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Infantile haemangiomas
Early Human Development (2006) 82, 789–795
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Infantile haemangiomas David J. Atherton ⁎ Paediatric Dermatology, Great Ormond Street Hospital for Children, London WC1N 3JH, United Kingdom
KEYWORDS Haemangioma; Endothelium; Tumour; Angiogenesis
Abstract Infantile haemangiomas are the commonest tumours occurring in infants, but regress spontaneously without causing major problems in the great majority of cases. However, in some infants they can cause life-threatening complications. Fortunately, if the decision to treat is made promptly, and the most appropriate form of treatment selected, these complications can usually be prevented. © 2006 Published by Elsevier Ireland Ltd.
1. Definition Infantile haemangioma is the favoured term for a benign type of capillary haemangioma which appears in early infancy, having a characteristic initial proliferative phase followed by a later involutional phase.
2. Aetiology Infantile haemangiomas are neoplastic proliferations of endothelial cells, which occur sporadically in the vast majority of cases. There is evidence that infantile haemangiomas occur with greater frequency following chorionic villous sampling; one study reported a 21% incidence, and in a third of the cases, the haemangiomas were multiple [1]. It would be anticipated that placental injury would lead to increased detachment of placental cells into the blood. Infantile haemangiomas might therefore result from embolisation of fetal placental endothelial cells via the right-to-left shunts characteristic of the fetal circulation. This hypothesis is supported by the finding that infantile haemangiomas share reactivity for GLUT1, an immunohistochemical marker also present in placental endothelium. Infantile haemangiomas, however,
⁎ Tel.: +44 2074059200; fax: +44 2078138274. E-mail address: [email protected].
do not express placental trophoblastic markers. Whatever the origin of the cells comprising these tumours, their rapid proliferation in the postnatal period may reflect loss of angiogenic inhibitors of placental and maternal origin [2].
3. Pathology [3] In the earliest phase of growth of infantile haemangiomas, there is a solid mass of proliferating endothelial cells and pericytes, with few if any lumina. Later in the proliferative phase, capillary-sized lumina are apparent, lined by plump endothelial cells. Initially, these lumina are slit-like, but gradually they become more dilated. Mast cells are plentiful during the proliferative phase. As involution proceeds, the haemangioma becomes progressively more organized, with distinct lobules separated by fibrous septa containing the larger feeding and draining vessels. The number of vascular channels progressively decreases, and the diameter of the lumina increases with flattening of the endothelial lining, resulting in a dcavernousT appearance, which must not be confused with the appearance of a venous malformation. There is a simultaneous progressive increase in intra- and interlobular connective tissue and fat. The endothelial cells comprising infantile haemangiomas show intense and persistent immunoreactivity for a number of tissue-specific markers termed FcãRII, Lewis Y antigen (LEY), merosin and GLUT1. This group of markers is highly characteristic of placental microvasculature. Positivity for
0378-3782/$ - see front matter © 2006 Published by Elsevier Ireland Ltd. doi:10.1016/j.earlhumdev.2006.09.011
790 GLUT1 can be very valuable in distinguishing infantile haemangiomas from other vascular tumours.
4. Clinical features [4] Infantile haemangiomas are the commonest tumours of infancy, with a prevalence of about 1–3% after the first few days of life, and up to 12% by the end of the first year. The prevalence of infantile haemangiomas at 1 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. There is an independent inverse relationship to birth weight in preterm infants. Thus, at 1 year, the prevalence in preterm babies with a birth weight below 1500 g is about 16%, and, in preterm babies with a birth weight below 1000 g, about 23%. Infantile haemangiomas become apparent during the first month of life in about 90% of cases, and virtually 100% by the 9th month. Approximately 60% of infantile haemangiomas are superficial, 15% deep and 25% mixed superficial and deep. The term ddeepT is preferable to dsubcutaneousT as most of those infantile haemangiomas that are covered with normal epidermis are situated largely in the dermis rather than in the subcutis, although they may extend to this depth. In the case of superficial lesions, an initial dprecursorT lesion is very frequently visible on the first day of life. These premonitory lesions may be quite subtle, and most characteristically take the form either of a macular area of hyperaemia resembling a bruise or a pale port-wine stain, or a macular area of pallor [5]. 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 develops within the area, rapidly enlarging and coalescing until the lesion is mature. However, apparently typical precursor lesions occasionally fail to progress into infantile haemangiomas. The superficial infantile haemangioma is most commonly known as a dstrawberryT naevus, 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. A plaque type is a distinctive but important variant of superficial haemangioma; this type has sometimes been termed dsegmentalT. The importance of this type of infantile haemangioma is a high risk of ulceration and a stronger association with developmental structural anomalies [6]. Infantile haemangiomas 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 in the remaining 20%, lesions are multiple; occasionally, very large numbers may occur (see miliary haemangiomatosis of infancy). Infantile haemangiomas increase in size over a period that varies from about 3–18 months. However, the great majority will have reached their maximum size within 12 months of their first appearance, and most within
D.J. Atherton 6 months. The final diameter may vary from less than 1 cm to 25 cm or more. There is frequently a deep element to superficial infantile haemangiomas of strawberry type, particularly when these are large; such lesions should be termed dmixedT infantile haemangiomas. In other cases, the infantile haemangiomas are entirely, or more or less entirely deep. Exclusively deep infantile haemangiomas take the form of soft, warm, round bluish masses beneath normal skin, although there may be a few branching telangiectases or an area of vascular staining on the surface. Deep infantile haemangiomas often feel like a dbag of wormsT, 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. Large superficial veins may be present in the skin at the periphery of larger infantile haemangiomas. Virtually all infantile haemangiomas undergo spontaneous regression, which is complete or almost complete in the great majority. Although there is considerable variation in the rate of involution of individual lesions, there is no evidence to suggest that deep lesions involute more slowly than superficial ones. Age at first appearance does not appear to affect materially the likely speed of resolution, but smaller lesions probably resolve more rapidly. 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. There is very little evidence to support the widely expressed theory that ulceration accelerates the initiation of resolution. Resolution of superficial infantile haemangiomas is heralded by the appearance of focal areas of greyish opacification in the central part 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 commonly it shows subtle atrophy and telangiectasia. With larger superficial lesions and at certain sites, particularly the lips, eyelids, and upper chest a residual sac of redundant and atrophic skin commonly remains. 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. Infantile haemangiomas at certain sites appear particularly to regress particularly slowly and generally incompletely. This is certainly true of lesions on the nose (sometimes termed the dCyranoT or dPinocchioT nose), the lips and the parotid area.
