Saudi Journal of Ophthalmology (2012) 26, 283291

Pediatric Ophthalmology Update

Infantile hemangiomas: A review

Alison B. Callahan, MD; Michael K. Yoon, MD

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

2012 Saudi Ophthalmological Society, King Saud University. All rights reserved.
http://dx.doi.org/10.1016/j.sjopt.2012.05.004

Introduction many names, including capillary hemangiomas, juvenile

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 le-
sions are not clear, insights have been gained during the pre-
ceding 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 manage-
ment of these lesions, the clinical course, pathogenesis, diag-
nosis, and management strategies are detailed.
Nomenclature
Although, these lesions have been recognized for centu-
ries, Lister was the first to formally characterize them.1 Collo-
quially referred to as strawberry nevi, these benign
vascular hamartomas of early childhood have been given
hemangiomas, hemangioblastomas, benign hemangioendot-
heliomas, and hypertrophic hemangiomas. More recently,
investigators have referred to these lesions as infantile
hemangiomas, and we have adopted this nomenclature.2 His-
torical ambiguity in naming and classification of hemangio-
mas ultimately required stricter categorization, yielding
our current definition of infantile hemangiomas as unique
vascular tumors that arise after birth during infancy, and un-
dergo a characteristic proliferative phase followed by sponta-
neous 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 45%.3 A large, multi-center prospective
study examining the demographics of IH found female gen-
der, Caucasian ethnicity, prematurity, low birth weight, multi-
ple gestations, and advanced maternal age as risk factors.4
Another potential risk factor includes chorionic villus sam-

Received 26 March 2012; received in revised form 5 May 2012; accepted 15 May 2012; available online 23 May 2012

Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

Ophthalmic Plastic Surgery, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA

Corresponding author. Address: 243 Charles Street, 10th Floor Boston, MA 02114, USA. Tel.: +1 617 573 5573; fax: +1 617 573 5525.
e-mail addresses: alison_callahan@meei.harvard.edu (A.B. Callahan), michael_yoon@meei.harvard.edu (M.K. Yoon).

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284 A.B. Callahan, M.K. Yoon

pling; however, the literature lacks robust confirmatory data

and further studies are warranted. There is a racial predilec-
tion for Caucasians (1012%) compared to blacks (1.4%)
and Taiwanese and Japanese (0.21.7%).4

