Infantile Haemangiomas: A Review
Keyword : Haemangiomas; Infant
The term haemangioma designates a proliferative blood vessel tumour. As a variety of vascular tumours may occur in older children and adults, the term 'infantile haemangioma' is preferable to describe the developmental type of haemangioma that arises in early infancy. This type of haemangioma has colourfully been called strawberry naevus or strawberry haemangioma, though in practice not all such lesions have a strawberry-like clinical appearance. The terms capillary naevus and capillary haemangioma have been used to describe infantile haemangiomas, but, although the description capillary haemangioma is perfectly correct and acceptable, the frequent and widespread misapplication of these terms to describe macular telangiectatic vascular naevi of salmon patch or port wine stain types means that it is probably best to avoid their use altogether for the time being.
Infantile haemangiomas must be differentiated from vascular malformations, whose clinical appearance may be similar in some cases, but whose aetiology, pathology and natural history are entirely different.1-3 Lesions that were previously called cavernous haemangiomas are frequently not haemangiomas at all, but vascular developmental malformations, and this term should be abandoned.
Several special terms have been used to describe the occurrence of large numbers of infantile haemangiomas in the neonate, including diffuse neonatal haemangiomatosis,4 disseminated haemangiomatosis,5 disseminated eruptive haemangiomas6 and miliary haemangiomata.7 Cutaneous haemangiomas of this type are particularly likely to be associated with systemic haemangiomas and, therefore, an increased mortality, but in most cases complications due to systemic lesions do not occur. An attempt has been made to separate cases with systemic lesions from those without, using the term disseminated eruptive neonatal haemangiomatosis for the former and the term benign neonatal eruptive haemangiomatosis8 for the latter. A distinction of this type is highly artificial since one cannot exclude the presence of systemic lesions without employing intensive investigation to do so, an approach that most clinicians would regard as unnecessary. The management of such cases requires a high level of awareness of the possible presence of visceral lesions and an alertness for the development of symptoms resulting from such lesions. Exclusion of visceral lesions in every case as a matter of routine is neither practical nor necessary. The author prefers the term multiple infantile haemangiomas when multiple skin lesions are present; multiple haemangiomatosis would be an acceptable alternative.
Aetiology. Infantile haemangiomas are benign proliferations of vascular elements. While many of the cells appear to be endothelial in nature, forming readily visible blood vessels, a large population of cells is present in these lesions which have not been fully categorised. Since pericytes and dermal dendrocytes have been identified in infantile haemangiomas in addition to endothelial cells,9 it has been suggested that they are tumours of a primitive cell type capable of differentiating in all these directions.10
Capillary endothelium has the capacity to develop new vessels under certain conditions.11 In particular, this requires the presence of angiogenic factors,12 and it is possible that infantile haemangioma cells are able to secrete such a factor themselves, as has been shown to be the case in certain other types of tumour.13 Certain other types of cell may play a 'helper' role in endothelial proliferation. The mast cell has been an important candidate for such a role;14,15 the finding that mast cell numbers are high in proliferating haemangiomas is therefore of great interest.16
It has also been proposed that endogenous steroid hormones may also play a role in the growth of infantile haemangiomas. Both increased serum levels of 17-beta oestradiol and increased numbers of tissue receptors for this hormone in proliterating infantile haemangiomas have been demonstrated.17
Pathology.18,19 In the earliest phase of growth of infantile haemangiomas, there is a solid mass of proliferating endothelial cells, with few if any lumina. The nuclei are not pleiomorphic and only occasional mitoses are visible. Later in the proliferative phase, capillary-size lumina are apparent, lined by plump endothelial cells. Reticulin staining confirms that each group of endothelial cells is surrounded by a limiting membrane of reticulin fibres. PAS staining shows a thickened basement membrane beneath the endothelial cells lining the lumina. Initially, these lumina are slit-like, but gradually they become more dilated. Mast cells are plentiful during the proliferative phase.
The haemangioma becomes progressively more organised with distinct lobules separated by fibrous septa containing the larger feeding and draining vessels. In children aged 2 years and older, the number of vascular channels decreases and the diameter of the lumina increases with flattening of the endothelial lining, resulting in a 'cavernous' appearance, that must not be confused with the appearance of a venous malformation. There is a simultaneous progressive increase in intra- and inter-lobular connective tissue and fat.
The location of individual lesions varies. The most superficial are confined to the papillary and subpapillary dermis, while deep lesions may partly extend into the subcutis.
