INFANTILE HEMANGIOMAS

MODERATOR : PROF.S.HANDA

COMMENTS BY : DR.RISHU

Presenter: Dr.Ariganesh

INTRODUCTION
Infantile hemangiomas (Hemangiomas of infancy)are common benign tumors of endothelial cells characterized by a unique pattern of rapid proliferation that occurs in the first months of life, followed by slow involution that may take years to complete. The term hemangioma has been applied indiscriminately to a variety of vascular anomalies with diverse biologic and pathologic features.

Clinical observations and pathologic studies, however, have clearly distinguished IHs from other vascular tumors and vascular malformations. A classification system first proposed by Mulliken and Glowacki was revised in 1996 by International Society for the Study of Vascular Anomalies based on clinical, radiologic,and hemodynamic characteristics,into vascular malformations and vascular tumours .

International Society for the Study of Vascular Anomalies Classification of Vascular Anomalies
Vascular tumours
Infantile haemangioma Hepatic haemangioma Neonatal haemangiomatosis Congenital haemangiomas -Rapidly involuting congenital haemangioma (RICH) -Non-involuting congenital haemangioma (NICH) Tufted angioma Kaposiform haemangioendothelioma Haemangiopericytoma Angiokeratoma arterial/lymphatic Syndromes with vascular tumours BannayanRileyRuvalcalba syndrome

Vascular malformations
High flow Arteriovenous + associated syndromes Low flow Capillary + associated syndromes Venous malformations + associated syndromes Lymphatic malformations + associated syndromes Mixed/combined : capillary/venous/

Vascular malformations Result from errors of vascular morphogenesis, present since birth M:F = 1:1

Hemangiomas Benign neoplasms, result from proliferation of endothelial cells, usually appear after birth F>M [3:1],premature infant <1500gm ,infant who had chorionic villous sampling 1st proliferate f/b involution Bright red colour deepens during 1st year Firm/rubbery consistency PHACES syndrome, spinal dysraphism.

Enlarge proportional to child s growth, non-involuting nonHave a persistent colour hue On palpation soft & easily compressible Frequent association with malformation syndromes eg, SturgeSturgeWeber, phakomatosis pigmentovascularis, Klippel Trenaunay syndrome etc.

Epidemiology Among the Caucasian population, IHs are present in 1.12.6% of neonates and in 1012% of infants by 12 months of age. The frequency is increased in preterm infants. The female to male ratio is variable from 1.4:1 to 4:1. A 21% incidence of IHs has been reported in infants who were subject to chorionic villus sampling. IHs are less common in those of African American or Asian descent.

PATHOGENESIS Placenta Theory There is considerable evidence to suggest that placenta is closely related to infantile hemangioma. One observation supporting this theory is that hemangiomas are more prevalent in infants whose mothers underwent chorionic villus sampling, a procedure that is believed to cause embolization of trophoblasts resulting from disruption of the placenta.

The natural progression of hemangiomas also parallels that of placenta that develops after conception, proliferates in early gestation, and stabilizes thereafter. During placental development, angiogenesis occurs at an extraordinary rate and is controlled by inhibitory factors that prevent inappropriate blood vessel growth. The placenta produces a soluble form of the VEGF transmembrane receptor, sFlt-1which inhibits angiogenesis by sequestering circulating VEGF and placental growth factor.

After birth the source of sFLt-1 is removed, allowing unopposed proliferation of endothelial cells. This mirrors the natural progression of IHs and also coincides chronologically with the appearance of IHs in the postnatal period. IHs have been found to express GLUT-1, a glucose transporter protein, which is a marker expressed in placental and barrier endothelial tissues. Placenta and IH tissue also share a number of other markers including Fc RII, Lewis Y antigen (LeY) and merosin.

This finding of a distinct constellation of tissuespecific markers that is uniquely coexpressed by hemangiomas and placental microvessels led to the hypothesis that placental tissue shears off during gestation and embolizes to fetal cutaneous vessels. Genes preferentially expressed in both placenta and hemangiomas have been identified, including 17- OH steroid dehydrogenase 2 and tissue factor pathway inhibitor 2.

