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Infantile hemangiomas: A review

Alison B. Callahan and Michael K. Yoon⁎


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Abstract
Infantile hemangiomas (IH) are the most common eyelid and orbital tumors of childhood.
Although they are considered benign lesions that have a generally self-limited course, in the
periocular region, they have the potential to cause amblyopia, strabismus, and severe
disfigurement. The decision for treatment can be a source of anxiety for patients, parents, and
physicians alike. There are numerous treatment modalities, including emerging therapies that
may make treatment safer and more effective than ever before. This review discusses our current
understanding of this disease, its management, and future therapies.

Keywords: Infantile hemangioma, Capillary hemangioma, Propranolol treatment


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Introduction
Infantile hemangiomas (IH) are the most common tumors of the head and neck in childhood.
These hamartomas vary greatly in phenotype and, consequently, their management and potential
sequelae. Their significance is dependent on location, size, age of lesion and cosmetic
implications. Although the exact etiology and pathophysiology of these lesions are not clear,
insights have been gained during the preceding decades. Treatment strategies have been
developed through research efforts and serendipitous breakthroughs, with particular progress and
excitement in the past several years. Variability in phenotype and presentation requires an
individualized approach to treatment. For proper management of these lesions, the clinical
course, pathogenesis, diagnosis, and management strategies are detailed.

Nomenclature

Although, these lesions have been recognized for centuries, Lister was the first to formally
characterize them.1 Colloquially referred to as “strawberry nevi”, these benign vascular
hamartomas of early childhood have been given many names, including capillary hemangiomas,
juvenile hemangiomas, hemangioblastomas, benign hemangioendotheliomas, and hypertrophic
hemangiomas. More recently, investigators have referred to these lesions as infantile
hemangiomas, and we have adopted this nomenclature.2 Historical ambiguity in naming and
classification of “hemangiomas” ultimately required stricter categorization, yielding our current
definition of infantile hemangiomas as unique vascular tumors that arise after birth during
infancy, and undergo a characteristic proliferative phase followed by spontaneous involution. IH
are distinct from congenital hemangiomas, which are fully-formed at birth, and should not be
confused with the content of this review.

Epidemiology

The incidence of IH is referenced in the literature between 3% and 10%. A recent literature
review confirmed that the incidence is likely 4–5%.3 A large, multi-center prospective study
examining the demographics of IH found female gender, Caucasian ethnicity, prematurity, low
birth weight, multiple gestations, and advanced maternal age as risk factors.4 Another potential
risk factor includes chorionic villus sampling; however, the literature lacks robust confirmatory
data and further studies are warranted. There is a racial predilection for Caucasians (10–12%)
compared to blacks (1.4%) and Taiwanese and Japanese (0.2–1.7%).4

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Clinical presentation
IH can occur anywhere on the skin, but are most common in the head and neck region.5 Rarely,
periocular IH are noted at birth, and nearly all are identified by six months of age.6 Their clinical
appearance can vary greatly in location, size, depth, and rate of growth. Lesions are categorized
into three main subtypes based on depth of involvement. Superficial lesions appear as bright red
papules or nodules that may be flat or have a bumpy appearance (Fig. 1A). They will blanch with
pressure, which can help distinguish these lesions from port-wine stains (nevus flammeus),
which are generally firm, rather than soft and easily compressible like IH. Deeper lesions cause
variable changes in the skin color depending on the distance to the surface. Occasionally, they
may have a blue or purple coloration, or they may have no discoloration at all (Fig. 1B). A third
subtype contains components of both superficial and deep lesions (Fig. 1C). While lesions are
often still described by their depth, morphological classification of lesions as localized (discrete)
or segmental (involving a broad anatomic or developmental area) has been shown to be
indicative of clinical course.7 The majority of lesions are localized (72%) with segmental and
multifocal lesions comprising 18% and 3%, respectively.8

Figure 1
Examples of different types of infantile hemangioma. (A) A superficial lesion affecting the left
upper eyelid, forehead, and temple with a deep red, pebbly surface. (B) A deep lesion of the
glabella (arrow) without any cutaneous discoloration. (C) A large ...