Clinical features. Infantile haemangiomas are the commonest tumours of infancy, with a prevalence of about 1-3% after the first few days of life,20,21 and about 10% by the end of the first year.22 There is good evidence of a higher incidence in infants born prematurely, about 13% at one year for all preterm infants, increasing in inverse relationship to birth weight.22 Thus, at one year, the prevalence in preterm babies with a birth weight below 1500 gm is about 16%, and, in preterm babies with a birth weight below 1000 gm, about 23%. Conversely, the prevalence in preterm babies with a birth weight over 1500 gm is no different to that of full term babies. In another recent study, the prevalence of infantile haemangiomas at one year in preterm infants was shown to be inversely related to gestational age at birth, being recorded as 8% for babies born after the 35th week, 11% for those born between the 30th and 35th weeks, and 19% for those born between the 25th and 29th weeks.23 Superficial infantile haemangiomas, sometimes multiple, have also been reported to occur with increased frequency in the fetal alcohol syndrome.24
Infantile haemangiomas become apparent during the first month of life in about 90% of cases, and virtually 100% by the ninth month. Approximately 65% of infantile haemangiomas are superficial, 15% deep and 20% mixed. The term 'deep' is preferable to 'subcutaneous' as most of those infantile haemangiomas that are covered with normal epidermis are situated largely in the dermis rather than in the subcutis, though they may extend to this depth.
In the case of superficial infantile haemangiomas, the initial lesion is often visible on the first day of life. These lesions may be quite subtle and most characteristically take the form either of a macular area of hyperaemia resembling a salmon patch or a pale port wine stain, or a macular area of pallor.25-27 The latter, pallid type of precursor lesion area may contain grouped punctate telangiectases from the outset, or these may develop within a day or two. A group of small, closely-packed angiomas usually then develop within the area, rapidly enlarging and coalescing until the lesion is mature. However, apparently typical precursor lesions occasionally fail to progress into infantile haemangiomas. In other cases, probably less than 20% of the total, superficial infantile haemangiomas are already present at birth, and sometimes they appear to arise de novo from previously entirely normal skin.
The superficial infantile haemangioma is most commonly known as a 'strawberry naevus' or 'strawberry haemangioma' on account of its usual clinical appearance in the form of a sharply circumscribed oval or round, soft, domed swelling of intense scarlet-red colour. The surface may be smooth or lobulated. These lesions may occur at any site, but about 60% occur on the head and neck. Next in frequency are lesions on the trunk, about 25% of the total, where favoured sites are the perianal area in both sexes, and the vulva in girls.
In some 80% of cases, a single lesion only is present, but it is not uncommon for there to be several, and, occasionally, large numbers may occur. Their ultimate size is generally reached within 3 to 6 months of their first appearance, and only exceptionally do lesions continue to enlarge beyond the first year of life. The final diameter may vary from less than 1 cm to 25 cm or more. Very large lesions have obstructed delivery.
Occasionally, infants are born with multiple small infantile haemangiomas of the 'strawberry' type, or develop these within the first few weeks of life.4,28 In such cases, the cutaneous lesions are characteristically relatively small, generally between 2 mm and 2 cm in diameter. The lesions may bleed, and quite often at least some are pedunculated.
There is frequently a deep element to superficial infantile haemangiomas of strawberry type, particularly when these are large; such lesions should be termed mixed infantile haemangiomas. In other cases, the lesion is entirely, or more or less entirely deep. Exclusively deep infantile haemangiomas take the form of soft, warm, round bluish masses beneath normal skin, though there may be a few branching telangiectases or an area of macular telangiectasia resembling a pale port wine stain on the surface. They show very little predilection as far as site is concerned. Deep infantile haemangiomas often feel like a 'bag of worms', and a useful feature in their distinction from other tumours is that they can generally be compressed to about half their original size, quickly regaining their original dimensions on release of pressure. Similarly, they often become larger and darker when the child screams or cries. Only about 7% of infantile haemangiomas are exclusively of this deep type. Where the naevus is mixed, it may be principally deep or principally superficial. The superficial element usually emerges from the centre of the swelling, often in several places.
It is commonly stated that deep infantile haemangiomas are more likely than superficial infantile haemangiomas to have been present at birth, and that they are more likely to be of 'cavernous' type histologically. However, such statements result from the previously widespread tendency to confuse deep infantile haemangiomas with venous vascular malformations, which are not angiomas at all and have an entirely different natural history.