There are some unanswered questions with this theory. First, there was no maternal-fetal chimerism if embolization of placental tissue to the fetus had occurred. It has been demonstrated that hemangioma endothelial cells matched the genotype of the child and not the maternal genotype. That would suggest that infantile hemangiomas are neither of maternal origin nor do they arise from fetal trophoblasts within the placenta.

In a fluorescence in situ hybridization-based study, no maternal XX cells were found in male XY tissues derived from IH specimens from boys. So it can be postulated that fetal placental cell could derive from either placental angioblasts or abnormal placental progenitor cells, and would circulate back to the embryo, potentially homing to receptive tissues, such as skin and liver.

Progenitor Cell Theory The link between hemangiomas and placenta might also be explained by a common origin. There is suggestion that hemangiomas result from a mutation in a primitive or precursor stem cell, which tilts further development of these cells towards placental characteristics. Cultured endothelial cells from intact hemangioma tissue show evidence of clonality, which suggests that IH may arise from clonal expansion of a single endothelial cell carrying a somatic mutation.

Endothelial progenitor cells (EPCs) co-expressing CD133 and CD34 have been detected both in proliferating infantile hemangioma tissues and grown in vitro. This finding suggests that EPCs play a crucial role in the development of hemangiomas. Cultured blood endothelial progenitor cells isolated from control and hemangioma patients express placental specific markers such as GLUT-1, Fc RII and merosin.

This suggests that endothelial progenitor cells may contribute to the rapid postnatal growth of hemangiomas. The coexpression of LYVE-1 and CD34 on hemangioma endothelial cells suggests that these cells have an immunophenotype similar to embryonic vein during normal vascular development. Recently, CD133 positive multipotential stem cells have been isolated from human IH tissue that give rise to hemangioma-like lesions in immunodeficient mice.

A very recent study revealed the presence of SALL4 positive stem cells in infantile hemangiomas. SALL4 is a stem cell gene that is also highly expressed in embryonal carcinomas.
(Sem in ophthal 2010)

Extrinsic Factor Theory The micro and macro environment may play an important role in the pathogenesis of hemangioma . The environment or an extrinsic factor may have a role in the timing of deposition of hemangioma precursor cells, with earlier events resulting in segmental hemangiomas and later events resulting in focal hemangiomas near lines of mesenchymal fusion.

 A hypoxic environment has been postulated to contribute to the pathogenesis of IHs. Local ischemia may create hypoxic conditions leading to an upregulation of hypoxia inducible factor 1 (HIF-1 ) responsive chemokines such as stromal cell derived factor-1 (SDF-1 ), and VEGF. Both chemokines are known to promote the recruitment and proliferation of endothelial progenitor cells.

Increased stabilization of HIF-1 , in concert with increased levels of estrogen, creates a milieu that promotes new blood vessel development. Another explanation regarding the pathogenesis of IH might be found within a somatic mutation of a gene regulating vascular control. Candidate genes involving blood vessel like FGF receptor-4, PDGF receptor, fms related tyrosine kinase-4, VEGF receptor, IGF-2 have been found to be involved, which lead to dysregulation of angiogenesis.

PATHOLOGY During the early phase of growth, haemangiomas have solid groups of endothelial cells with few lumina and nonpleomorphic nuclei. The endothelial cells then flatten out as lumina develop and start to bulge outward. The cells are surrounded by a thickened basement membrane. As involution proceeds, the haemangioma has a more obvious lobular appearance, with islands of fibrous and fatty tissue separating these lobules.

Mast cells are also seen at all phases of haemangiomas Immunohistochemical studies of IH show positive staining of markers for factor VIII, CD31 and VwF.. In the growth phase, cells express proliferating cell nuclear antigen, VEGF and the integrin Eselectin.

CLINICAL FEATURES In most cases, the diagnosis of IH is established on the basis of a well-recognized natural history associated with typical clinical patterns. Haemangiomas usually appear within the first month of life although they may present as a precursor lesion in the immediate perinatal period. This can be very subtle, with a faint telangiectatic patch or a patch of naevus anemicus-like pallor.