Clinical course

IH are distinguished from other vascular malformations of early childhood by their characteristic
clinical course. Although each lesion may have a distinct growth pattern, most follow a typical
course divided into six proposed stages: (1) nascent, (2) early proliferative, (3) late proliferative,
(4) plateau, (5) involution, and (6) abortive.7,9–11 The nascent stage is the newborn stage prior
to emergence of lesions, which typically lasts 0–3 months. During the next 6–10 months,
proliferation occurs in two stages: an early proliferative stage which brings rapid growth in the
first few months of life during which lesions attain most of their size, followed by a late
proliferative stage with less rapid growth. In general, 80% of IH attain their maximum size by
five months. As compared to superficial or localized lesions, deep or segmental lesions appear to
have slightly prolonged proliferative phases extending slightly beyond 6 months; however, most
lesions still cease growth by nine months of age.7 The proliferative stage is followed by a
plateau or stabilization phase of variable duration. Involution is typically heralded by a change in
color from bright red to gray or purple, as well as a softening texture and flattening or diminution
in size. Approximately half of IH involute by four years of age and three quarters by age
seven.12

Although most IH have an uncomplicated clinical course, some can cause significant morbidity,
necessitating treatment. Amblyopia is the most common ophthalmic complication of IH and
affects 40–60% of IH patients.6,13 Lesions of the periocular area greater than 1 cm in greatest
dimension may be predictive of amblyopia and a need to treat.14 In the eyelid, induced
astigmatism causing anisometropic amblyopia is the most common complication, as well as
occlusion of the visual axis resulting in deprivation amblyopia (Fig. 2). Orbital lesions are less
common; however, secondary to their mass effect, they may result in strabismus, proptosis,
exposure keratopathy or compressive optic neuropathy.6 The presence of any of these
complications requires urgent intervention. Although not a functional impairment, the presence
of early disfigurement or the potential for this complication also warrants treatment. In fact, 40–
80% of IH can leave permanent residua even after tumor involution.15

Figure 2
A left lower eyelid hemangioma causing induced astigmatism. (Courtesy of Timothy J.
McCulley, MD).

IH in non-ocular locations are associated with other complications. Ulceration is the most
frequent complication and occurs more commonly in ano-genital, lower lip, and neck regions.
This may result in significant blood loss, pain, and predisposition to secondary infection. IH
within the airway can cause airway obstruction and are therefore most worrisome; they are
associated with concomitant IH in a beard distribution. Other systemic complications are
associated with multifocal IH (more than five cutaneous lesions), visceral (e.g., liver)
hemangiomas predisposing to high-output heart failure, and large segmental facial hemangiomas
as part of the PHACE syndrome (Posterior fossa malformations, Hemangioma, Arterial
abnormalities, Cardiac defects/aortic coarctation and Eye abnormalities).16 These lesions may be
more resistant to typical treatments and require multidisciplinary consultation making referral to
associated specialists essential.

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Pathogenesis
Although the exact pathogenesis of hemangiomas is not completely understood, histopathologic
and cell surface marker studies have improved our understanding of this entity. Genetic factors
have been investigated, with twin studies suggesting that heredity does not play a large role. This
is consistent with observations that IH usually occur sporadically. Others, however, have
speculated a genetic contribution as evidenced by a doubling of risk if present in a family
member,17 while the racial predilection in Caucasians compared to non-whites also suggests
some genetic component.

Examination of molecular markers expressed by in vivo IH cells, cultured IH endothelial cells


(HemEC), and hemangioma-derived stem cells (HemSC) have shed considerable light on
possible mechanisms. Both angiogenesis (i.e., proliferation or migration from preexisting
vessels) and vasculogenesis (i.e., de novo formation of vessels from progenitor cells) have been
implicated in the pathogenesis of IH. In vivo IH cells express endothelial cell and immature
vascular markers.18 Further study of expression patterns of cultured IH endothelial cells
(HemEC) have discovered upregulated glucose transporter protein type-1 (GLUT-1), vascular
endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), among others, with
downregulation of other markers, such as CD146.2,17 GLUT-1 is a particularly useful cell
surface marker in the diagnosis of these lesions as they are found exclusively in IH.19 This
research on HemEC expression patterns suggests a clonal proliferation of partially differentiated,
immature vascular cells, implicating angiogenesis in the formation of IH.