5. Diagnosis There is rarely any difficulty making the diagnosis of infantile haemangioma,particularlyinthecaseofthesuperficialtype. The main problem is to distinguish vascular malformations from deep haemangiomas of infancy. The literature contains many reports in which lesions called dhaemangiomaT, often dcavernousThaemangioma,clearlyrelatetovascularmalformations;thesereportsarefrequentlyconcernedwiththefailureof such lesions to resolve spontaneously, or the fact that they may
Infantile haemangiomas
Figure 1 Tufted angioma on the back of an infant, associated with consumption coagulopathy.
791 Clinically, these tumours take the form of a poorly delineated, pinkish macule that evolves into a deep-red or purplish, indurated plaque or nodule, up to 20 cm in diameter (Fig. 1). The lesion may be a fully developed plaque or mass at birth. Most lesions are tender. The lesion may extend deeply through the subcutis, fascia and into muscle. It is now clear that this tumour and kaposiform haemangio-endothelioma (see below) are together responsible for the great majority of cases of the Kasabach–Merritt phenomenon [9]. Most tufted angiomas expand slowly for a period of months or years, after which they stabilise. Although they probably mostly remain unchanged unless treated, on occasions they may slowly resolve spontaneously. Kaposiform haemangioendothelioma is a rare vascular tumour occurring exclusively in childhood. Most cases present in infancy, though later onset has been reported. Though many of these tumours arise in the retroperitoneum, they may also arise in the skin, often in the subcutis. They are often the cause of the Kasabach–Merritt phenomenon. Histologically, kaposiform haemangioendothelioma is composed of lobules or sheets of tightly packed spindled or more rounded endothelial cells and pericytes, with an infiltrative pattern in the dermis, subcutaneous fat and muscles. They contain few vascular lumina. It is possible that tufted angioma and kaposiform haemangioendothelioma are the polar forms of a single pathological entity, and histological overlap has been observed. Glomangiomatosis. Glomangiomas may be mistaken for infantile haemangiomas, particularly in the disseminated form. In this condition multiple plaques of purplish nodules may continue to develop throughout life (Fig. 2).
6. Complications enlarge, at puberty for example. The principal features distinguishing vascular malformations are: (i) the history of a lesion more or less fully developed at birth, (ii) the lack of any tendency to spontaneous resolution, and (iii) the frequent presenceintheareaofthelesionofotherelementssuchasportwinestainingorsuperficiallymphangioma. Congenital haemangiomas are clinically and pathologically distinct from infantile haemangiomas, and are characterised by being fully developed at birth. These tumours have been detected by ultrasound from the 12th week of gestation. The commonest type is the rapidly involuting congenital haemangioma (RICH) which has most often more or less fully involuted by the end of the first year [7]. These tumours are usually single and take the form of a blue or purple tumour or plaque. Involution is accompanied by marked skin atrophy. The rarer variant of congenital haemangioma is the non-involuting type (NICH). Both types are GLUT1-negative. Tufted angioma is a rare type of vascular tumour, which is seen most often in prepubertal children of either sex. Most cases have had an onset during infancy [8]. Histologically, there is a lobular proliferation of plump, oval cells surrounding tiny slit-like lumina. These blood vessels are tightly packed and organised in rounded tufts, scattered in the dermis, and often described as resembling cannon-balls. Thin-walled lymphatic channels may be seen at the periphery of the cellular masses or throughout the dermis.
Ulceration and haemorrhage: Ulceration is a frequent complication of superficial infantile haemangiomas, and occurs most often but not exclusively during the proliferative phase, and most frequently in the plaque type [10] (Fig. 3). Ulceration is commonest at sites which are vulnerable to trauma or maceration, particularly the anogenital area (Fig. 4), where it may result in dysuria or pain on defaecation. Other sites at which ulceration often occurs are the ears, nose and lips, where it may rapidly lead to
Figure 2 Gradually enlarging glomangioma on the back of a 10 year old girl.