Soon after this, the precursor lesion begins to become palpable, often in a cluster giving rise to the strawberry appearance. The overall clinical appearance is dependent on how deep into the skin they extend. IH may be classified into superficial, deep or mixed according to the depth of the lesion or they may be multifocal.

And each type is sub-classified according to the size, the anatomical localization or the morphological subtype into localized, segmental, indeterminate. Superficial IH (50 to 60%) are often described as a strawberry haemangioma that presents as a bright red tumour with an irregular hummocky surface, edged in relief surrounding a normal tegument.

 Subcutaneous IH (approximately 15%) corresponds to a swelling protruding, rounded and warm, under normal or bluish skin. Mixed IH (25 to 35%) is a combination of a primary superficial component associated with a later deep subcutaneous extension. In a prospective study conducted at the US paediatric dermatology clinics, the majority of IH where localized forms (67%) whereas indeterminate (16.5%), segmental (13%) and multifocal (3.6%) forms were less frequent.

SITES Although IH may occur on any part of the body, they demonstrate a striking predilection for the head and neck region. In a large series, 60% of IH occurred on the head and neck, followed by 25% on the trunk, and 15% on extremities. Furthermore, facial IH seem to be nonrandomly distributed and occur in 2 morphologic forms.

The majority are focal tumor like lesions that tend to occur near lines of embryonic fusion. Less commonly, they involve a region of skin corresponding to a derivation from the embryologic mesenchymal prominences and tend to be more plaque like in character. These so-called segmental IH are more likely to be associated with complications, structural anomalies, or extracutaneous IH.

LIFE CYCLE IH usually appears within the days or weeks following birth. This delay between birth and the appearance of the vascular tumour is a good diagnostic tool for defining the diagnosis of IH, especially in subcutaneous forms. The growth phase is usually achieved during the first 3 months but may extend until the 6th to 8th month for the surface forms, and until the 9th to 12th month for the IH with subcutaneous component .

During this growth phase, 80% of IH will double their original size, 5% triple and less than 5% will dramatically extend until involving functional, vital or aesthetic prognosis. Following this growth phase, most IH stabilize spontaneously, then regress over several months or years. The involution is slow and gradual with a primary development of central whitening on superficial component followed by a collapse of the subcutaneous component.

However, in some cases, these two phases may overlap ,while the subcutaneous component still continues to grow. The regression is complete in 60% of cases at the age of 4 and 76% at the age of 7. Some IH may live a postregression fibrofatty residual tissue and altered skin. The evolutionary curve of subcutaneous lesions is delayed and the regression is slower and more incomplete.

ASSOCIATIONS AND COMPLICATIONS

COMPLICATIONS Ulceration Heart failure Visual impairment Airway obstruction Auditory canal obstruction Kasabach Merritt syndrome Disfigurement Interference with feeding Congestive heart failure Deformation of bone Infection

ASSOCIATED SYNDROMES Haemangiomatosis PHACES syndrome SACRAL syndrome and PELVIS syndrome

LIFE THREATENING COMPLICATIONS Respiratory distress can be a complication of IH of the upper airways, especially in subglottic IH. An airway IH is present in 1 3 of neonates with an IH of the beard area. Heart failure may complicate extensive IH, especially hepatic haemangiomatosis. Hepatic haemangiomatosis is usually associated with multifocal IH, particularly in the presence of more than five IH on the skin. In rare cases, abundant bleeding is noted, especially in case of digestive IH.

Local complications: ULCERATION Ulceration is the most common complication of IH. Ulceration often occurs 2 to 3 months following birth but may sometimes be found as early as the neonatal period. Pathogenesis of ulceration is not known, but possible contributory factors include friction, local bacterial colonization or tissue hypoxia due to rapid expansion. Ulceration occurs in up to 813% of IHs. Ulceration is more commonly seen in centro-facial region and perineum regions.