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 le-
sions 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 le-
sions 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 local-
ized (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)
Clinical course without any cutaneous discoloration. (C) A large mixed superficial and
deep lesion of the scalp with features of both. (Courtesy of Timothy J.
McCulley, MD).
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: the most common complication, as well as occlusion of the vi-
(1) nascent, (2) early proliferative, (3) late proliferative, (4) pla- sual axis resulting in deprivation amblyopia (Fig. 2). Orbital
teau, (5) involution, and (6) abortive.7,911 The nascent stage lesions are less common; however, secondary to their mass
is the newborn stage prior to emergence of lesions, which effect, they may result in strabismus, proptosis, exposure ker-
typically lasts 03 months. During the next 610 months, pro- atopathy or compressive optic neuropathy.6 The presence of
liferation occurs in two stages: an early proliferative stage any of these complications requires urgent intervention.
which brings rapid growth in the first few months of life dur- Although not a functional impairment, the presence of early
ing which lesions attain most of their size, followed by a late disfigurement or the potential for this complication also war-
proliferative stage with less rapid growth. In general, 80% of rants treatment. In fact, 4080% of IH can leave permanent
IH attain their maximum size by five months. As compared to residua even after tumor involution.15
superficial or localized lesions, deep or segmental lesions ap- IH in non-ocular locations are associated with other com-
pear to have slightly prolonged proliferative phases extend- plications. Ulceration is the most frequent complication and
ing slightly beyond 6 months; however, most lesions still occurs more commonly in ano-genital, lower lip, and neck re-
cease growth by nine months of age.7 The proliferative stage gions. This may result in significant blood loss, pain, and pre-
is followed by a plateau or stabilization phase of variable disposition to secondary infection. IH within the airway can
duration. Involution is typically heralded by a change in color cause airway obstruction and are therefore most worrisome;
from bright red to gray or purple, as well as a softening tex- they are associated with concomitant IH in a beard distribu-
ture and flattening or diminution in size. Approximately half tion. Other systemic complications are associated with multi-
of IH involute by four years of age and three quarters by focal IH (more than five cutaneous lesions), visceral (e.g.,
age seven.12 liver) hemangiomas predisposing to high-output heart fail-
Although most IH have an uncomplicated clinical course, ure, and large segmental facial hemangiomas as part of the
some can cause significant morbidity, necessitating treat- PHACE syndrome (Posterior fossa malformations,
ment. Amblyopia is the most common ophthalmic complica- Hemangioma, Arterial abnormalities, Cardiac defects/aortic
tion of IH and affects 4060% of IH patients.6,13 Lesions of the coarctation and Eye abnormalities).16 These lesions may be
periocular area greater than 1 cm in greatest dimension may more resistant to typical treatments and require multidisci-
be predictive of amblyopia and a need to treat.14 In the eye- plinary consultation making referral to associated specialists
lid, induced astigmatism causing anisometropic amblyopia is essential.
Infantile hemangiomas: A review
Figure 2. A left lower eyelid hemangioma causing induced astigmatism.
(Courtesy of Timothy J. McCulley, MD).
Pathogenesis
Although the exact pathogenesis of hemangiomas is not
completely understood, histopathologic and cell surface mar-
ker 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 sporadi-
cally. Others, however, have speculated a genetic contribu-
tion as evidenced by a doubling of risk if present in a family
member,17 while the racial predilection in Caucasians com-
pared to non-whites also suggests some genetic component.
Examination of molecular markers expressed by in vivo IH
cells, cultured IH endothelial cells (HemEC), and hemangi-
oma-derived stem cells (HemSC) have shed considerable
light on possible mechanisms. Both angiogenesis (i.e., prolif-
eration or migration from preexisting vessels) and vasculo-
genesis (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 mark-
ers.18 Further study of expression patterns of cultured IH
endothelial cells (HemEC) have discovered upregulated glu-
cose transporter protein type-1 (GLUT-1), vascular endothe-
lial growth factor (VEGF), basic fibroblast growth factor
(bFGF), among others, with downregulation of other mark-
ers, such as CD146.2,17 GLUT-1 is a particularly useful cell sur-
face 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 differenti-
ated, 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 prolif-
erating phase but not in the involuting phase of IH. This find-
ing 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-jB, 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 mesen-
285
chymal support that is required by other cell populations.23
Cumulatively, this implicates HemSC in vasculogenic forma-
tion of IH.
Research investigating the cellular origin of the hemato-
poietic 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 endothe-
lium 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 heman-
gioma 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.2729 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 vascu-
lar pattern.20 Finally, as lesions involute, mitosis gradually de-
creases, and vascular tissue is replaced by fibrofatty tissue,
leading to fibrosis and eventual atrophy.27
Diagnosis
Most superficial lesions can be identified clinically. The
clinical course, bright color and blanching with pressure usu-
ally make the diagnosis obvious. Moreover, IH deepen in col-
or 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 phe-
notype, 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 com-
ponents, imaging studies should be performed to support
the diagnosis and examine the extent of involvement. Ultra-
sonography 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 struc-
tures may be limited with this modality.31 Magnetic reso-
nance imaging (MRI) demonstrates well-circumscribed
lesions that are isointense to extraocular muscles on T1 imag-
ing and hyperintensity on T2. They enhance brightly with con-
trast (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 vulner-
able 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.
286
It must be emphasized that biopsy of lesions of unclear eti-
ology, 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 tu-
mors 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. Treat-
ment is generally aggressive to limit their destructive course.
Tufted angiomas are skin or subcutaneous lesions that fea-
ture 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 re-
sult in a severe, life-threatening coagulopathy.33
Vascular malformations are distinct from tumors in that
they are formed from defects in vascular development, have
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.
A.B. Callahan, M.K. Yoon
non-proliferating endothelium, and generally persist without
regression (though they may enlarge commensurately with
growth of the patient). The most common head and neck vas-
cular 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.
Management
One of the great difficulties in management of IH lies with-
in the decision to initiate therapy. Since many IH may resolve
spontaneously and interventions carry risk, the need to inter-
vene is not always obvious. Parents and physicians alike ap-
proach the decision to intervene with anxiety and a degree
of uncertainty. As per the Guidelines of care for hemangio-
mas 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-threat-
ening complications, prevention of permanent disfigure-
ment, diminution of psychosocial stress for the patient and
family, avoidance of aggressive or detrimental interventions
in lesions that may have excellent prognosis without treat-
ment, 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 pres-
ent.6,13 The effect of disfigurement should not be underesti-
mated in the normal functional and psychological
development of children. Some lesions, particularly those
that are large and severe, cause damage to skin and sur-
rounding structures, leaving behind a fibrofatty scar which re-
mains 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 throm-
bocytopenia in a child, systemic steroids (usually 25 mg/kg/
day) have been shown to decrease IH and represent the
historical mainstay of treatment.35 In larger studies, predni-
sone was given in large doses (20 mg daily for 38 weeks),
which demonstrated an 84% response rate after two months
of therapy. Others have needed up to 6 months of therapy.
Infantile hemangiomas: A review 287