Virtually 100% of infantile haemangiomas undergo spontaneous regression, which is complete or almost complete in about 95%.29,30 The same rate of resolution is demonstrated by all lesions, including deep ones. About 30% of infantile haemangiomas will have resolved by the fourth birthday, about 50% by the fifth, and 75% by the seventh. The likelihood of early resolution is not affected by the size of the lesion, its site, or by the number of lesions present. Neither does the age at first appearance, or the age at which maximum size is reached materially affect the likely speed of resolution. On the other hand, an early onset of resolution is generally associated with a more rapid disappearance and a superior cosmetic result. Conversely, a late start to resolution is generally associated with a higher chance of incomplete regression. Lesions that resolve completely have almost always started to regress by the age of 5 years. There is very little evidence to support the widely held theory that ulceration accelerates the initiation of resolution. Resolution of superficial infantile haemangiomas is heralded by a softening of the lesion and by the appearance of opaque pinkish-grey areas in the centre of the surface. These foci gradually become confluent and extend towards the periphery of the lesion. When resolution has ceased, the affected area may be perfectly normal, but more commonly it shows subtle atrophy and telangiectasia, and at certain sites, particularly the lips and eyelids, it is common for there to be a residual sac of redundant and slightly atrophic skin. Areas of previous ulceration frequently leave yellowish scars. Lesions in the scalp usually resolve without permanent alopecia in the affected area unless previous ulceration has occurred. Perhaps the commonest lesions which fail to show complete resolution are lesions on the nose, ears and lips. The small multiple type of infantile haemangiomas often involute more rapidly than other infantile haemangiomas.31
There is rarely any difficulty making the diagnosis of haemangioma of infancy, particularly in the case of the superficial type. The main problem has been to distinguish vascular malformations from deep or mixed deep and superficial haemangiomas of infancy. The literature contains many reports in which lesions called 'haemangioma', often 'cavernous haemangioma', clearly relate to vascular malformations; these reports are frequently concerned with failure of such lesions to resolve spontaneously, or the fact that they may enlarge, at puberty for example.31 The principal features distinguishing vascular malformations are (i) the history of a lesion present since birth, (ii) the lack of any tendency to spontaneous resolution, and (iii) the frequent presence in the area of the lesion of other elements such as port wine staining, eccrine angiomatous naevus and lymphangioma circumscriptum. Currently ultrasound and CT and MRI scanning are of limited value in making the distinction as both lesions tend to be reported as 'haemangioma'. However, the distinction is a very important one, and fundamental to the patient's correct management as it has such great effects on prognosis and therapy.
Several types of tumour occurring in infancy may present with cutaneous nodules resembling superficial, deep or mixed haemangiomas, these include granuloma telangiectaticum,32 neuroblastoma,33,34 infantile myofibromatosis,35,36 rhabdoid,37,38 fibrous hamartoma of infancy,39 fibrosarcoma,40 congenital leukaemia,41 haemangiopericytoma,42,43 rhabdomyosarcoma,44,45 and leiomyosarcoma.46
Complications of infantile haemangiomas
Ulceration. Superficial infantile haemangiomas are not infrequently complicated by bleeding and ulceration, particularly larger lesions. Ulceration is less common than bleeding, though it is particularly likely to complicate lesions in the anogenital area, where it may result in dysuria or pain on defaecation. Ulceration similarly tends to complicate lesions at other sites which are vulnerable to trauma, such as the ears, nose or the lips.
Ulceration is frequently complicated by infection, and when it occurs on the ears, nose or lips, permanent loss of tissue and mutilation may result, sometimes very rapidly.
Haemorrhage. Only rarely is bleeding from an infantile haemangioma substantial, except in the Kasabach-Merritt syndrome or during surgery.47 However, where such bleeding has occurred, parents may become extremely anxious, fearing their child may exsanguinate when out of their sight, especially at night. Occasionally, an enuresis warning blanket may provide reassurance in this situation.48 Normally, compression will stop bleeding, but in an emergency, tissue adhesive sclerosis may be life-saving.49
Infection. Secondary infection may complicate infantile haemangiomas in the event of ulceration or following any type of surgical interference. Occasionally this may lead to septicaemia, with a potentially disastrous outcome.50-52 Group A streptococci appear to be particularly dangerous in this situation. Where the epidermis is broken over an infantile haemangioma in infancy, a high level of suspicion must be maintained for evidence of the onset of this complication.