Particular clinical forms of IH such as telangiectatic IH of the head and genitals, neonatal rapidly growing IH with red and shiny appearance, segmental facial IH are more often complicated with ulceration. Iatrogenic causes include imiquimod application and pulsed dye laser. Usually, the first clinical signs include blackish spots of the surface of red zones. Ulceration can be very painful and it can be complicated by secondary infection and bleeding, which if not valued may cause anaemia. Finally disfiguring scarring usually follows wounding.

AESTHETIC RISK Extensive telangiectatic IH, especially on exposed areas (face, hand and forearm) and perineal area, with severe Necrosis. Other sites such as the nose (referred to as the Cyrano nose) and the lower cheeks are known not to fare well in the long term. Plastic reconstruction may be challenging in centro-facial IH

Infantile haemangiomas with large subcutaneous component responsible for anatomical deformities. In all these cases, IH may be responsible for psychological impact in both parents and further in children when they grew up.

SYNDROMES IN ASSOCIATION WITH IHS HAEMANGIOMATOSIS Haemangiomatosis is a condition characterized by multiple IHs. They appear bright red and range from a few to hundreds. Benign and disseminated neonatal haemangiomatosis are two distinct categories of disease. Benign haemangiomatosis is asymptomatic or has no visceral involvement. It has a relatively good prognosis with complete regression often occurring by 3 years of age.

In disseminated haemangiomatosis, visceral involvement may lead to life-threatening complications such as high output congestive heart failure, haemorrhage from haemangiomas of the gastrointestinal or respiratory tract, consumptive coagulopathy or obstructive hydrocephalus. The liver is the most commonly involved organ, but any other viscera can be affected. Patients with disseminated haemangiomatosis need appropriate imaging studies and close followup. Untreated mortality rates may be as high as 77%.

PHACES syndrome The acronym PHACE (S) has been established in 1996 by Frieden et al and includes the following anomalies: Posterior fossa abnormalities Facial haemangioma (segmental IH) Arterial abnormalities intra- and extra-cranial Cardiac and aortic defects Eye anomalies Sternal agenesia or supra-umbilical raphe.

The true frequency of the PHACES syndrome is unknown. In a prospective multicenter study conducted in the U.S. in 1096 children with IH, 20% of the 200 segmental facial IH were associated with PHACES syndrome and 88% of these cases were girls. In practice, every newborn with a segmental facial IH, particularly when location S1, S4 or S3 is noted, should undergo additional exploration including cerebral MRI, echocardiography of the major cervical and thoracic vessels, ophthalmological examination and abdominal USG.

SACRAL syndrome The acronym SACRAL syndrome stands for IHs of lumbosacral localization in association with spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal and urological anomalies. PELVIS syndrome The characteristic findings of the PELVIS syndrome are perineal haemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus and skin tags.

All neonates with a spreading IH of the perineal area, even if neurologically asymptomatic, should undergo an evaluation by medullar and pelvic MRI.

DIFFERENTIAL DIAGNOSIS
Other vascular anomalies and tumors Capillary malformation Venous malformation Lobular capillary hemangioma (pyogenic granuloma) Spindle cell hemangioendothelioma Kaposiform hemangioendothelioma

Lymphatic malformation Arteriovenous malformation NICH RICH Tufted angioma

Fibrosarcoma Rhabdomyosarcoma Myofibromatosis (including hemangiopericytoma) Nasal glioma Encephalocele Lipoblastoma Dermatofibrosarcoma protuberans (and giant-cell fibroblastoma) Neurofibroma

INVESTIGATIONS IMAGING Doppler ultrasound and magnetic resonance imaging (MRI) are the two most efficient modalities for imaging hemangiomas. The choice of which modality to use depends on the clinical situation and the availability and expertise at each institution. Ultrasonography is useful for distinguishing a deep hemangioma from other entities, because it shows high flow vessels.

Ultrasonography, however, is highly operatordependent and may not be able to predict the extent of the lesion and presence of other anomalies. Magnetic resonance imaging is the study of choice when documentation of the extent of disease or associated anomalies is needed.