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).

Intralesional steroids

In an effort to reduce the systemic side effects of oral ste-

roids, 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 com-
plications, 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 12 ml, depending on the size
of the lesion. Response may be drastic and rapid, with
improvement in days (Fig. 5).
However, as subsequent ophthalmic literature has demon-
strated, due to direct communication between lesion and
systemic vasculature, periocular intralesional steroid injec-
Figure 5. Involution of hemangioma following intralesional steroid
tions carry with them a small but very real risk of ophthalmic injection. (A) Prior to treatment. (B) One week following injection, there
artery embolization.4042 Other local complications include is a mild decrease in the size of the lesion. (C) Four weeks later, marked
cutaneous hypopigmentation, fat atrophy, calcification, and improvement in lesion size has occurred.
full-thickness eyelid necrosis.4347 Although rare, adrenal dys-
function may occur with local steroids as well.43 These poten-
tial complications make careful patient selection and nate), 1/3 had a good response, 1/3 a partial response, and
informed consent critical. Intralesional steroids are now gen- the rest failed to respond.50 While this treatment modality
erally second line therapy for refractory lesions. avoids many more serious side effects of systemic and in-
jected steroids, it still carries with it potential side effects of
skin hypopigmentation, hypertrichosis, glaucoma, and cata-
Topical steroids ract formation when used over time, and is only effective
for superficial lesions.
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
Interferon-alpha
levels. In 2005, in a series of 34 patients using ultrapotent
Capitalizing on its anti-angiogenic properties, interferon-
steroids (clobetasol propionate 0.05% once or twice daily,
alpha was also investigated as a possible steroid-sparing
halobetasol propionate 0.05%, or betamethasone dipropio-
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 spas-
tic diplegia. Later consensus was that despite its efficacy,
interferon-alphas 1030% risk of neurotoxicity was unaccept-
ably high and the treatment was abandoned.52

Vincristine

Vincristine is an alkaloid cancer chemotherapy, which

works by inducing apoptosis through mitotic spindle microtu-
bule 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 hemato-
logic toxicity. Although effective, these side effects have
made it a third-line treatment for refractory cases.53