Malignant change. Though malignant change may be a complication of hepatic haemangiomas,53 it probably never complicates cutaneous infantile haemangiomas. However, true malignant vascular tumours in infants might conceivably be initially mistaken for infantile haemangiomas, particularity when they have a deep location. Such tumours include malignant haemangioendotheliomas54 and malignant haemangiopericytomas.55
Heart failure. Shunting of large volumes of blood through infantile haemangiomas may lead to high-output heart failure.56,57 This complication is particularly likely to occur in association with multiple infantile haemangiomas, when it is usually due to shunting through one or more, hepatic haemangiomas.58
Systemic haemangiomas. Visceral infantile haemangiomas may occur with or without co-existent cutaneous infantile haemangiomas.59 In dermatological practice, they are most often, but not necessarily,60 encountered in association with the small, multiple type of infantile haemangiomas. Such lesions may be found in the liver,61,63,4,58,64-68 gastrointestinal tract,4,7,60,65,67,69-70 spleen,64,69,71-72 pancreas,7 adrenals,73 lungs,4,7,64,72 heart,64 skeletal muscle,4,64 salivary glands,74 kidneys,4,64 bladder,64,74 testes,75 thymus,4 thyroid,4 bone,4,73 meninges,64,76 brain4,7,64,72 and eyes.64,77,78
Where such systemic lesions are extensive, mortality appears to be high,4,7,63,64,79 death generally occurring within the first few months of life. High output cardiac failure is the commonest cause of death, and this is most often induced by arteriovenous shunting in the liver or lungs. Other complications have included the Kasabach-Merritt syndrome,4,64,80-82 convulsions,64 intestinal haemorrhage60 and obstructive jaundice.68,72
Certain investigations are therefore more or less mandatory in any infant with multiple infantile haemangiomas whether or not there is clinical evidence of systemic involvement. These include a full blood count including a platelet count, urinalysis to exclude bleeding, faecal occult blood testing, a chest X-ray to determine heart size, and an ultrasound examination of the liver. Where suspected on clinical grounds, lesions in other organs may be sought by appropriate investigations, including the use of technetium 99m-labelled red cells.6,83
Kasabach-Merritt syndrome. Consumption coagulopathy is an uncommon but highly characteristic complication of infantile haemangiomas.
Haemorrhage in the Kasabach-Merritt syndrome appears to be a consequence of platelet sequestration and consumption of clotting factors within the vascular bed of the angioma.84-86 Activation of the fibrinolytic system may then lead to the development of chronic consumption coagulopathy in which increased consumption of platelets and clotting factors is balanced by their increased production. Activation of the fibrinolytic system in this situation can be detected by the appearance of fibrin degradation products in the circulation. Under certain circumstances eg. surgical procedures, it is possible for acute disseminated intravascular coagulopathy to supervene with disastrous results.87,88
Infantile haemangiomas leading to the Kasabach-Merritt syndrome are generally single deep lesions of larger size, but the disorder can very occasionally occur in association with smaller and more superficial lesions.89 The responsible infantile haemangioma will most commonly occur on the trunk, neck and proximal parts of the limbs, particularly the thighs and shoulders and, relatively uncommonly, on the head.
Infantile haemangiomas responsible for the Kasabach-Merritt syndrome are frequently but not invariably present at birth. The coagulation defect almost always becomes apparent during the first few weeks of life,90 but may already be apparent at birth.91 On the other hand, a later onset of the haemorrhagic diathesis has been documented in non-involuting lesions in older children and in adults.81,88,92-94 The onset of defective coagulation is most commonly heralded by bleeding into and around the haemangioma itself, manifest by an increase in size, induration, tenderness and superficial ecchymoses. The resulting rapid expansion of the angioma may cause potentially lethal compression of neighbouring vital structures, particularly when the lesion is in the cervicofacial area. Internal bleeding may occur at a great variety of sites, and is associated with a significant mortality, which reaches 40% of cases in some reported series.90,95
If there is any doubt about the location of the angioma responsible for the Kasabach-Merritt syndrome, a 111-Indium-labelled platelet scan may be invaluable.96
Impairment of vision. 97-102 Infantile haemangiomas involving the eyelids can interfere with vision in several ways. Firstly, obstructive amblyopia may result if the lesion directly obscures the line of vision. Secondly, such lesions may also lead to astigmatism, even when the line of vision is not obstructed, probably due to a direct pressure effect on the cornea; this can lead to astigmatic amblyopia. Currently available data suggest that closure of the eye for only a few days during the first year can result in obstructive amblyopia, so that obstruction of the line of vision by an eyelid infantile haemangioma should be regarded as an emergency.