792 permanent and potentially disfiguring tissue loss. Ulceration will almost certainly be followed by scarring. Infection. Secondary infection may occur in an ulcerated haemangioma, and may occasionally lead to septicaemia with a potentially disastrous outcome. Group A streptococci appear to be particularly dangerous in this situation. High-output cardiac failure. Shunting of large volumes of blood through a large infantile haemangioma may occasionally lead to high-output heart failure [11]. This is however more likely to occur in hepatic haemangiomas occurring in the context of miliary haemangiomatosis. Systemic haemangiomas. Visceral haemangiomas may occur with or without coexistent cutaneous infantile haemangiomas. They most often, but not exclusively occur in association with miliary haemangiomatosis. Impairment of vision. Infantile haemangiomas involving the eyelids and/or the orbit can interfere with vision in several ways (Fig. 5). Firstly, obstructive amblyopia may result if the lesion directly obscures the line of vision. 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. Secondly, lesions in the eyelid or orbit may 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. Eyelid lesions able to cause astigmatism may be only a few millimeters in diameter. The only clue to orbital involvement, other than an eyelid haemangioma, is proptosis. Eyelid haemangioma should prompt referral to an ophthalmologist familiar with these issues. Airway obstruction: This complication most characteristically results from subglottic haemangioma extending from a cutaneous lesion in the lower part of the face, or the neck [12]. Symptoms most characteristically first develop between weeks 6 and 12, with progressive stridor which is most marked during feeding or crying. Cough, hoarseness and cyanosis may also be present. Acute airway obstruction may occur suddenly during a period of rapid enlargement, or as a result of haemorrhage within the tumour, and it has been estimated that untreated subglottic haemangiomas are associated with a mortality approaching 50%. Any suspicion
Figure 3 Plaque type of infantile haemangioma on an infant's hand, with spontaneous ulceration.
D.J. Atherton
Figure 4 Ulcerated infantile haemangioma in the genital area, causing dysuria.
of subglottic haemangioma 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, although inability to breathe through the nose is likely to interfere with sucking and thereforewithnutrition. Interference with feeding: Feeding difficulties may complicate haemangiomas on the lips, particularly if ulcerated, and those that restrict nasal breathing. Obstruction of the external auditory canal: Infantile haemangiomas that encroach on the ear, particularly those in the parotid area, may obstruct the external auditory canal. Although this will interfere with hearing in the short term, it will generally not affect the development of normal ear function in the longer term. Spinal dysraphism and anogenital anomalies: Infantile haemangiomas in the lumbosacral area may be associated with underlying spinal dysraphism, tethered spinal cord, sacral anomalies, lipomeningocoele, imperforate anus, and genital and renal anomalies. Magnetic resonance imaging is indicated if there appears to be a risk of such an association, which appears to be highest when the haemangioma is of plaque type, when it crosses the midline and when there is an underlying swelling, which is likely to indicate an associated lipoma, the presence of which may be suggested by deviation of the upper end of the gluteal cleft. PHACES syndrome (Posterior fossa malformations, Haemangioma, Arterial anomalies, Coarctation of the aorta and cardiac anomalies, Eye abnormalities, Sternal defects): An association between posterior fossa brain abnormalities and large facial infantile haemangiomas is now well recognised and appears to be much more common in female infants [13] (Fig. 6). The facial haemangiomas most characteristically take the form of extensive plaques, which may initially be
Infantile haemangiomas
Figure 5 Upper eyelid infantile haemangioma, likely to cause astigmatism by pressure on the eyeball.
mistaken for port-wine stains. They may be either unilateral or bilateral. Ulceration is common. The commonest posterior fossa abnormality is the Dandy–Walker malformation, but a variety of other abnormalities have been recorded. These posterior fossa abnormalities may be reflected clinically by macrocephaly, enlarging head circumference, hemiparesis, developmental delay, or may be found on imaging in the absence of symptoms. The next most common extracutaneous manifestation is arterial anomalies of the head and neck, which are associated with a risk of aneurysms and cerebral infarction. Cardiac anomalies are also frequent, particularly coarctation of the aorta, pharyngeal or laryngeal haemangioma, a wide variety of eye abnormalities, including glaucoma, and ventral developmental defects, most characteristically sternal clefting or a supraumbilical raphe.
793 Treatment options include systemic or intralesional corticosteroids, surgical excision and intravenous vincristine. Cryotherapy is popular in some countries for smaller lesions. Tunable dye laser therapy may be valuable in accelerating healing in ulcerated lesions, but probably has little other value in the treatment of infantile haemangiomas. Recombinant interferon-α has been used in the past but is now generally avoided because of the high risk of neurological toxicity in infants. Systemiccorticosteroids: Systemic corticosteroids are the treatment of choice in most situations in which therapy is indicated. However, it is important to be aware that they are only effective during the proliferative phase. For this reason, there is some urgency in making the decision to start treatment. Oral corticosteroid therapy should therefore be initiated at the first sign that the patient is developing a significant eyelid lesion, cardiac failure or upper airway obstruction. Prednisolone should be given in a daily dose of 3–4 mg/kg body weight for 4–8 weeks, followed by gradual reduction of the dose over a period of several weeks. A good response can be anticipated in the great majority of cases if treatment is started sufficiently early at a dose no less than 3 mg/kg/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. Since such lesions can generally be expected to continue to proliferate during the first 6 months of life, it is usually unwise to discontinue therapy altogether until the seventh month. Infants tolerate this type of therapy remarkably well, and it is very unusual for adverse effects to occur that will not reverse within months of discontinuing therapy.
7. Treatment In the absence of complications or substantial aesthetic handicap, the most appropriate management of infantile haemangiomas is generally expectant. No treatment is indicated where a good aesthetic outcome can be predicted with reasonable confidence, and where complications appear unlikely to supervene. It is very important to be aware of the speed with which these lesions can enlarge during their initial phase of growth. The progress of lesions that 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 stabilized. Even small lesions may result in major aesthetic handicap at certain sites, such as the tip of the nose, the lip or the forehead, 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 aesthetic handicap is significant, immediate treatment should be contemplated.
