Infantile Hemangioma

Subbia srinivASAN
Infantile hemangiomas (IHs) are benign tumors of endothelial cells that show
a rapid proliferating phase usually followed by variable degrees of
spontaneous regression.

Because of this unique behavior, most IHs can be left untreated, but IHs
located in areas of particular concern, such as periorbital, oropharyngeal,
preauricular, or parotid regions, may need rapid and active treatment to prevent
permanent sequelae.

Moreover, ulcerated IHs usually need to be treated.

• The mechanisms for the development of infantile hemagiomas are
not completely understood. The current theory is that endothelial
precursor cells in circulation respond to hypoxic stimuli and undergo
vasculogenesis (the formation of primitive blood vessels from
angioblasts), leading to the formation of infantile hemangiomas.

PATHOPHYSIOLOGY
• Several risk factors for the development of infantile hemangiomas
exist, including female sex, Caucasian race and preterm birth.
Increased maternal age, multiple gestation, pre-eclampsia, placenta
previa, maternal history of infertility, chorionic villus sampling,
assisted reproductive technologies and ovulation promotion

RISK FACTORS
• In 2008 a child with obstructive hypertrophic cardiomyopathy was

treated with 3mg/kg/dose of propranolol. the child had an associated

hemangioma which coincidently improved.

DISCOVERY OF PROPRANOLOL
• Hemangiomas are composed of a number of cell types including

endothelial cells. the capillary endothelial cells express beta 2

adrenergic receptors.propranolol exerts its effects on growing

hemangiomas by 3 different mechanisms - vasoconstriction, inibition

of angiogenesis and induction of apoptosis.

MECHANISM OF ACTION OF
PROPRANOLOL
Infantile haemangiomas are classified as superficial, deep or mixed

lesions. They may be localised (confined to a small area) or segmental

(involving a larger neuroectodermal unit).

• The superficial infantile haemangiomas is also called capillary

haemangioma, capillary naevus, strawberry haemangioma,

strawberry naevus, and haemangioma simplex. The blood vessels in

uppermost layers of the skin are dilated.

CLASSIFICATION OF HEMANGIOMAS
• Deep infantile haemangiomas are also called cavernous

haemangiomas and are more deeply set in the dermis and subcutis.

They appear as a bluish soft to firm swelling.

• Both types of haemangiomas may occur together in mixed

angiomatous naevi. A strawberry naevus overlies a bluish swelling.

• Segmental haemangiomas are more serious than localised
haemangiomas.

• They occur at a younger age and grow up to ten times larger

• They are consequently more unsightly

• Other congenital anomalies may be associated with facial segmental

haemangiomas (PHACE syndrome). These include posterior fossa
abnormalities, haemangiomas, arterial abnormalities, cardiac
abnormalities, and eye abnormalities.

SEGMENTAL HEMANGIOMAS
• Likewise, segmental infantile haemangiomas involving the perineum

may be associated with pelvic congenital anomolies, the PELVIS

syndrome (perineal hemangioma with any of the following: external

genital malformations, lipomyelomeningocele, vesicorenal

abnormalities, imperforate anus, or skin tag)

Hemangiomas go through three stages of development and decay:

• In the proliferation stage, a hemangioma grows very quickly. This

stage can last up to twelve months.

• In the rest stage, there is very little change in a hemangioma's

appearance. This usually lasts until the infant is one to two years old.

• In the involution phase, a hemangioma finally begins to diminish in

size. 50% of lesions will have disappeared by 5 years of age, and the
vast majority will have gone by 10

Stages of development
• This is the most frequent complication and typically occurs in deep,

rapidly enlarging hemangiomas or in those located in trauma- or

pressure-prone areas of the body. These can be excruciatingly painful

and carry the risk of infection, hemorrhage and scarring.

• When hemorrhage occurs, blood loss usually is minimal and can be

controlled with direct pressure.

Complications - ulceration
• Hemangiomas of the anogenital region are particularly at risk for

ulceration and infection and are accompanied by severe pain upon

urination or defecation. Superinfection may lead to cellulitis,

osteomyelitis, septicemia and, in some cases, has been lethal.

Complications - ulceration
• Periorbital hemangiomas pose considerable risk to vision and should be
carefully monitored with early involvement by an ophthalmologist to
prevent permanent damage including blindness, Astigmatism, caused by
insidious compression on the cornea by the growing hemangioma or
extension of the tumor into the retrobulbar space, is the most common
complication.