Whatever form of treatment is selected for the haemangioma, it is important to patch the unaffected eye, in order to minimise amblyopia and strabismus.
Airway obstruction. 103-105 It is important to consider the possibility that any infant with a cutaneous haemangioma may concurrently have a subglottic haemangioma. This is most likely if the cutaneous lesion is in the neck,56 from which there may be direct extension into the subglottic airway. It has been estimated that untreated subglottic haemangiomas are associated with a mortality approaching 50%95 due to airway obstruction, which may occur suddenly during a period of rapid enlargement, or as a result of haemorrhage within the tumour. Such an event may require an emergency tracheotomy for its relief. More often, however, such infants develop stridor, usually between the 6th and 8th weeks. Any suspicion of subglottic angioma is an indication for X-rays of the area, followed, if necessary, by direct laryngoscopy.
Involvement of the nose in the neonatal period may also obstruct respiration, as neonates normally will not breathe through the mouth. However, the obstruction generally occurs slowly enough to allow the infant to adapt, though inability to breathe through the nose is likely to interfere with sucking and therefore with nutrition.
Interference with feeding. Feeding difficulties may complicate haemangiomas in the mouth and those that obstruct nasal breathing.
Obstruction of the external auditory canal. Haemangiomas that encroach on the ear may obstruct the external auditory canal. Though this will interfere with hearing in the short term, it will generally not affect the development of normal ear function in the longer term. Bilateral obstruction after the age of about a year would however be likely to interfere with normal speech development, but must be very rare.
Other Associations of Infantile Haemangiomas
The medical literature contains many descriptions of 'haemangiomas' occurring in association with a variety of genetically determined and malformation disorders, but careful review reveals that in the majority of cases these lesions have been macular telangiectatic naevi, or other types of vascular malformation, rather than true haemangiomas.106 The following are the principal situations in which an association with haemangiomas of infancy is established.
Posterior fossa anomalies
There have been a number of reports of posterior fossa brain abnormalities in infants with large facial infantile haemangiomas.107-113 The facial haemangiomas have been extensive, and have been both unilateral and bilateral. The commonest posterior fossa abnormality has been the Dandy-Walker syndrome, but other abnormalities have included arachnoid cyst, cerebellar atrophy with enlarged cisterna magna and fourth ventricle, and cerebellar atrophy with vermis agenesis.
The posterior fossa abnormalities were found as a result of investigation of macrocephaly and enlarging head circumference, hemiparesis, developmental delay, or coincidentally on imaging.
Intracranial abnormalities have also been reported in an infant with multiple infantile haemangiomas,114 who was found to have absence of the corpus callosum.
Several of these patients also had coarctation of the aorta, and several also had pharyngeal or laryngeal haemangioma and/or eye abnormalities, indicating that there is likely to be a syndrome of posterior fossa anomalies, coarctation of the aorta, laryngeal and pharyngeal haemangioma and facial haemangioma, which is most often only partially expressed, and which may reflect a developmental field abnormality.107
Coarctation of the aorta
Coarctation of the aorta has been reported in association with extensive infantile haemangiomas of the face and, in some cases, the upper trunk.56,108,115-117 As mentioned above, many of these infants have also demonstrated haemangioma of the pharynx and/or larynx, and posterior fossa anomalies.107
Ventral developmental defects
There appears to be a definite association between infantile haemangioma of the face and anterior trunk, a sternal cleft, and a median abdominal raphe.114,118-122 One child also had subglottic and intestinal haemangiomas.119 It is considered likely that this association also reflects a developmental field abnormality.
It is clear that lumbosacral haemangiomas are not infrequently associated with occult spinal dysraphism and/ or a tethered cord.106,123,124 It is recommended that magnetic resonance imaging be undertaken in all infants with haemangiomas at this site, whether a plain spinal X-ray is normal or not.
Genitourinary developmental defects and imperforate anus
An association between sacral haemangiomas, imperforate anus and a range of genitourinary developmental defects has been reported.124
Treatment of Infantile Haemangiomas
In the absence of complications or substantial cosmetic handicap, the correct management of infantile haemangiomas is generally expectant. No treatment is indicated where a good cosmetic result can be predicted with reasonable confidence and where complications appear unlikely to supervene. It can sometimes be helpful to show parents serial photographs illustrating the spontaneous resolution which has been observed in other cases.