The following are the recommendations for imaging in IHs (Ped J Der 2005) 1 ) Large hemangiomas of the head and neck should be studied with MRI of the affected area, adjacent soft tissues, and the brain when they become problematic or require pharmacologic therapy. These hemangiomas should be imaged because of the risk of intracranial and airway involvement and associated cerebral and cerebrovascular anomalies.

2 )Cutaneous hemangiomas over the spine should be studied with ultrasound, then MRI with gadolinium (if abnormalities are present on ultrasound) as soon as they are recognized. 3) Multiple (> 4) cutaneous hemangiomas should be screened with ultrasonography of the liver and brain when the skin lesions are enlarging or increasing in number.

In cases of extensive, high flow, or enlarging lesions, MRI with and without gadolinium should be obtained. 4 ) Extensive perineal hemangiomas in the presence of urogenital or anal anomalies should be imaged with an MRI of the pelvis and spine because of the association with structural ano-genitourinary anomalies.

5) Atypical presentations: Any presumed hemangioma in the presence of severe thrombocytopenia should be imaged with MRI with gadolinium because it is likely a Kaposiform hemangioendothelioma (KHE). A suspected hemangioma that presents after 6 months of age should be investigated with biopsy or excision because it may be a KHE, vascular tumor, or rhabdomyosarcoma.

6) Imaging is not necessary for cutaneous hemangiomas with typical clinical appearance and behavior that do not require therapy. OTHER INVESTIGATIONS Platelet count: KMP occurs more in tufted angiomas and KHE than IH. So it is not routinely required. Thyroid function tests: large hepatic hemangiomas may lead to hypothyroidism.

IH are GLUT1 positive (as well as merosin, Fcg receptor II and Lewis Y antigen positive), Other benign vascular lesions are GLUT1 negative Immunohistochemical detection of WT1 could be a useful tool to routine evaluation of vascular anomalies allowing the distinction of vascular tumors and proliferations from vascular malformations.

TREATMENT
Early rapid growth during the early proliferating phase followed by spontaneous involution is the historical hallmark of IH. Therefore the management of IH is challenging. It should balance between conservative decision based on the probability of spontaneous involution and aggressive treatment as to prevent or reverse any life or function-threatening complications.

Therefore, the decision to treat by systemic therapy requires individual evaluation and therapeutic risks should be cautiously weighed against potential benefits. Indications of treatment The expectation of the natural regression is not possible for a number of alarming IH listed below: Those that are life threatening. Those which threaten function. Those which are complicated by painful or extensive ulceration.

The major goals of management of infantile haemangiomas Prevention or reversal of life-threatening complications Prevention of permanent disfigurement from skin changes following involution Reduction of psychological distress to a minimum Reduction of toxicity and resultant sequelae from systemic therapy Avoidance of excessive scarring from aggressive surgery Treatment of ulceration to minimize scarring.

Active nonintervention In many cases, choosing not to treat is the best approach. The term active nonintervention is preferable to benign neglect. This is a valuable approach for children with small, innocuous hemangiomas where parental anxiety may be much greater than the actual threat of the condition. Parents of children with IH can experience disbelief, panic, fear, and mourning as the tumor develops on an infant who in most cases looked completely normal at birth.

Public information sources such as the Internet can contribute to this anxiety, because most parents lack the training or perspective to understand where their child fits in the continuum of severity. In a study of 25 children with facial IH, half of families interviewed expressed dissatisfaction with aspects of the medical care received. A proactive approach on the part of the physician may help to alleviate some of these frustrations.

At the initial visit, the natural history of the lesion and a general sense of prognosis should be given. The advantages and disadvantages of various treatment options should be discussed. Photographs demonstrating the natural involution of IH can be very reassuring to parents as long as the shown cases are with similar features to the infant in question.

Frequent visits during the proliferating phase with measurements and photographs to document growth velocity are also recommended. In rare instances referral to a counsellor may be warranted.

