due to amblyopia. In infants, it may be difficult for parents to notice.

Clinical Findings

It commonly occurs on the upper eyelid, appearing as a bright red, raised, nodular lesion. It blanches with pressure and has a spongy elasticity. No pulsation or vascular bruit is observed.

When it extends into the orbit, it causes proptosis and ocular deviation. It may also be accompanied by mechanical ptosis.

Amblyopia is the most important complication of infantile hemangioma and occurs through the following three mechanisms.

Anisometropic astigmatic amblyopia

Most common mechanism: The tumor compresses the cornea, causing astigmatism.

Anisometropia: Refractive error in only one eye can cause amblyopia.

Visual deprivation amblyopia

Occlusion of the visual axis: The tumor covers the pupillary area, blocking form vision.

Poor prognosis: Visual deprivation amblyopia leads to the most severe visual impairment.

Strabismic Amblyopia

Ocular deviation: Eye deviation caused by the tumor leads to strabismus.

Secondary amblyopia: Suppression occurs due to strabismus, leading to amblyopia.

Q Why does amblyopia develop?

The most common mechanism is that the tumor compresses the cornea, causing astigmatism and leading to anisometropic amblyopia. It may also obstruct the visual axis, causing deprivation amblyopia. Since infancy is the critical period for visual development, early intervention for amblyopia is important.

3. Causes and Risk Factors

Infantile hemangioma is a benign tumor resulting from proliferation of vascular endothelial cells, and can be strictly called a “tumor.” On the other hand, among lesions clinically referred to as “hemangiomas,” some involve proliferation of multiple cell types that form a mass, such as capillary malformations (e.g., port-wine stains) and venous malformations (e.g., cavernous hemangiomas). Since these are not proliferations of a single cell type, they are strictly classified as vascular malformations rather than tumors, and distinguishing between the two is important.

The following are known risk factors.

Low birth weight infants: Increased risk of developing the condition¹⁾
Preterm infants: Prematurity is an independent risk factor¹⁾
Female infants: More common in girls, with a male-to-female ratio of 1:3

4. Diagnosis and Examination Methods

The diagnosis of infantile hemangioma is primarily based on clinical findings. The appearance in early infancy, spontaneous regression, and GLUT-1-positive immunohistochemical features support the diagnosis ¹⁾.

Imaging Studies

Imaging studies are useful for evaluating the extent of deep lesions and for differential diagnosis.

Imaging modality	Characteristic findings
CT	High attenuation, marked enhancement with contrast
MRI	T1 isointense to slightly hyperintense, T2 hyperintense, strong contrast enhancement

On imaging, it appears as a lobulated mass with indistinct margins.

Ultrasound: Shows irregular acoustic structure and high internal echoes. It is noninvasive and suitable for initial evaluation in infants.
Pathological findings: Capillary proliferation with small lumens lined by a single layer of endothelial cells. GLUT-1 positivity is confirmed.

Differential Diagnosis

Differentiation from the following diseases is important.

Port-wine stain (Sturge-Weber syndrome): Well-demarcated red patch, not elevated. Does not show growth or regression.
Lymphangioma: Cystic lesion that does not blanch with pressure.
Metastatic neuroblastoma: Rapidly growing orbital tumor requiring systemic evaluation.

5. Standard Treatment

Infantile hemangiomas have a tendency to regress spontaneously, so observation is the basic approach unless there is a risk of amblyopia or functional impairment. Treatment intervention is indicated when there is a risk of amblyopia (visual axis obstruction, astigmatism due to corneal compression, or strabismus).

Beta-blockers (first-line)

Beta-blockers are the first-line pharmacotherapy for infantile hemangiomas.

Oral propranolol: Systemic administration. Marked regression has been reported even in a 5-year-old case. Cardiopulmonary evaluation is essential, and administration should be under pediatric supervision. Not covered by insurance; investigational stage.
Timolol ophthalmic solution 0.5%: Apply to the surface of the hemangioma twice daily. Used for superficial lesions. Not covered by insurance.

Beta-blockers

First-line: Oral propranolol or topical timolol.

Mechanism of action: Vasoconstriction, decreased bFGF and VEGF expression, induction of apoptosis.

Deep example: Systemic administration of propranolol (under pediatric management).

Steroids

Intralesional injection: Shrinkage effect within 2 weeks. Risk of central retinal artery occlusion and skin necrosis.

Systemic administration: Risk of rebound growth and growth retardation.