• Stimulus-deprivation amblyopia may result from physical obstruction of

the visual axis by the hemangioma.

Complications – functional
impairment
• Periocular hemangiomas can be subtle without cutaneous

manifestations and may extend deep into the orbit causing

exophthalmos or globe displacement.

• Hemangiomas involving the ear may obstruct the external auditory

canal, resulting in otitis externa or a temporary conductive hearing

loss, which ultimately may cause speech delay.

Complications – functional
impairment
• Large nuchal hemangiomas may impair neck range of motion, albeit

temporarily. Airway hemangiomas can be life-threatening and do not

always occur in the setting of cutaneous findings.

Complications – functional
impairment
• Hemangiomas of the beard distribution (preauricular region, chin,
lower lip, mandibular region and anterior neck) pose the greatest risk.

• Subglottic hemangiomas can cause hoarseness and stridor (noisy

breathing) with progression to respiratory failure, often occurring at 6
to 12 weeks of age. In these cases, direct endoscopic visualization of
the airway is warranted.

Complications – functional
impairment
• The location, rate of growth and depth within the skin of the
hemangioma, the age of the patient and presence of complications
govern the likelihood that hemangiomas will cause permanent
damage.

• Hemangiomas with prominent dermal components, particularly those

involving the lips, nose, ears and forehead, and those with deep
ulceration, are at greatest risk for scarring

Complications – permanent
disfigurement
• In these locations large or rapidly growing lesions will leave residual
fibrofatty tissue, even after the hemangioma has involuted. In some
instances the fibrofatty tissue is relatively easy to surgically remove
(nasal tip), whereas in others the surgical scar may be quite
conspicuous (upper lip).

Complications – permanent
disfigurement
• Treatment of infantile hemangiomas is designed to control growth,
minimize deformity, preserve function and limit the amount of
psychological and emotional stress on the patient and parents.

• Systemic pharmacotherapy is used to treat large lesions, lesions that

present a surgical challenge or those causing functional or life-threatening
problems.

• Incase of an ulcerating hemangioma, systemic pharmacotherapy can help

limit the extent of spread of ulcer and can aid in early healing thereby
reducing morbidity.

treatment
• Since the initial report of propranolol use for treatment of infantile
hemangiomas in 2008, there has been a flurry of publications
describing its efficacy and potential side effects

• Based on case reports and case series in the literature, oral

propranolol appears to have a favorable safety profile in children akin
to the well-established profile in adults.

• The most common serious adverse effects of oral propranolol include

bradycardia and hypotension. Bronchospasm can be seen in patients
with reactive airway disease or during an acute respiratory illness

Safety profile
• Hypoglycemia has emerged as the most common serious adverse

event for use of propranolol for infantile hemangioma.

• Hypoglycemia is a recognized adverse effect of propranolol therapy

that usually is related to poor oral intake, such as might occur with an

intercurrent illness or prior to general anesthesia.

Drug adverse effect -

hypoglycemia
• Mild hypoglycemia produces symptoms associated with counter-

regulatory epinephrine action, including sweating, shakiness,

tachycardia, anxiety and hunger. With propranolol-induced Beta-

adrenergic blockade, early symptoms may be masked; as sweating is

not typically blocked by Beta-blockers, this may be the more reliable

symptom for diagnosis.

Drug adverse effect -

hypoglycemia
• More severe hypoglycemia produces symptoms of neuroglycopenia,
including lethargy, stupor, poor feeding, seizures, apnea, loss of
consciousness and hypothermia.

• Symptomatic hypoglycemia and hypoglycemic seizures have been

reported in infants with hemangiomas treated with oral propranolol.

• These cases occurred in both newborns and toddlers, but often were
associated with poor oral intake or concomitant infection.

Drug adverse effect -

hypoglycemia
• Most of the reported patients who developed hypoglycemia were

prescribed relatively low doses (1.25-2 mg/kg/day), suggesting that

hypoglycemia associated with propranolol may not be dose dependent.

• Other milder adverse effects include gastrointestinal symptoms, sleep

disturbances and mood changes with depression in older treated

patients.

Drug adverse effect - others

• In a study conducted by Price CJ et al, regarding the efficacy of

propranolol when compared against the traditional corticosteroids,

included 110 patients with IHs.

literature
• The mean duration of treatment was 7.9 months for propranolol and
5.2 months for oral corticosteroids. Fifty-six of 68 patients (82%) who
were receiving propranolol achieved clearance of 75% or more
compared with 12 of 42 patients (29%) who were receiving oral
corticosteroids (P < .01).