More recently, however, attention has turned toward angioproliferative signaling molecules such
as VEGF, a key molecule in vessel formation and likely a fundamental part of IH formation.
Increased serum VEGF-A levels have been noted in patients with proliferating IH compared to
involuting IH as well as negative controls.20 Similarly, stem cells isolated from human IH
demonstrate VEGF-A expression in the proliferating phase but not in the involuting phase of IH.
This finding was further examined in the setting of the traditional therapeutic agent of choice,
corticosteroids. In vivo mouse studies showed that dexamethasone treatment blocked secretion of
VEGF-A from IH-derived stem cells.21 Related work provides evidence for a possible
mechanism related to steroid inhibition of NF-κB, a molecule associated with both inflammation
as well as angiogenesis.22 Additionally, HemSC have been shown to be capable of forming
functional vessels with an IH-like phenotype without additional mesenchymal support that is
required by other cell populations.23 Cumulatively, this implicates HemSC in vasculogenic
formation of IH.
Research investigating the cellular origin of the hematopoietic IH stem cells points to a
population of hematopoietic stem cells called endothelial progenitor cells (EPCs). This is
supported by findings of increased EPCs in peripheral blood of IH patients, EPC-associated
markers localized to endothelium of proliferating IH, and markers associated with primitive
hematopoietic cells found in forming capillary endothelium.24 However, earlier studies
implicate a possible placental origin based on research demonstrating cross-similarities in
hemangioma endothelial cell and placental cellular markers.25,26

Ultimately, there is much still to be understood about the molecular pathogenesis of IH;
however, the recent advances described above offer new targets for future therapies, most
notably the VEGF cascade.

Histopathology

The clinical course of IH is mirrored by histopathological changes. Early proliferating IH are


composed of cellular masses of compact immature capillaries lined by plump endothelial cells
with high mitotic rates.27–29 By contrast, endothelial cells diminish in later stage lesions, which
are composed of more formed vascular structures lined by flat endothelial cells, thereby
conferring a more prominent vascular pattern.20 Finally, as lesions involute, mitosis gradually
decreases, and vascular tissue is replaced by fibrofatty tissue, leading to fibrosis and eventual
atrophy.27

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Diagnosis
Most superficial lesions can be identified clinically. The clinical course, bright color and
blanching with pressure usually make the diagnosis obvious. Moreover, IH deepen in color as
they enlarge whereas other vascular malformations generally do not change in hue. When there
are lesions that have an unusual appearance, growth pattern, or other phenotype, several
diagnostic modalities have been utilized. Some have investigated urinary bFGF and serum
VEGF as markers for IH.20,30 When lesions have deep or orbital components, imaging studies
should be performed to support the diagnosis and examine the extent of involvement.
Ultrasonography shows an increased vessel density and high-flow pattern in IH, which may be
helpful in diagnosis, although imaging of its full extent and impact on surrounding structures
may be limited with this modality.31 Magnetic resonance imaging (MRI) demonstrates well-
circumscribed lesions that are isointense to extraocular muscles on T1 imaging and
hyperintensity on T2. They enhance brightly with contrast (Fig. 3).32 Although generally more
expensive and less available than computed tomography (CT), we recommend MRI to prevent
radiation exposure to children in this vulnerable age group. If CT is necessary, the radiation
dosage should be reduced to an age and size appropriate level, and the total number of studies
should be considered. With CT imaging, IH appear well-circumscribed and enhance with
contrast. Angiography using digital subtraction, magnetic resonance, or computed tomography
may be useful in select cases.
Figure 3
Magnetic resonance imaging. T1 post-contrast fat-suppressed axial (A) and sagittal (B) images
demonstrate a well-circumscribed, brightly enhancing lesion of the left brow and upper eyelid.