Figure 6 PHACES syndrome: complex head and face haemangiomas associated with coarctation of the aorta.
794 Intralesional corticosteroids: Intralesional injection of corticosteroids may effect rapid shrinkage, and is a very popular treatment for lesions of the eyelids. In general, two or three treatments are required at approximately 6-week intervals. It is important to bear in mind that substantial quantities of corticosteroid are being injected and that significant adrenal suppression may occur. Local complications are unusual, but have included subcutaneous fat atrophy and eyelid necrosis, orbital fat atrophy, eyelid depigmentation and localised dystrophic calcification. Retrobulbar haemorrhage may occur, and there have been several reports of central retinal artery occlusion and blindness. This treatment has been used successfully to arrest proliferation and to shrink infantile haemangiomas at other sites. Vincristine and cyclophosphamide: Both vincristine and cyclophosphamide have been reported as being effective in treating life-threatening infantile haemangiomas. 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 (Fig. 7). Surgical excision is also indicated in certain situations earlier in the evolution of infantile haemangiomas. This approach is particularly suitable for those lesions that are fairly spherical, particularly where these are of mixed type as this allows closure to be straightforward. Surgical excision should be considered for eyelid lesions, where it may sometimes be preferable to other techniques, similarly for disfiguring but small facial lesions, such as those that occur on the forehead. A particular situation where surgery can be very successful is the nasal tip haemangioma, which can lead to significant cosmetic handicap, and which is notoriously reluctant to resolve spontaneously. Extensive and complicated infantile haemangiomas affecting the head and neck may warrant surgical treatment in selected cases, and may be most appropriately treated by combining different treatment approaches.
D.J. Atherton
Figure 8
Miliary haemangiomatosis.
Reconstructive surgery is indicated where tissue destruction has occurred during the proliferative phase of infantile haemangiomas. This is most commonly appropriate in relation to the face, when ulceration has led to the loss of parts of the nose, lips or ears.
8. Miliary haemangiomatosis of infancy
Figure 7 Residual sac in an 8-year old, following resolution of an infantile haemangioma.
Occasionally, infants are born with very large numbers, generally many hundreds of small infantile haemangiomas of dstrawberryT type, or develop these within the first few weeks of life. In such cases, the cutaneous lesions are characteristically relatively small, generally between 2 mm and 2 cm in diameter (Fig. 8). This condition, which is perhaps best termed miliary haemangiomatosis of infancy, should not be confused by the relatively common situation in which a child develops a number of otherwise standard infantile haemangiomas. In these cases, appropriately termed multiple infantile haemangiomas, the number of lesions present will rarely number more than 10, in great contrast to miliary haemangiomatosis of infancy, in which lesions will generally number several hundreds, often thousands. Major complications may supervene, generally due to the presence of associated systemic haemangiomas, and these are responsible for a significant mortality. The most serious of all complications is high-output cardiac failure, which is
Infantile haemangiomas almost invariably due to shunting through one or more large hepatic haemangiomas, and which may be present at birth. Apart from the liver, haemangiomas are also commonly present in the gastrointestinal tract, spleen, pancreas, salivary glands, adrenals, larynx, lungs, heart, skeletal muscle, kidneys, bladder, testes, thymus, thyroid, bone, meninges, brain and eyes. Potentially lethal complications include convulsions, intestinal haemorrhage and obstructive liver disease. Certain investigations are therefore more or less mandatory in any infant with miliary haemangiomatosis, 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 to identify lung lesions that might cause arteriovenous shunting, echocardiography to establish output status, and an abdominal ultrasound examination to examine the liver. The small haemangiomas that characterize miliary haemangiomatosis of infancy involute spontaneously and typically do so more rapidly than standard infantile haemangiomas. The skin lesions often have more or less disappeared by the age of 12 months. Management is essentially as for single or multiple infantile haemangiomas. Treatment is not always indicated, and the need for intervention should be guided by careful evaluation of the risk of serious complications. It appears probable that prompt initiation of pharmacological treatment can reduce the risk of development of high-output cardiac failure where this is not yet established, and can be valuable when it is. Where such complications are already present, systemic corticosteroid therapy is urgently indicated and the authors would recommend oral prednisolone in a dose of 3–5 mg/kg/day, preceded, when appropriate, by pulsed intravenous methylprednisolone. Where high-output failure is established and fails to respond to pharmacological therapy, selective arterial embolization of the responsible high-flow lesions in the liver will need to be considered urgently.