MANAGEMENT OPTIONS First-line therapy Corticosteroids (topical, intralesional, systemic), Propranolol

Second-line therapy Interferon-alpha (2a-2b) Laser therapy Surgical therapy Other therapy Cyclophosphamide Imiquimod Vincristine Timolol maleate solution

Becamplarine Angiogenesis inhibitors- imiquimod, eosin, batimastat, TIMP-2, VEGF toxin conjugate, and TNP-470 Sclerotherapy Embolization

Corticosteroids They are amongst the first line treartments for hemangiomas. Their mechanism of action is poorly understood. In a study by Hasan et al it was concluded that steroids act by stimulating apoptosis via the increase of cytochrome b, as well as by stimulating the release of antiangiogenic factors via an increase in mast cells.

Recently, it has been demonstrated in a murine model that dexamethasone inhibits the vasculogenic potential of stem cells derived from human infantile haemangioma. In addition, steroids also inhibits the expression of VEGF-A by haemangioma- derived stem cells and silencing of VEGF-A expression in these cells inhibit vasculogenesis in vivo.

Corticosteroid treatment suppresses other proangiogenic factors in hemangioma-derived stem cells, including urokinase plasminogen activator receptor, IL-6, monocyte chemoattractant protein 1, and MMP1.
(N Engl J Med 2010)

The most commonly used molecules are prednisone and prednisolone at the dosage of 2 and 5 mg kg day for 2 months with progressive tapering as to cover the period of evolutionary months.

Even at these high doses, the response rate (simple regression or stabilization) remains average between 30 and 60%. Efficacy of the treatment usually appears between the 2nd and 3rd weeks of therapy. Progressive rebound is usual in case of rapid decrease in corticosteroid dosage with a possible loss of the obtained benefit.

In a meta-analysis by Bennett et al 24 original case series of hemangiomas treated with systemic corticosteroids were reviewed. Patients were given a mean prednisone equivalent daily dose of 2.9 mg/kg for a mean of 1.8 months. The response rate was 84%. A dosage of prednisolone of 3 mg/kg per day was found to be more effective than 2 mg/kg per day.
(JAAD 2006)

Side-effects of corticosteroids are numerous. Most are transient and benign; i.e. Cushingoid facies, insomnia, irritability, gastroesophageal reflux, acne, hair growth, growth retardation and osteoporosis. Some serious side-effects such as hypertension, opportunistic infections, obstructive hypertrophic cardiomyopathy and adrenal insufficiency may occur rarely.

Topical corticosteroids In 2 small case series topical clobetasol has been reported to be of some beneficial results in treating orbital hemangiomas . Garzon at al recently reported on their retrospective experience of treating 34 patients with superficial or mixed superficial and deep IH with ultrapotent topical steroids. They found that 74% had a good response to therapy.
(JAAD 2006)

The use of superpotent topical steroids is probably best for small superficial hemangiomas at risk for ulceration or small periocular lesions.

Intralesional corticosteroids They are restricted to progressive but localized IH, where oral pharmacological treatment or surgery does not seem appropriate. Local injections are administered at several points under short general anaesthesia in a surgical unit.

These injections are usually repeated monthly for 2 or 3 months with a response of 50%. Compared with oral corticosteroids, side-effects are limited and mostly localized; hypochromia, linear atrophy. In IH of the periorbital area, serious ocular complications including ophthalmic artery occlusion, retinal embolization and central retinal artery occlusion may occur with a risk of blindness.

PROPRANALOL: In 2008, Leaute-Labreze et al described their serendipitous observation of an antiproliferative effect of propranolol on IH. Propranolol has since become the first choice of therapy for complicated IH. Propranolol is a nonselective betaadrenergic antagonist, which competitively inhibits b1- and b2-adrenoceptors with the same affinity.

Possible mechanisms of action of propranolol in IH include the following: (BJD 2010) (1) Control of vascular tone. Beta-adrenergic agonists lead to vasodilation via release of NO. Conversely, beta-adrenergic antagonists like propranolol lead to vasoconstriction (through inhibition of NO synthesis and NO release)

(2) Angiogenesis.: Beta-adrenergic agonists stimulate the synthesis of proangiogenic factors like growth factors (VEGF and bFGF) and matrix metalloproteinases (MMP-2 and MMP-9)] and activate proangiogenic cascades (ERK MAPK cascade) thereby promoting angiogenesis. In contrast, beta blockers like propranolol lead to a downregulation of these proangiogenic proteins and to an inhibition of the ERK MAPK cascade thus repressing angiogenesis.