However, it is important to be aware of the speed with which these lesions can enlarge during their initial phase of growth. The progress of lesions which are still increasing in size should therefore be supervised, especially where they occur at or close to the special sites mentioned above. The need for therapeutic intervention should be kept under review until the situation has stabilised. Despite the good prognosis for spontaneous resolution of most infantile haemangiomas, there is no justification for therapeutic nihilism. The need for treatment of individual lesions should be carefully and sympathetically considered, and procrastination should be avoided because delay may severely reduce the opportunities for successful treatment. Even small lesions may result in major cosmetic handicap at certain sites, such as the tip of the nose, and, while a good result may ultimately be anticipated following spontaneous resolution, sufficient psychological harm may have been done in the meantime to justify earlier therapeutic intervention.
Where infantile haemangiomas are causing or threatening tissue, loss secondary to ulceration (e.g. on the nose or ears), where airway obstruction is threatened or feeding is impeded, where there is interference with important structures such as the eyelids, or where the cosmetic handicap is significant, immediate treatment should be contemplated. Treatment options include (i) systemic corticosteroids, (ii) intralesional corticosteroids, (iii) laser therapy, (iv) compression, (v) surgical excision, (vi) embolization, (vii) vincristine, (viii) cryotherapy, (ix) interferon-alpha, (x) sclerosant injection, and (xi) radiotherapy. Attempts to apply one treatment procedure routinely to infantile haemangiomas is illogical and dangerous. Each case requires careful assessment and observation, and a knowledge of the advantages and disadvantages of the available therapeutic options.
(i) systemic corticosteroids.
Systemic corticosteroids are the treatment of choice in the majority of cases, though they only tend to be effective if treatment is initiated during the proliferative phase.56,61,125,128 Once lesions have stabilised, systemic corticosteroids may have little effect. For this reason, there is some urgency in making the decision to start treatment. Therefore, oral corticosteroid therapy should be given at the first sign that the patient is developing a significant eyelid lesion, cardiac failure, upper airway obstruction or the Kasabach-Merritt syndrome.
Prednisolone should be given in a daily dose of 2-5 mg/kg body weight for 4-8 weeks followed by gradual reduction of the dose over a period of several weeks. Alternate daily dosage regimes have also been advocated, but tend to be less effective if used from the start of treatment. If no response is seen after 3-4 weeks, this approach should be abandoned. In the author's experience, a good response can be anticipated in about 60% of cases if treatment is started sufficiently early at a dose of 3 mg/kg per day. Treatment should also be contemplated when the integrity of the nose, ears or lips is threatened. Rebound increase in size may occur if treatment is discontinued too soon in early rapidly proliferative lesions. Infants tolerate this type of therapy remarkably well, and it is very unusual for any other than transient adverse effects to occur.
It is of interest to note that corticosteroids were first used in an attempt to improve thrombocytopenia associated with infantile haemangiomas, and an unexpected shrinkage of the tumour itself occurred. The mechanism by which corticosteroids prevent further growth and reduce the bulk of infantile haemangiomas remains unclear.
(ii) intralesional corticosteroids.
Intralesional injection of corticosteroids may effect rapid shrinkage, and is a very popular treatment for lesions of the eyelids.127-130 In general, two or three treatments are required at approximately 6-week intervals, and there is a definite failure rate of around 30%. It is important to bear in mind that substantial quantities of corticosteroid are being injected and that significant adrenal suppression may occur.131 Local complications are unusual,132 but have included fat atrophy and eyelid necrosis.133-135 Accidental intravascular injection may lead to central retinal artery occlusion and blindness.136,137 The incidence of complications, which include accidental injection of the eye itself and damage to the optic nerve, is higher when retrobulbar lesions are treated.
This treatment has been used for lesions at other sites.138
(iii) laser therapy.
There is increasing evidence that therapy of infantile haemangiomas with the 585 nm flashlamp-pumped pulsed dye laser139-141 can be effective at preventing enlargement when used at the macular or initial plaque stage during their early development. However, such treatment may fail to prevent enlargement of deeper elements of an infantile haemangioma.142 The 585 nm flashlamp-pumped pulsed dye laser can be used to lighten any superficial haemangiomas and to flatten thin lesions (ie less than 4 mm), but flattening cannot be anticipated in thicker lesions because the depth of penetration is limited to about 2 mm.