795
References [1] Burton BK, Schulz CJ, Angle B, Burd LI. An increased incidence of haemangiomas in infants born following chorionic villous sampling. Prenat Diagn 1995;15:209-14. [2] North PE, Waner M, Brodsky MC. Are infantile hemangiomas of placental origin? Ophthalmology 2002;109:633-4. [3] Gonzales-Crussi F, Reyes-Mugica M. Cellular hemangiomas (dhemangio-endotheliomasT) in infants: light microscopic, immunochemical and ultrastructural observations. Am J Surg Pathol 1991;15:769-78. [4] Esterly NB. Hemangiomas in infants and children: clinical observations. Pediatr Dermatol 1992;9:353-5. [5] Esterly NB. Cutaneous hemangiomas, vascular stains and malformations and associated syndromes. Curr Probl Dermatol 1995;7:65-108. [6] Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relation to race, ethnicity and gender. Arch Dermatol 2002;138:1567-76. [7] Boon LM, Enroljas O, Mulliken JB. Congenital hemangioma: evidence of accelerated involution. J Pediatr 1996;128:329-35. [8] Herron MD, Coffin CM, Vanderhooft SL. Tufted angiomas: variability of the clinical morphology. Pediatr Dermatol 2002;19: 394-401. [9] Enroljas O, Mulliken JB, Wassef M, Frieden PM, Rieu PN, Burrows PE, et al. Residual lesions after Kasabach–Merritt phenomenon in 41 patients. J Am Acad Dermatol 2000;42: 225-35. [10] Kim HJ, Colombo M, Frieden IJ. Ulcerated hemangiomas: clinical characteristics and response to therapy. J Am Acad Dermatol 2001;44:962-72. [11] Enroljas O, Riche MC, Merland JJ, Escande JP. Management of alarming hemangiomas in infancy: a review of 25 cases. Pediatrics 1990;85:491-8. [12] Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic haemangiomas of the airway in association with cutaneous haemangiomas in a dbeardT distribution. J Pediatr 1997;131: 643-6. [13] Metry DW, Dowd CF, Barkovich AJ, Frieden IJ, et al. The many faces of PHACE syndrome. J Pediatr 2001;139:117-23.
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Infantile haemangiomas David J. Atherton ⁎ Paediatric Dermatology, Great Ormond Street Hospital for Children, London WC1N 3JH, United Kingdom
KEYWORDS Haemangioma; Endothelium; Tumour; Angiogenesis
Abstract Infantile haemangiomas are the commonest tumours occurring in infants, but regress spontaneously without causing major problems in the great majority of cases. However, in some infants they can cause life-threatening complications. Fortunately, if the decision to treat is made promptly, and the most appropriate form of treatment selected, these complications can usually be prevented. © 2006 Published by Elsevier Ireland Ltd.
1. Definition Infantile haemangioma is the favoured term for a benign type of capillary haemangioma which appears in early infancy, having a characteristic initial proliferative phase followed by a later involutional phase.
2. Aetiology Infantile haemangiomas are neoplastic proliferations of endothelial cells, which occur sporadically in the vast majority of cases. There is evidence that infantile haemangiomas occur with greater frequency following chorionic villous sampling; one study reported a 21% incidence, and in a third of the cases, the haemangiomas were multiple [1]. It would be anticipated that placental injury would lead to increased detachment of placental cells into the blood. Infantile haemangiomas might therefore result from embolisation of fetal placental endothelial cells via the right-to-left shunts characteristic of the fetal circulation. This hypothesis is supported by the finding that infantile haemangiomas share reactivity for GLUT1, an immunohistochemical marker also present in placental endothelium. Infantile haemangiomas, however,
⁎ Tel.: +44 2074059200; fax: +44 2078138274. E-mail address: [email protected].
do not express placental trophoblastic markers. Whatever the origin of the cells comprising these tumours, their rapid proliferation in the postnatal period may reflect loss of angiogenic inhibitors of placental and maternal origin [2].
3. Pathology [3] In the earliest phase of growth of infantile haemangiomas, there is a solid mass of proliferating endothelial cells and pericytes, with few if any lumina. Later in the proliferative phase, capillary-sized lumina are apparent, lined by plump endothelial cells. Initially, these lumina are slit-like, but gradually they become more dilated. Mast cells are plentiful during the proliferative phase. As involution proceeds, the haemangioma becomes progressively more organized, with distinct lobules separated by fibrous septa containing the larger feeding and draining vessels. The number of vascular channels progressively decreases, and the diameter of the lumina increases with flattening of the endothelial lining, resulting in a dcavernousT appearance, which must not be confused with the appearance of a venous malformation. There is a simultaneous progressive increase in intra- and interlobular connective tissue and fat. The endothelial cells comprising infantile haemangiomas show intense and persistent immunoreactivity for a number of tissue-specific markers termed FcãRII, Lewis Y antigen (LEY), merosin and GLUT1. This group of markers is highly characteristic of placental microvasculature. Positivity for
0378-3782/$ - see front matter © 2006 Published by Elsevier Ireland Ltd. doi:10.1016/j.earlhumdev.2006.09.011