Laser treatments
Figure 4. Twin infants. The one on the right received oral corticosteroids
and shows growth delay compared to his twin. (Courtesy of Timothy J. One of the non-medicinal modalities of treatment em-
McCulley, MD). ployed in IH is laser. Several types of laser have been tried,
288
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 penetra-
tion 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 12 months. In their ser-
ies of 617 cases, Hohenleutner et al. found that PDL arrested
progression of 97% of IH, completely resolved 14% and par-
tially 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 pro-
tection. 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 re-
solve the IH) and may have additional risk of long-term disfig-
urement, 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 re-
moval of 12 visually significant hemangiomas, half of which
had failed prior therapy; however, two of those cases also
necessitated intraoperative blood transfusions due to hemor-
rhage.62 Patients must be selected very carefully for excision
accounting for the size, location, and surgical risk to sur-
rounding structures (Fig. 6). Surgery is generally reserved
for lesions that are refractory to less invasive treatments. Var-
ious techniques and technologies have aided in limiting and
controlling intraoperative bleeding,63 rendering surgical exci-
sion a more favorable option in appropriate clinical scenarios.
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 ser-
ies, they treated an infant with hypertrophic obstructive car-
diomyopathy with oral propranolol, after which the infants
coincident nasal tip IH was noted to regress. They subse-
quently confirmed this observation by treating an additional
ten cases of IH (seven of which had some periorbital involve-
ment) 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 success-
ful treatment of a refractory left orbital and periorbital hem-
angioma, while Fay et al. reported the successful use of
propranolol as primary therapy for a deep intraconal
A.B. Callahan, M.K. Yoon
Figure 6. Intraoperative photograph. Despite repeated injection, the
brow hemangioma continued to increase. It was excised with a subbrow
incision without complication.
IH.65,66 Haider et al. reported a series of 17 patients with per-
iocular 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 pa-
tients with periocular IH treated with oral propranolol.68 Dha-
ybi et al. echoed these findings in their case series of 18
patients with periocular IH and noted the tendency for great-
er 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 im-
proved 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, dou-
ble-blind, controlled trial to date comparing propranolol to
placebo. The study found that growth stopped in all propran-
olol 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, broncho-
spasm, congestive heart failure, hypothermia, and sleep dis-
turbance, 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 bradycar-
dia.44 Otherwise, propranolol was tolerated with only minor
side effects in the majority of patients including gastrointes-
tinal upset, reflux, and fatigue.43 Literature also points out
that while many series report 100% efficacy in at least arrest-
ing lesions, cases of failure in which IH progress despite pro-
pranolol therapy are well-known, necessitating the use of
alternate modalities of treatment.73
With the flurry of favorable reports with limited side ef-
fects, 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, fur-
ther 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 Mas-
sachusetts Eye and Ear Infirmary and Massachusetts General
Infantile hemangiomas: A review
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, hypo-
tension, bradycardia, and diabetes mellitus. Parents are in-
formed 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 dos-
ing begins at 0.5 mg/kg/day either orally or intravenously di-
vided 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 sys-
temic 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 treat-
ment 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 48 weeks
with a reduction in size ranging from 5595%.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 dai-
ly.76 The only side effect was one patient who developed
sleep disturbance requiring discontinuation of the medica-
tion. 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-block-
er injection for IH.77 In this prospective, non-randomized
study, ten consecutive patients received intralesional triam-
cinolone 40 mg/ml while the following 12 patients received
intralesional propranolol 1 mg/ml (up to 1 ml). In this uncon-
trolled study, there were similar results with approximately
40% achieving an excellent response, 4045% a fair or
good response, and 1720% that did not respond at all.
No side effects were reported. This series merits further
investigation to explore the safety and efficacy of intralesion-
al/intravascular beta-blocker therapy.
Possible mechanisms of the effect of beta-blockers include
an early (13 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 Re-
search to further elucidate this mechanism continues.
Conclusion
Recent advances in the treatment of IH have inspired a re-
newed interest in the natural course, pathogenesis and suc-
289
cessful 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 set-
ting, expert consultation is recommended. The recent discov-
ery of propranolols effect on IH has heralded a new era in IH
management that is still in its early phase. All available inter-
ventions in the physicians armamentarium should be consid-
ered 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.
Acknowledgment
The authors thank Timothy J. McCulley, MD for providing
figures for this manuscript.
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