It must be emphasized that biopsy of lesions of unclear etiology, unusual appearance, orbital
location, or other atypical features should be performed to rule out other entities and arrive at a
definitive diagnosis. GLUT-1 is expressed only in IH endothelium, and may confirm the
diagnosis.

Differential diagnosis

There are several vascular tumors that can share a similar appearance to IH. Congenital
hemangiomas are fully-formed at birth, which helps to distinguish them from IH. They are
categorized into rapidly involuting and non-involuting forms. Kaposiform
hemangioendotheliomas are rare vascular tumors which may be locally aggressive due to their
rapid and massive growth pattern. They are generally formed at birth as well, although may
appear shortly afterward. Treatment is generally aggressive to limit their destructive course.
Tufted angiomas are skin or subcutaneous lesions that feature slow and progressive growth and a
generally benign course. Both Kaposiform hemangioendothelioma and tufted angiomas can be
associated with Kasabach-Merritt syndrome, a platelet sequestration phenomenon that can result
in a severe, life-threatening coagulopathy.33

Vascular malformations are distinct from tumors in that they are formed from defects in vascular
development, have non-proliferating endothelium, and generally persist without regression
(though they may enlarge commensurately with growth of the patient). The most common head
and neck vascular malformation is the capillary malformation, also known as nevus flammeus or
port-wine stain. These lesions may be associated with Sturge-Weber syndrome. They have a
clinical appearance similar to IH, but do not blanch with pressure.

In cases with diagnostic uncertainty, expert consultation and/or biopsy are recommended to
distinguish IH from other lesions.

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Management
One of the great difficulties in management of IH lies within the decision to initiate therapy.
Since many IH may resolve spontaneously and interventions carry risk, the need to intervene is
not always obvious. Parents and physicians alike approach the decision to intervene with anxiety
and a degree of uncertainty. As per the “Guidelines of care for hemangiomas of infancy”
published in the Journal of the American Academy of Dermatology, major goals of management
are prevention or reversal of life-threatening or function-threatening complications, prevention of
permanent disfigurement, diminution of psychosocial stress for the patient and family, avoidance
of aggressive or detrimental interventions in lesions that may have excellent prognosis without
treatment, and prevention or treatment of ulceration to lower scarring, infection, and pain.34
Appropriate counseling and education regarding the natural history, treatment options, and
expected outcomes is mandatory for a well-informed and appropriate decision.

The medical implications of intervention depend on the size, location, age of the patient/lesion
(indicative of the stage of the IH), and potential for sequelae of each lesion. All of these factors
should be evaluated and the final decision for treatment should depend on the relative impact of
each. Most IH run a benign course and involute spontaneously. Small lesions that are not causing
abnormalities in vision or other vital function may be observed as the initial treatment of choice.
However, existing or impending sequelae can necessitate intervention, despite the self-limited
nature of the lesions. Amblyopia is a feared and common complication of periocular IH, making
intervention mandatory in cases where anisometropia, occlusion, or strabismus are present.6,13
The effect of disfigurement should not be underestimated in the normal functional and
psychological development of children. Some lesions, particularly those that are large and
severe, cause damage to skin and surrounding structures, leaving behind a fibrofatty scar which
remains even after resolution of the IH. Concern for continually enlarging, very large, or
destructive lesions generally prompt intervention.

Steroids

Discovered serendipitously in 1963 while treating a thrombocytopenia in a child, systemic


steroids (usually 2–5 mg/kg/day) have been shown to decrease IH and represent the historical
mainstay of treatment.35 In larger studies, prednisone was given in large doses (20 mg daily for
3–8 weeks), which demonstrated an 84% response rate after two months of therapy. Others have
needed up to 6 months of therapy. However, this relatively high response rate is accompanied by
a 35% rate of side effects including behavioral changes, irritability, cushingoid appearance, and
growth delay.36 In the event of growth delay, catch-up growth may occur in many cases,
although the effect may be permanent or long-lasting (Fig. 4).