790 GLUT1 can be very valuable in distinguishing infantile haemangiomas from other vascular tumours.
4. Clinical features [4] Infantile haemangiomas are the commonest tumours of infancy, with a prevalence of about 1–3% after the first few days of life, and up to 12% by the end of the first year. The prevalence of infantile haemangiomas at 1 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. There is an independent inverse relationship to birth weight in preterm infants. Thus, at 1 year, the prevalence in preterm babies with a birth weight below 1500 g is about 16%, and, in preterm babies with a birth weight below 1000 g, about 23%. Infantile haemangiomas become apparent during the first month of life in about 90% of cases, and virtually 100% by the 9th month. Approximately 60% of infantile haemangiomas are superficial, 15% deep and 25% mixed superficial and deep. The term ddeepT is preferable to dsubcutaneousT as most of those infantile haemangiomas that are covered with normal epidermis are situated largely in the dermis rather than in the subcutis, although they may extend to this depth. In the case of superficial lesions, an initial dprecursorT lesion is very frequently visible on the first day of life. These premonitory lesions may be quite subtle, and most characteristically take the form either of a macular area of hyperaemia resembling a bruise or a pale port-wine stain, or a macular area of pallor [5]. 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 develops within the area, rapidly enlarging and coalescing until the lesion is mature. However, apparently typical precursor lesions occasionally fail to progress into infantile haemangiomas. The superficial infantile haemangioma is most commonly known as a dstrawberryT naevus, 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. A plaque type is a distinctive but important variant of superficial haemangioma; this type has sometimes been termed dsegmentalT. The importance of this type of infantile haemangioma is a high risk of ulceration and a stronger association with developmental structural anomalies [6]. Infantile haemangiomas 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 in the remaining 20%, lesions are multiple; occasionally, very large numbers may occur (see miliary haemangiomatosis of infancy). Infantile haemangiomas increase in size over a period that varies from about 3–18 months. However, the great majority will have reached their maximum size within 12 months of their first appearance, and most within
D.J. Atherton 6 months. The final diameter may vary from less than 1 cm to 25 cm or more. There is frequently a deep element to superficial infantile haemangiomas of strawberry type, particularly when these are large; such lesions should be termed dmixedT infantile haemangiomas. In other cases, the infantile haemangiomas are entirely, or more or less entirely deep. Exclusively deep infantile haemangiomas take the form of soft, warm, round bluish masses beneath normal skin, although there may be a few branching telangiectases or an area of vascular staining on the surface. Deep infantile haemangiomas often feel like a dbag of wormsT, 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. Large superficial veins may be present in the skin at the periphery of larger infantile haemangiomas. Virtually all infantile haemangiomas undergo spontaneous regression, which is complete or almost complete in the great majority. Although there is considerable variation in the rate of involution of individual lesions, there is no evidence to suggest that deep lesions involute more slowly than superficial ones. Age at first appearance does not appear to affect materially the likely speed of resolution, but smaller lesions probably resolve more rapidly. 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. There is very little evidence to support the widely expressed theory that ulceration accelerates the initiation of resolution. Resolution of superficial infantile haemangiomas is heralded by the appearance of focal areas of greyish opacification in the central part 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 commonly it shows subtle atrophy and telangiectasia. With larger superficial lesions and at certain sites, particularly the lips, eyelids, and upper chest a residual sac of redundant and atrophic skin commonly remains. 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. Infantile haemangiomas at certain sites appear particularly to regress particularly slowly and generally incompletely. This is certainly true of lesions on the nose (sometimes termed the dCyranoT or dPinocchioT nose), the lips and the parotid area.
5. Diagnosis There is rarely any difficulty making the diagnosis of infantile haemangioma,particularlyinthecaseofthesuperficialtype. The main problem is to distinguish vascular malformations from deep haemangiomas of infancy. The literature contains many reports in which lesions called dhaemangiomaT, often dcavernousThaemangioma,clearlyrelatetovascularmalformations;thesereportsarefrequentlyconcernedwiththefailureof such lesions to resolve spontaneously, or the fact that they may
Infantile haemangiomas
Figure 1 Tufted angioma on the back of an infant, associated with consumption coagulopathy.
791 Clinically, these tumours take the form of a poorly delineated, pinkish macule that evolves into a deep-red or purplish, indurated plaque or nodule, up to 20 cm in diameter (Fig. 1). The lesion may be a fully developed plaque or mass at birth. Most lesions are tender. The lesion may extend deeply through the subcutis, fascia and into muscle. It is now clear that this tumour and kaposiform haemangio-endothelioma (see below) are together responsible for the great majority of cases of the Kasabach–Merritt phenomenon [9]. Most tufted angiomas expand slowly for a period of months or years, after which they stabilise. Although they probably mostly remain unchanged unless treated, on occasions they may slowly resolve spontaneously. Kaposiform haemangioendothelioma is a rare vascular tumour occurring exclusively in childhood. Most cases present in infancy, though later onset has been reported. Though many of these tumours arise in the retroperitoneum, they may also arise in the skin, often in the subcutis. They are often the cause of the Kasabach–Merritt phenomenon. Histologically, kaposiform haemangioendothelioma is composed of lobules or sheets of tightly packed spindled or more rounded endothelial cells and pericytes, with an infiltrative pattern in the dermis, subcutaneous fat and muscles. They contain few vascular lumina. It is possible that tufted angioma and kaposiform haemangioendothelioma are the polar forms of a single pathological entity, and histological overlap has been observed. Glomangiomatosis. Glomangiomas may be mistaken for infantile haemangiomas, particularly in the disseminated form. In this condition multiple plaques of purplish nodules may continue to develop throughout life (Fig. 2).
6. Complications enlarge, at puberty for example. The principal features distinguishing vascular malformations are: (i) the history of a lesion more or less fully developed at birth, (ii) the lack of any tendency to spontaneous resolution, and (iii) the frequent presenceintheareaofthelesionofotherelementssuchasportwinestainingorsuperficiallymphangioma. Congenital haemangiomas are clinically and pathologically distinct from infantile haemangiomas, and are characterised by being fully developed at birth. These tumours have been detected by ultrasound from the 12th week of gestation. The commonest type is the rapidly involuting congenital haemangioma (RICH) which has most often more or less fully involuted by the end of the first year [7]. These tumours are usually single and take the form of a blue or purple tumour or plaque. Involution is accompanied by marked skin atrophy. The rarer variant of congenital haemangioma is the non-involuting type (NICH). Both types are GLUT1-negative. Tufted angioma is a rare type of vascular tumour, which is seen most often in prepubertal children of either sex. Most cases have had an onset during infancy [8]. Histologically, there is a lobular proliferation of plump, oval cells surrounding tiny slit-like lumina. These blood vessels are tightly packed and organised in rounded tufts, scattered in the dermis, and often described as resembling cannon-balls. Thin-walled lymphatic channels may be seen at the periphery of the cellular masses or throughout the dermis.