Another laser that has been used for infantile haemangiomas is the neomydium: yttrium aluminium garnet (Nd:YAG) laser, which emits in the near infra-red region and can produce photocoagulation to a depth of almost 1 cm. Successful treatment of fully developed infantile haemangiomas has been reported, albeit with some post-treatment scarring.142,143 Improvements in the treatment of thick haemangiomas with the Nd:YAG laser may follow the introduction of special techniques such as skin surface cooling during irradiation or compression of lesions using cooled glass,144,145 and the use of interstitial radiation using light guides.146
Treatment with the 585nm flashlamp-pumped pulsed dye laser is able to reduce pain and to initiate healing in ulcerated infantile haemangiomas.147,148
Another approach to the treatment of infantile haemangiomas that may be useful in individual cases is compression bandaging or intermittent pneumatic compression.149-153 While it is not proven that this treatment can accelerate spontaneous resolution, compression bandaging can provide temporary reduction of bulk that may allow a child with a giant infantile haemangioma on the trunk or a limb to wear normal clothes. Compression can be an effective treatment for suitably accessible cutaneous lesions responsible for the Kasabach-Merritt syndrome.149,154
When contemplating compression therapy, it should be borne in mind that one could provoke respiratory distress and/or cardiac failure.154,155
(v) surgical excision.
Surgical excision is most often indicated for the redundant folds of atrophic skin that frequently persist after spontaneous involution of larger infantile haemangiomas.
Surgical excision is also indicated in certain situations earlier in the evolution of infantile haemangiomas, for example for eyelid lesions that require therapy but have not responded adequately to oral or intralesional corticosteroids. Plastic surgery is also indicated where tissue destruction has occurred during the proliferative phase of infantile haemangiomas. This is most commonly appropraite in the case of extensive lesions on the face, where ulceration has led to the loss of parts of the nose, lips or ears.
Surgical excision may also be indicated for cosmetic reasons in lesions present in young children beyond infancy in whom systemic or intralesional corticosteroid would be unlikely to be beneficial. Sympathetic consideration is warranted for lesions on the face in school-aye children, and occasionally in younger children, and the arguments for and against such intervention need to be carefully considered. A uniformly negative approach to treatment of infantile haemangiomas is currently widespread among dermatologists, and is an approach which, in the author's view, may result in much unnecessary morbidity. A particular situation where surgery may be very successful is the relatively common occurrence of infantile haemangiomas on the tip of the nose,156-158 where even small lesions can lead to significant cosmetic handicap. Extensive and complicated infantile haemangiomas affecting the head and neck may warrant surgical treatment in selected cases,159 but such a procedure should rarely be initiated before a trial of systemic corticosteroid therapy in appropriate dosage.
Embolisation techniques have been found to be useful in the treatment of hepatic haemangiomas, particularly in infants with high-output cardiac failure or consumptive coagulopathy.160,161 There has been considerable interest in the possible value of these techniques for the treatment of complicated infantile haemangiomas in the skin, particularly those that threaten vision, and for the relief of airway obstruction caused by oropharyngeal and subglottic haemangiomas.162,163 The author has seen dramatic response to embolisation in the Kasabach-Merritt syndrome.
There has been a preliminary report indicating the potential value of vincristine given orally as a single weekly dose of 2 mg per square metre of body surface area in the treatment of life-threatening haemangiomas.164
Excellent results have been claimed for cryotherapy in the treatment of superficial and deep infantile haemangiomas,165 though there is undoubtedly some risk of scarring.166
(ix) interferon alpha.
Recombinant interferon alpha was originally developed as an antiviral agent.167 During trials in patients with the acquired immunodeficiency syndrome, it was found that interferon alpha-2a had an inhibitory effect on Kaposi's sarcoma. Following reports of beneficial effects in non-cutaneous haemangiomas, early trials in complicated cutaneous infantile haemangiomas have suggested a useful effect for interferon alpha-2a.168-172 Toxicity has generally been low, but the cost of treatment is very substantial.
It is extremely difficult to evaluate the results of this treatment in open studies in a disorder in which spontaneous resolution is the norm,173 and lack of benefit has been reported.174 For the present, therefore, the true value of interferon alpha remains unestablished. It does not appear as effective as systemic corticosteroid given early in adequate dosage, and, like systemic corticosteroids, is often ineffective when given after the proliferative phase.
(x) sclerosant injection.
Where involution is incomplete and accurate serial measurements over a period of at least a year show no further involution, the injection of sclerosing solutions175 may shrink deep infantile haemangiomas. The solutions preferred include sodium citrate 30%, monoethanolamine oleate 5%, glucose 30% and saturated saline. Using a small needle, 0.5-5.0 ml is injected at fortnightly or monthly intervals. Excellent results have been claimed.