Figure 4
Twin infants. The one on the right received oral corticosteroids and shows growth delay
compared to his twin. (Courtesy of Timothy J. McCulley, MD).

Intralesional steroids
In an effort to reduce the systemic side effects of oral steroids, investigators began experimenting
with locally applied steroid therapy. Kushner first reported the successful use of intralesional
steroid injections in an initial four cases.37 Other case reports followed, as well as a more robust
series of 25 patients in which Kushner confirmed his previous findings, demonstrating responses
of varying degrees, without complications, in all patients.38,39 A mixture of betamethasone
6 mg/ml and triamcinolone 40 mg/ml in a 1:1 ratio is injected intralesional, with a volume of 1–
2 ml, depending on the size of the lesion. Response may be drastic and rapid, with improvement
in days (Fig. 5).

Figure 5
Involution of hemangioma following intralesional steroid injection. (A) Prior to treatment. (B)
One week following injection, there is a mild decrease in the size of the lesion. (C) Four weeks
later, marked improvement in lesion size has occurred.

However, as subsequent ophthalmic literature has demonstrated, due to direct communication


between lesion and systemic vasculature, periocular intralesional steroid injections carry with
them a small but very real risk of ophthalmic artery embolization.40–42 Other local
complications include cutaneous hypopigmentation, fat atrophy, calcification, and full-thickness
eyelid necrosis.43–47 Although rare, adrenal dysfunction may occur with local steroids as
well.43 These potential complications make careful patient selection and informed consent
critical. Intralesional steroids are now generally second line therapy for refractory lesions.

Topical steroids

Topical steroids have also been investigated and have shown moderate effects. After initial
publication in the mid 1990s,48,49 popularity of this modality failed to achieve high levels. In
2005, in a series of 34 patients using “ultrapotent” steroids (clobetasol propionate 0.05% once or
twice daily, halobetasol propionate 0.05%, or betamethasone dipropionate), 1/3 had a good
response, 1/3 a partial response, and the rest failed to respond.50 While this treatment modality
avoids many more serious side effects of systemic and injected steroids, it still carries with it
potential side effects of skin hypopigmentation, hypertrichosis, glaucoma, and cataract formation
when used over time, and is only effective for superficial lesions.

Interferon-alpha

Capitalizing on its anti-angiogenic properties, interferon-alpha was also investigated as a


possible steroid-sparing agent. Indeed, interferon-alpha induced regression of half or more in
90% of cases in one series.51 However, serious side effects occurred with its use including
neutropenia and spastic diplegia. Later consensus was that despite its efficacy, interferon-alpha’s
10–30% risk of neurotoxicity was unacceptably high and the treatment was abandoned.52

Vincristine

Vincristine is an alkaloid cancer chemotherapy, which works by inducing apoptosis through


mitotic spindle microtubule interference, and has been used as a steroid-sparing agent for IH. It
carries many known side effects, including peripheral neuropathy, constipation, jaw pain, and
hematologic toxicity. Although effective, these side effects have made it a third-line treatment
for refractory cases.53

Laser treatments

One of the non-medicinal modalities of treatment employed in IH is laser. Several types of laser
have been tried, including argon laser, Nd-YAG laser, carbon dioxide laser, fractional
photothermolysis, and pulsed dye laser (PDL).54–57 Of these lasers, PDL is the most widely
investigated and utilized. This works via destruction of the hemangioma using light of the same
wavelength as vessels. With a laser penetration depth of approximately 1.2 mm, this modality
has been shown to have efficacy in the treatment of superficial lesions. In general, treatments are
performed with multiple passes, with up to 8 or more sessions every 1–2 months. In their series
of 617 cases, Hohenleutner et al. found that PDL arrested progression of 97% of IH, completely
resolved 14% and partially regressed another 15%.34