• Adverse effects were minimal in the propranolol group: 1 patient had

hypoglycemia and 2 patients had a nonspecific skin eruption that was
not associated with propranolol therapy.

literature
• All 42 patients in the corticosteroid group had 1 or more adverse
effects (P < .01). Relapse after discontinuation of propranolol therapy
occurred in 2 of the 68 patients; however, both patients responded to
propranolol therapy on reinitiation of treatment.

• Surgical referrals after treatment were required in 8 patients (12%) in

the propranolol group and 12 patients (29%) in the oral corticosteroid
group (P < .01).

literature
• Every patient in the corticosteroids group (42 participants) suffered at
least one adverse event. IH relapse in patients receiving propranolol
occurred in 2 of 68 patients, although both patients responded to
propranolol therapy on reinitiation of treatment.

• At the conclusion of treatment, surgical referrals were needed for

12% of patients in the propranolol group and 29% of patients in the
oral corticosteroids group.

literature
• Propranolol therapy was more clinically effective and more cost-
effective than oral corticosteroids in treating IHs.

• It also resulted in fewer surgical interventions and demonstrated better

tolerance, with minimal adverse effects, compared with oral
corticosteroids.

• Therefore, propranolol should be considered a first-line agent given its

safety and efficacy in the treatment of IHs.

literature
• In an additional finding, the cost effectiveness of propranolol
treatment was better than that of corticosteroids. The overall average
per-patient treatment costs were $205.32 and $416.00 in the
propranolol and oral prednisolone groups, respectively, a more than
50% reduction in cost.

literature
• Propranolol therapy was more clinically effective and more cost-
effective than oral corticosteroids in treating IHs.

• It also resulted in fewer surgical interventions and demonstrated

better tolerance, with minimal adverse effects, compared with oral
corticosteroids.

• Therefore, propranolol should be considered a first-line agent given

its safety and efficacy in the treatment of IHs.

Literature - conclusion
• In conclusion propranolol therapy has been determined to be the safer
and cost effective alternative to the traditional corticosteroid therapy
by multiple randomized trails.

conclusion
• Georgountzou, A., Karavitakis, E., Klimentopoulou, A., Xaidara, A. and Kakourou, T.
(2012), Propranolol treatment for severe infantile hemangiomas: a single-centre 3-year
experience. Acta Paediatrica. doi: 10.1111/j.1651-2227.2012.02783.x

• Zvulunov, A., McCuaig, C., Frieden, I. J., Mancini, A. J., Puttgen, K. B., Dohil, M., Fischer,
G., Powell, J., Cohen, B. and Amitai, D. B. (2011), Oral Propranolol Therapy for Infantile
Hemangiomas Beyond the Proliferation Phase: A Multicenter Retrospective Study. Pediatric
Dermatology, 28: 94–98. doi: 10.1111/j.1525-1470.2010.01379.x

• I. Betlloch-Mas, M.T. Martínez-Miravete, A. Lucas-Costa, A.I. Martin de Lara, J. Selva-

Otalaurruchi, Tratamiento de hemangiomas infantiles con propranolol en régimen de control
ambulatorio. Estudio prospectivo, Actas Dermo-Sifiliográficas, 2012,

• Christine J. Schupp, Johann-Baptist Kleber, Patrick Günther, Stefan Holland-

Cunz, Propranolol Therapy in 55 Infants with Infantile Hemangioma: Dosage, Duration,
Adverse Effects, and Outcome, Pediatric Dermatology, 2011, 28, 6

references
• Price CJ, Lattouf C, Baum B, et al. Propranolol vs corticosteroids for
infantile hemangiomas: a multicenter retrospective analysis. Arch Dermatol.
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• Chamlin SL, Haggstrom AN, Drolet BA, et al. Multicenter prospective study
of ulcerated hemangiomas. J Pediatr. 2007;151(6):684–689.
• Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo
JB, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med.
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• Sans V, de la Roque ED, Berge J, et al. Propranolol for severe infantile
hemangiomas: follow-up report. Pediatrics. 2009;124(3):e423–e431. Epub
Aug 2009.
• Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic hemangiomas
of the airway in association with cutaneous hemangiomas in a “beard”
distribution. J Pediatr. 1997;131(4):643–646.

references