(3) Apoptosis. Beta-adrenergic agonists inhibit apoptosis via src MAPK. In contrast, beta blockers induce apoptosis. (4)Action on MMPs: MMP-9 is important for the migration of endothelial cells and tubulogenesis. The expression of MMP-9 and MMP-2 is regulated via b-adrenoceptors.

The expression of MMP-2 and MMP-9 can be inhibited by propranolol. Reduced expression of these leads to an inhibition of tubulogenesis of endothelial cells and thus also provides a conclusive mechanism for the antiangiogenic effect of propranolol.

In a multicenter retrospective study involving 71 infants with infantile hemangiomas who were treated with oral propranolol, 1 mg kg BD, propranolol was found to be a rapid and effective treatment for infantile hemangiomas at various time periods from 4 to 32 weeks. The response of infantile hemangiomas to propranolol was similar regardless of sex, age at onset of treatment, type of involvement, facial segments affected, special locations , ulceration, and depth of infantile hemangiomas.
(Ped derm 2011)

There are also many smaller reports to confirm this effect. Potential life threatening symptoms such as dyspnoea or haemodynamic abnormalities usually resolve within 48 h. In case of orbital IH with palpebral occlusion, spontaneous ocular opening may be observed within 7 days .
(JEADV 2011)

After these dramatic initial responses, all symptoms of IH usually continue to improve in colour and thickness. When performed, ultrasound examination may disclose objective regression in thickness associated with an increase of resistivity parameters of IH vascularization.

Adverse effects can be noted during propranolol treatment including bradycardia, asymptomatic blood pressure drop, onset of wheezing, insomnia, agitation and nightmares. Parents should be informed of the risk of hypoglycaemia and the child should be carefully monitored and advised to feed the child every 34 hours.

In a study of 28 patients of IH treated with propranolol side effects that needed intervention or close monitoring included symptomatic hypoglycemia (n = 2), hypotension (n = 16, 1 was symptomatic), and bronchial hyperreactivity (n = 3) Restless sleep (n = 8), constipation (n = 3) and cold extremities (n = 3).
(JAAD 2011)

a) At 6 weeks of age,. (b) Seven days after initiation of propranolol treatment (c) After 8 months of propranolol treatment

Response of a large IH to propranolol therapy: before treatment (A); at 4 weeks (B); at 8 weeks (C); and at 24 weeks (D).

TOPICAL TIMOLOL A pilot study of small uncomplicated infantile haemangiomas in six patients showed improvement with 0.5% timolol maleate gel, applied for an average duration of 3.3 months.
(Arch derm 2010)

In patient with large facial hemangioma and PHACES syndrome showed a dramatic response to topical timolol 0.5% ophthalmic lotion applied over the haemangiomas. There was a decrease in redness within 3 days and almost complete resolution of the haemangiomas by 8 weeks.
(BJD 2011)

At 4 and 12 weeks after topical timolol application

Interferon -2a and 2b Interferon is an antiangiogenic agent that decreases the proliferation of endothelial cells by down regulation of bFGF. It is indicated in severe complicated IH not responding to corticosteroids. Duration of the treatment is long and may vary from 6 to 12 months. A complete response rate of 4050% has been reported with the first signs of regression appearing between the 2nd and the 12th weeks of treatment.

Side-effects are common with fever and muscle aches (flu-like symptoms), especially early in treatment. Other side-effects have been reported such as hepatic and haematological toxicity, hypothyroidism and depressive syndrome. Severe neurotoxicity with spastic diplegia and developmental delay is reported to occur in 10 30% of cases.