Status: Use has decreased since the introduction of beta-blockers.

Other

Laser photocoagulation: Adjunctive therapy for superficial lesions.

Surgical excision: Considered when conservative treatment is ineffective.

Amblyopia treatment: Refractive correction plus occlusion therapy performed concurrently.

Corticosteroids

Considered when beta-blockers cannot be used or are insufficiently effective.

Intralesional injection: Reduction is observed within 2 weeks after administration. Complications include central retinal artery occlusion and skin necrosis.
Systemic administration: Used limitedly due to risks of rebound enlargement and growth retardation.

Other treatments

Pulsed dye laser therapy: Effective for superficial hemangiomas, actively performed mainly in plastic surgery departments in Japan. Irradiation before tumor enlargement allows early regression and suppression of protrusion.
Surgical excision: Surgery is performed when a large mass persists after regression, when skin sagging, wrinkles, or scarring is prominent, or when cavernous hemangioma is present.
Amblyopia treatment: Refractive correction and occlusion therapy are performed concurrently with hemangioma treatment. Early intervention is important because delay in amblyopia treatment can lead to irreversible visual impairment.

Q What are the side effects of propranolol treatment?

The main side effects are bradycardia, bronchospasm, hypotension, and hypoglycemia. Cardiopulmonary evaluation is mandatory before administration. When PHACES syndrome is present, there is a risk of cerebrovascular stenosis, and evaluation by MRI/MRA and cardiology consultation are required.

6. Pathophysiology and Detailed Pathogenesis

Infantile hemangioma is a benign tumor classified as a hamartoma, characterized by abnormal proliferation of vascular endothelial cells. During the proliferative phase, vascular endothelial cells actively divide, leading to an increase in capillaries that form lumens. During the involution phase, fibrosis and hyalinization progress, and the vascular components are replaced by adipose tissue.

GLUT-1 is positive throughout all phases of infantile hemangioma, while it is negative in other vascular tumors and vascular malformations ¹⁾. This immunohistochemical feature is useful as a diagnostic marker.

Mechanism of Action of Propranolol

The transcription factor SOX18 has been identified as a therapeutic target of propranolol²⁾.

Overman et al. (2022) reported that propranolol inhibits the DNA-binding ability of the transcription factor SOX18, which is downstream of the Ras/MAPK pathway²⁾. SOX18 is a transcription factor that regulates angiogenesis, and its functional inhibition leads to suppression of endothelial cell proliferation.

The mechanism of action of propranolol is multifaceted, and the following effects have been reported.

Vasoconstriction: A rapid effect observed immediately after administration.
Decreased bFGF/VEGF expression: Production of growth factors is suppressed.
Induction of apoptosis: Promotes programmed cell death of vascular endothelial cells.
SOX18 inhibition: Angiogenesis is suppressed by inhibition of DNA binding ability²⁾.

7. Latest Research and Future Prospects (Research Stage Reports)

Therapeutic Strategies Targeting SOX18

The identification of the SOX18 transcription factor as a molecular target of propranolol has raised expectations for the development of more selective therapies ²⁾. SOX18 regulates angiogenesis downstream of the Ras/MAPK pathway, and specific inhibition of this pathway may lead to reduced side effects.

Associated Syndromes

The following syndromes are known to be associated with infantile hemangioma.

PHACES syndrome: A condition that combines posterior fossa anomalies, large facial hemangioma, arterial anomalies, cardiac anomalies, eye anomalies, and sternal clefting. There is a risk of cerebrovascular stenosis, and careful evaluation is necessary when using beta-blockers.
Kasabach-Merritt syndrome: A severe condition in which a giant hemangioma is complicated by thrombocytopenia and consumptive coagulopathy. It is more common in kaposiform hemangioendothelioma than in infantile hemangioma.
Maffucci syndrome: A combination of multiple enchondromas and multiple hemangiomas. There is a risk of malignant transformation.

8. References

Hammill AM, et al. Infantile hemangioma: a common lesion in a vulnerable population. Pediatr Dermatol. 2023. (PMC10139075)
Overman J, Fontaine F, Wylie-Sears J, et al. A transcription factor is the target of propranolol treatment in infantile hemangioma. JCI Insight. 2022;7(6):e151109.
Davies BW, Pierce KK, Holck DE. Capillary hemangioma treatment. Ophthalmology. 2012;119(9):1938.e1-2. PMID: 22944499.