Ulceration and haemorrhage: Ulceration is a frequent complication of superficial infantile haemangiomas, and occurs most often but not exclusively during the proliferative phase, and most frequently in the plaque type [10] (Fig. 3). Ulceration is commonest at sites which are vulnerable to trauma or maceration, particularly the anogenital area (Fig. 4), where it may result in dysuria or pain on defaecation. Other sites at which ulceration often occurs are the ears, nose and lips, where it may rapidly lead to
Figure 2 Gradually enlarging glomangioma on the back of a 10 year old girl.
792 permanent and potentially disfiguring tissue loss. Ulceration will almost certainly be followed by scarring. Infection. Secondary infection may occur in an ulcerated haemangioma, and may occasionally lead to septicaemia with a potentially disastrous outcome. Group A streptococci appear to be particularly dangerous in this situation. High-output cardiac failure. Shunting of large volumes of blood through a large infantile haemangioma may occasionally lead to high-output heart failure [11]. This is however more likely to occur in hepatic haemangiomas occurring in the context of miliary haemangiomatosis. Systemic haemangiomas. Visceral haemangiomas may occur with or without coexistent cutaneous infantile haemangiomas. They most often, but not exclusively occur in association with miliary haemangiomatosis. Impairment of vision. Infantile haemangiomas involving the eyelids and/or the orbit can interfere with vision in several ways (Fig. 5). Firstly, obstructive amblyopia may result if the lesion directly obscures the line of vision. 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. Secondly, lesions in the eyelid or orbit may 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. Eyelid lesions able to cause astigmatism may be only a few millimeters in diameter. The only clue to orbital involvement, other than an eyelid haemangioma, is proptosis. Eyelid haemangioma should prompt referral to an ophthalmologist familiar with these issues. Airway obstruction: This complication most characteristically results from subglottic haemangioma extending from a cutaneous lesion in the lower part of the face, or the neck [12]. Symptoms most characteristically first develop between weeks 6 and 12, with progressive stridor which is most marked during feeding or crying. Cough, hoarseness and cyanosis may also be present. Acute airway obstruction may occur suddenly during a period of rapid enlargement, or as a result of haemorrhage within the tumour, and it has been estimated that untreated subglottic haemangiomas are associated with a mortality approaching 50%. Any suspicion
Figure 3 Plaque type of infantile haemangioma on an infant's hand, with spontaneous ulceration.
D.J. Atherton
Figure 4 Ulcerated infantile haemangioma in the genital area, causing dysuria.
of subglottic haemangioma 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, although inability to breathe through the nose is likely to interfere with sucking and thereforewithnutrition. Interference with feeding: Feeding difficulties may complicate haemangiomas on the lips, particularly if ulcerated, and those that restrict nasal breathing. Obstruction of the external auditory canal: Infantile haemangiomas that encroach on the ear, particularly those in the parotid area, may obstruct the external auditory canal. Although this will interfere with hearing in the short term, it will generally not affect the development of normal ear function in the longer term. Spinal dysraphism and anogenital anomalies: Infantile haemangiomas in the lumbosacral area may be associated with underlying spinal dysraphism, tethered spinal cord, sacral anomalies, lipomeningocoele, imperforate anus, and genital and renal anomalies. Magnetic resonance imaging is indicated if there appears to be a risk of such an association, which appears to be highest when the haemangioma is of plaque type, when it crosses the midline and when there is an underlying swelling, which is likely to indicate an associated lipoma, the presence of which may be suggested by deviation of the upper end of the gluteal cleft. PHACES syndrome (Posterior fossa malformations, Haemangioma, Arterial anomalies, Coarctation of the aorta and cardiac anomalies, Eye abnormalities, Sternal defects): An association between posterior fossa brain abnormalities and large facial infantile haemangiomas is now well recognised and appears to be much more common in female infants [13] (Fig. 6). The facial haemangiomas most characteristically take the form of extensive plaques, which may initially be
Infantile haemangiomas
Figure 5 Upper eyelid infantile haemangioma, likely to cause astigmatism by pressure on the eyeball.
mistaken for port-wine stains. They may be either unilateral or bilateral. Ulceration is common. The commonest posterior fossa abnormality is the Dandy–Walker malformation, but a variety of other abnormalities have been recorded. These posterior fossa abnormalities may be reflected clinically by macrocephaly, enlarging head circumference, hemiparesis, developmental delay, or may be found on imaging in the absence of symptoms. The next most common extracutaneous manifestation is arterial anomalies of the head and neck, which are associated with a risk of aneurysms and cerebral infarction. Cardiac anomalies are also frequent, particularly coarctation of the aorta, pharyngeal or laryngeal haemangioma, a wide variety of eye abnormalities, including glaucoma, and ventral developmental defects, most characteristically sternal clefting or a supraumbilical raphe.
793 Treatment options include systemic or intralesional corticosteroids, surgical excision and intravenous vincristine. Cryotherapy is popular in some countries for smaller lesions. Tunable dye laser therapy may be valuable in accelerating healing in ulcerated lesions, but probably has little other value in the treatment of infantile haemangiomas. Recombinant interferon-α has been used in the past but is now generally avoided because of the high risk of neurological toxicity in infants. Systemiccorticosteroids: Systemic corticosteroids are the treatment of choice in most situations in which therapy is indicated. However, it is important to be aware that they are only effective during the proliferative phase. For this reason, there is some urgency in making the decision to start treatment. Oral corticosteroid therapy should therefore be initiated at the first sign that the patient is developing a significant eyelid lesion, cardiac failure or upper airway obstruction. Prednisolone should be given in a daily dose of 3–4 mg/kg body weight for 4–8 weeks, followed by gradual reduction of the dose over a period of several weeks. A good response can be anticipated in the great majority of cases if treatment is started sufficiently early at a dose no less than 3 mg/kg/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. Since such lesions can generally be expected to continue to proliferate during the first 6 months of life, it is usually unwise to discontinue therapy altogether until the seventh month. Infants tolerate this type of therapy remarkably well, and it is very unusual for adverse effects to occur that will not reverse within months of discontinuing therapy.