However, PDL also carries a risk of hyperpigmentation and atrophic scarring,35,58 although the
development of dynamic surface cooling devices has resulted in better epidermal protection.
Subsequent randomized control trials of PDL versus observation showed no significant
difference in outcome at one year.59 Longer term follow up of these patients after 5 years again
showed no difference in clearance, but did find a significant increase of scarring in the PDL
cohort.36 Although PDL may primarily halt progression (rather than resolve the IH) and may
have additional risk of long-term disfigurement, it may still prove effective for select lesions,
particularly those with ulceration.60

Surgery

Surgery continues to be a viable alternative to all of the above modalities.61 Although it yields
nearly instantaneous resolution of the lesion, it carries with it the risk of bleeding, despite the
well-circumscribed nature of IH. Walker et al. demonstrated impressive clinical results following
surgical removal of 12 visually significant hemangiomas, half of which had failed prior therapy;
however, two of those cases also necessitated intraoperative blood transfusions due to
hemorrhage.62 Patients must be selected very carefully for excision accounting for the size,
location, and surgical risk to surrounding structures (Fig. 6). Surgery is generally reserved for
lesions that are refractory to less invasive treatments. Various techniques and technologies have
aided in limiting and controlling intraoperative bleeding,63 rendering surgical excision a more
favorable option in appropriate clinical scenarios.
Figure 6
Intraoperative photograph. Despite repeated injection, the brow hemangioma continued to
increase. It was excised with a subbrow incision without complication.

Beta-blockers

A recent paradigm shift in the treatment of IH occurred following Leaute-Labreze et al.


serendipitous discovery of the efficacy of propranolol in 2008. In their landmark case series, they
treated an infant with hypertrophic obstructive cardiomyopathy with oral propranolol, after
which the infant’s coincident nasal tip IH was noted to regress. They subsequently confirmed
this observation by treating an additional ten cases of IH (seven of which had some periorbital
involvement) with oral propranolol.64 This systemic treatment showed promise for large, deep,
and difficult to access lesions.

Subsequent to this, dozens of case reports and series demonstrating positive results have
followed, including other periocular cases. Taban and Goldberg reported the successful treatment
of a refractory left orbital and periorbital hemangioma, while Fay et al. reported the successful
use of propranolol as primary therapy for a deep intraconal IH.65,66 Haider et al. reported a
series of 17 patients with periocular IH showing 100% arrest of progression, more than 50%
regression in 10 patients, and moderate regression in 6 patients.67 Missoi et al. demonstrated
even more favorable results with reduction in size (median 61%) in all of 17 patients with
periocular IH treated with oral propranolol.68 Dhaybi et al. echoed these findings in their case
series of 18 patients with periocular IH and noted the tendency for greater regression to occur
with earlier treatment.69 This series, as well as a smaller series by Fabian et al. further outlined
the clinical significance of these results by documenting improved astigmatism (by greater than
half the initial diopters) following treatment with oral propranolol.45,70 Although, not specific
to periocular lesions, there is one randomized, double-blind, controlled trial to date comparing
propranolol to placebo. The study found that growth stopped in all propranolol patients by week
4 (versus week 16 for placebo) and that there was a significant decrease in volume of the
propranolol cohort at all weeks.71

Alongside great excitement over this new and effective modality in the treatment of IH came
cautionary words as well. As warned by Siegfried et al., propranolol is not devoid of several very
serious side effects including hypotension, bradycardia, a blunted hypoglycemic response,
bronchospasm, congestive heart failure, hypothermia, and sleep disturbance, and therefore
warrants close monitoring in infants.72 In the aforementioned case series, one patient was
discontinued on therapy for symptomatic hypotension45 and one patient experienced a benign
episode of bradycardia.44 Otherwise, propranolol was tolerated with only minor side effects in
the majority of patients including gastrointestinal upset, reflux, and fatigue.43 Literature also
points out that while many series report 100% efficacy in at least arresting lesions, cases of
failure in which IH progress despite propranolol therapy are well-known, necessitating the use of
alternate modalities of treatment.73
With the flurry of favorable reports with limited side effects, oral propranolol has become a first-
line treatment for many institutions. It must be emphasized that although this modality may
prove to be the best available treatment, further confirmatory studies must be conducted, and
patients and families should be appropriately counseled. There are a number of ongoing trials
currently, and more conclusive data will be forthcoming.