Vincristine : It is an antiangiogenic agent that interferes with mitotic microtubules and induces apoptosis of tumour cells in vitro. Similarly, it is indicated in severe complicated IH not responding to corticosteroids. Treatment modality includes a weekly intravenous administration of 0.05 mg kg or 1 mg m for at least 15 weeks.

Efficacy rate is nearly 100%, with regression of the haemangioma beginning usually 3 weeks following treatment initiation. Side-effects may include fatigue, alopecia, constipation, abdominal pain, transient pain in jaw, peripheral neuropathy, haematological toxicity and inappropriate secretion of antidiuretic hormone.

Surgery Surgical treatment includes early and late interventions with quite different indications and outcomes. Early surgery during the growth phase, may be considered in some types of IH; well-localized function-impairing IH not responding to medical treatment ,IH without significant regression in size after 8 to 12 months and IH with persistent bleeding or ulceration.

Early surgery may also be useful for symptomatic laryngeal IH. The main risk of surgery is posthealing residual scarring which should always be weighted to sequels of untreated IH. Late surgery following regression of IH is essential in some cases. It aims to repair postregression cutaneous (atrophic wrinkling, discoloration, redundant skin fibro-fatty residual tissue) and anatomical sequels.

Lasers The pulsed dye laser is effective in superficial vascular abnormalities and may help to accelerate healing in some cases of ulcerated IH. However, it has no impact on deep dermal components. In a randomized clinical trial, pulsed dye laser did not show any benefit in the early uncomplicated treatment of flat IH when compared with a wait and see policy. In later stages, it has an aesthetic interest in erasing the residual telangiectasia.

The usage of CO2 laser or Erbium laser devices is restricted to postregression phases with residual scarring. Others Imiquimod Topical imiquimod, has ability to induce the production of interferon, TNF- , and the antiangiogenesis factor- TIMMP and has been recently reported to be efficacious in the treatment of IH.

In a study involving 18 children treated with imiquimod 5% cream for a mean duration of 17 weeks, All superficial IH improved, and remission was achieved in 4 hemangiomas.
(JAAD 2007)

There was little improvement in mixed IH with no or minimal change in all deep hemangiomas. One case with ulcerated hemangioma substantially improved with accelerated ulcer healing and hemangioma size reduction. Irritation and crusting were the most common reactive effects.

Therapeutic arterial embolization Sclerotherapy Radiation therapy Becaplermin Gel (Recombinant Human PlateletDerived Growth Factor) Batimastat- synthetic MMP inhibitor In Ulcerated haemangiomas dressing with vaseline, hydrocellular and hydrocolloids gels have a remarkable analgesic effect.

Therapeutic strategy For common non-alarming IH, therapeutic abstention is the rule in most instances. IH during proliferative phase : Concerning complicated IH, there are no official treatment guidelines. However, given the recent proven rapid efficacy and safety of beta-blockers in the therapy of IH, many teams propose oral propranolol, 2 to 3 mg kg day, as first-line therapy.

Treatment should be maintained until the end of the growth phase of the IH lasting to 9 to 10 months in medium size IH and 12 to 18 months in the most severe cases. Propranolol has also been found to reduce the healing delay of ulcerated IH, while reducing the pain. Systemic corticosteroids, interferons and vincristine should be considered as second or thirdline therapy in this context.

Surgery is possible at early stage of IH only in case of localized IH. Local treatments have not yet provided evidence of a good benefit risk ratio and their efficacy is not clearly established. There has been a positive experience with topical timolol but further studies are required to establish its efficacy.

IH beyond the proliferative phase: Recently propranolol has shown beneficial effect to reduce the size and coloration of fully developed IH. This efficacy may help to treat infants before entering at school in case of facial IH or before surgery to reduce the tumour facilitating intervention. In general, surgery and lasers are the main tools for the management of IH sequelae.

SUMMARY

REFERENCES:
Rooks Textbook of dermatology Fitzpatricks Dermatology in general medicine JEADV 2007, 201 1 JAAD 2003, 2006,2007, 2009, 2010, 201 1 Pediatric dermatology 2005, 201 1 BJD 2010, 201 1 Seminars in Opthalmology 2009 Archives of dermatology 2004