Metallic magnesium is a powerful sclerosant, and its insertion into rapidly proliferating infantile haemangiomas has been reported to be an effective treatment approach.176
Though radiotherapy is still sometimes employed, its use is not justified, except possibly in the treatment of hepatic haemangiomas when other approaches have failed. The results of a controlled trial cast doubt on the effectiveness of radiotherapy for infantile haemangiomas.177 Furthermore, there are a number of undesirable long term sequelae, including disturbed bone growth and hypoplasia of soft tissues such as the breast178,179 and larynx,180 and of cataract following therapy of eyelid lesions.181 There also appears to be an increased risk of malignancy,182 particularly the development at the site of the irradiation of basal cell carcinomas,183 squamous carcinoma184 or angiosarcoma,185 also bone, thyroid, breast and soft tissue tumours.186-189
Treatment of cardiac failure. Early therapy aimed at reduction of the shunt is essential if life is to be saved once high output cardiac failure become manifest, though medical treatment may occasionally be effective.190 Systemic corticosteroids may lead to regression of hepatic haemangiomas and reversal of cardiac failure.56 If this approach fails, hepatic artery ligation,58 partial lobectomy66 or transarterial embolisation160,161 may be indicated.
Treatment of the Kasabach-Merritt syndrome. Because spontaneous resolution can be anticipated,89,191 treatment is only indicated when there appears to be a threat to the patient's life. However, one need not hesitate to initiate systemic corticosteroid administration, which can not only reduce the size of the angioma, but can also independently have a directly beneficial effect on the disturbed coagulation-fibrinolysis system.192 Initial dosage should be between 2 and 4 mg/kg/day of prednisolone. Pulse therapy may be useful as a short-term measure.193
Systemic corticosteroids may, however, make little impact in cases with profound coagulation defects. Where this is the case, the choice of further treatment will be determined by several factors, particularly the severity of the coagulation defect, the site of the causative haemangioma, and the presence or absence of associated mechanical compression of neighbouring viscera.
Benefit has been reported for injections of interferon alpha-2a,194 but where the patient is in danger, any benefit is likely to be too slow.
Improved haemostasis can be accomplished in the short term by the use of platelet transfusions and fresh plasma, though the effect tends to be abbreviated by rapid consumption of the platelets and clotting factors. The principal use of this approach is in the preparation of the patient for surgical procedures including embolisation.
Inhibitors of platelet function do not appear to have a role, though this has been disputed by reports of successful use of ticlopidine combined with aspirin,195 and of pentoxfylline.196 There have been reports suggesting a role for inhibitors of fibrinolysis in patients who show no evidence of disseminated intravascular coagulation.84,197 The concept of anti-fibrinolytic therapy with agents such as tranexamic acid198 or aminocaproic acid is that local thrombosis will be encouraged within the angioma vascular bed, reducing blood flow, but the author has not found these agents to be helpful in practice. Cryoprecipitate may also be required as a source of fibrinogen. Clearly, there must be a risk of more widespread thrombosis with such therapy.
Although the spleen is often enlarged, splenectomy appears to be not only dangerous but' also ineffective.
Preliminary experience suggests that continuous bandage or intermittent pneumatic compression may be an effective treatment for suitably accessible cutaneous lesions responsible for the Kasabach-Merritt syndrome.149
Embolisation techniques may be particularly valuable in the Kasabach-Merritt syndrome,193,194 and the author has seen this form of treatment result in permanent reversal of severe consumptive coagulopathy within hours.
Surgical extirpation of large haemangiomas in the Kasabach-Merritt syndrome has been achieved in a number of cases with rapid relief of the coagulation defect,200 so long as adequate intra-operative haemostasis can be achieved. In the absence of adequate control of bleeding, surgical intervention may be catastrophic, and for this reason should not be contemplated unless embolisation has been considered.
Radiotherapy may be effective in improving the coagulation defect,201 though the benefit may be rather delayed. Despite the risk of long-term complications, this approach has its advocates,95 and requires consideration in particularly difficult cases, though generally embolisation should be preferred.
In general terms, the management of patients with defective coagulation in association with an infantile haemangioma should be as conservative as possible. Serial clotting studies and platelet counts should be undertaken, and the levels of fibrinogen and fibrin degradation products should be monitored. Oral corticosteroid therapy should be initiated early, and the lesion should be compressed where this is possible. If the situation deteriorates, the relative merits of embolisation, surgery and radiotherapy should be weighed up. The likelihood of eventual spontaneous recovery of normal haemostasis and regression of the angioma should be borne in mind at all times, and wherever possible, an approach which is as conservative as possible is to be preferred.
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