There are a number of protocols that have been used for the evaluation of patients, administration
of medication, and surveillance for drug-related complications. At the Massachusetts Eye and
Ear Infirmary and Massachusetts General Hospital in Boston, Massachusetts, USA, the
combined Hemangiomas and Vascular Malformations Clinic utilizes the following protocol.
Patient history is gathered, with special attention to previous reactive airway disease, asthma,
hypotension, bradycardia, and diabetes mellitus. Parents are informed of and consented for off-
label use of propranolol. Patients are admitted with pediatric consultation for 48 h, where vital
signs and blood glucose are monitored. The dosing begins at 0.5 mg/kg/day either orally or
intravenously divided into three daily doses. This is increased to a maximum dose of
2 mg/kg/day. Patients are followed up at week one and then monthly with medication
adjustments made for changes in weight. The medication is continued for 1 year and then tapered
over 10 days.

Topical beta-blockers

As with the use of steroids, in an effort to minimize the systemic side effects of oral propranolol,
topical beta-blockers have been investigated. Guo reported the first successful case of topical
timolol 0.5% applied twice daily for the treatment of IH causing significant astigmatism.74 After
7 weeks of treatment, astigmatic error was no longer anisometropic, and there was substantial
improvement in the size, thickness, and color of the IH. Thereafter, the same group published an
additional 7 cases, all of which responded within 4–8 weeks with a reduction in size ranging
from 55–95%.75 None of these cases were associated with any side effects. A larger, multi-
center, retrospective series examined 73 patients with smaller and superficial IH anywhere on the
body treated with either 0.1% or 0.5% gel-forming timolol maleate twice daily.76 The only side
effect was one patient who developed sleep disturbance requiring discontinuation of the
medication. Overall, initial data suggests that top ical beta-blockers can be safe and effective for
superficial lesions with longer duration of treatment yielding better effects.

Intralesional beta-blockers

There has been a single report of intralesional beta-blocker injection for IH.77 In this
prospective, non-randomized study, ten consecutive patients received intralesional triamcinolone
40 mg/ml while the following 12 patients received intralesional propranolol 1 mg/ml (up to
1 ml). In this uncontrolled study, there were similar results with approximately 40% achieving an
“excellent” response, 40–45% a “fair or good” response, and 17–20% that did not respond at all.
No side effects were reported. This series merits further investigation to explore the safety and
efficacy of intralesional/intravascular beta-blocker therapy.

Possible mechanisms of the effect of beta-blockers include an early (1–3 days) vasoconstrictive
effect due to nitrous oxide (NO) release, an inhibition of proangiogenic factors (such as VEGF
and basic fibroblast growth factor) that halt growth in intermediate phases, and induced apoptosis
of proliferating endothelial cells resulting in regression in later stages.78 Research to further
elucidate this mechanism continues.

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Conclusion
Recent advances in the treatment of IH have inspired a renewed interest in the natural course,
pathogenesis and successful treatment of this common tumor of childhood. Although most
lesions have a benign and self-limited course, a significant number of lesions necessitate
treatment to avoid permanent vision loss, disfigurement, or life-threatening complications from
airway or visceral involvement. In this setting, expert consultation is recommended. The recent
discovery of propranolol’s effect on IH has heralded a new era in IH management that is still in
its early phase. All available interventions in the physician’s armamentarium should be
considered to employ the strategy most likely to alleviate suffering from these lesions. The
promise of further understanding of this tumor brings hope for even more effective and targeted
treatment.

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Acknowledgment
The authors thank Timothy J. McCulley, MD for providing figures for this manuscript.

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Footnotes
Peer review under responsibility of King Saud University.

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