7. Treatment In the absence of complications or substantial aesthetic handicap, the most appropriate management of infantile haemangiomas is generally expectant. No treatment is indicated where a good aesthetic outcome can be predicted with reasonable confidence, and where complications appear unlikely to supervene. It is very important to be aware of the speed with which these lesions can enlarge during their initial phase of growth. The progress of lesions that 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 stabilized. Even small lesions may result in major aesthetic handicap at certain sites, such as the tip of the nose, the lip or the forehead, 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 aesthetic handicap is significant, immediate treatment should be contemplated.
Figure 6 PHACES syndrome: complex head and face haemangiomas associated with coarctation of the aorta.
794 Intralesional corticosteroids: Intralesional injection of corticosteroids may effect rapid shrinkage, and is a very popular treatment for lesions of the eyelids. In general, two or three treatments are required at approximately 6-week intervals. It is important to bear in mind that substantial quantities of corticosteroid are being injected and that significant adrenal suppression may occur. Local complications are unusual, but have included subcutaneous fat atrophy and eyelid necrosis, orbital fat atrophy, eyelid depigmentation and localised dystrophic calcification. Retrobulbar haemorrhage may occur, and there have been several reports of central retinal artery occlusion and blindness. This treatment has been used successfully to arrest proliferation and to shrink infantile haemangiomas at other sites. Vincristine and cyclophosphamide: Both vincristine and cyclophosphamide have been reported as being effective in treating life-threatening infantile haemangiomas. 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 (Fig. 7). Surgical excision is also indicated in certain situations earlier in the evolution of infantile haemangiomas. This approach is particularly suitable for those lesions that are fairly spherical, particularly where these are of mixed type as this allows closure to be straightforward. Surgical excision should be considered for eyelid lesions, where it may sometimes be preferable to other techniques, similarly for disfiguring but small facial lesions, such as those that occur on the forehead. A particular situation where surgery can be very successful is the nasal tip haemangioma, which can lead to significant cosmetic handicap, and which is notoriously reluctant to resolve spontaneously. Extensive and complicated infantile haemangiomas affecting the head and neck may warrant surgical treatment in selected cases, and may be most appropriately treated by combining different treatment approaches.
D.J. Atherton
Figure 8
Miliary haemangiomatosis.
Reconstructive surgery is indicated where tissue destruction has occurred during the proliferative phase of infantile haemangiomas. This is most commonly appropriate in relation to the face, when ulceration has led to the loss of parts of the nose, lips or ears.
8. Miliary haemangiomatosis of infancy
Figure 7 Residual sac in an 8-year old, following resolution of an infantile haemangioma.
Occasionally, infants are born with very large numbers, generally many hundreds of small infantile haemangiomas of dstrawberryT type, or develop these within the first few weeks of life. In such cases, the cutaneous lesions are characteristically relatively small, generally between 2 mm and 2 cm in diameter (Fig. 8). This condition, which is perhaps best termed miliary haemangiomatosis of infancy, should not be confused by the relatively common situation in which a child develops a number of otherwise standard infantile haemangiomas. In these cases, appropriately termed multiple infantile haemangiomas, the number of lesions present will rarely number more than 10, in great contrast to miliary haemangiomatosis of infancy, in which lesions will generally number several hundreds, often thousands. Major complications may supervene, generally due to the presence of associated systemic haemangiomas, and these are responsible for a significant mortality. The most serious of all complications is high-output cardiac failure, which is
Infantile haemangiomas almost invariably due to shunting through one or more large hepatic haemangiomas, and which may be present at birth. Apart from the liver, haemangiomas are also commonly present in the gastrointestinal tract, spleen, pancreas, salivary glands, adrenals, larynx, lungs, heart, skeletal muscle, kidneys, bladder, testes, thymus, thyroid, bone, meninges, brain and eyes. Potentially lethal complications include convulsions, intestinal haemorrhage and obstructive liver disease. Certain investigations are therefore more or less mandatory in any infant with miliary haemangiomatosis, 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 to identify lung lesions that might cause arteriovenous shunting, echocardiography to establish output status, and an abdominal ultrasound examination to examine the liver. The small haemangiomas that characterize miliary haemangiomatosis of infancy involute spontaneously and typically do so more rapidly than standard infantile haemangiomas. The skin lesions often have more or less disappeared by the age of 12 months. Management is essentially as for single or multiple infantile haemangiomas. Treatment is not always indicated, and the need for intervention should be guided by careful evaluation of the risk of serious complications. It appears probable that prompt initiation of pharmacological treatment can reduce the risk of development of high-output cardiac failure where this is not yet established, and can be valuable when it is. Where such complications are already present, systemic corticosteroid therapy is urgently indicated and the authors would recommend oral prednisolone in a dose of 3–5 mg/kg/day, preceded, when appropriate, by pulsed intravenous methylprednisolone. Where high-output failure is established and fails to respond to pharmacological therapy, selective arterial embolization of the responsible high-flow lesions in the liver will need to be considered urgently.
795
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