Hemangioma of infancy

Abstracts

As novas classificações disponíveis e os modernos recursos diagnósticos por imagem não só permitiram a diferenciação entre os tumores e as malformações vasculares, mas também modificaram de forma substancial a abordagem e o tratamento dessas anomalias. O hemangioma da infância, o mais comum dos tumores vasculares dessa faixa etária e objeto deste trabalho, é revisto do ponto de vista de suas características clínicas e laboratoriais, diagnóstico diferencial e opções terapêuticas. Embora a conduta expectante permaneça como o tratamento de escolha para a maioria dos casos, o julgamento crítico é crucial para o emprego de outras modalidades terapêuticas.

hemangioma; hemangioma capilar; literatura de revisão

CONTINUING MEDICAL EDUCATION

Hemangioma of infancy^*

Bernardo Gontijo^I; Cláudia Márcia Resende Silva^II; Luciana Baptista Pereira^III

^IAdjunct Professor- Ph.D. in Dermatology, Faculty of Medicine, Federal University of Minas Gerais (UFMG); Coordinator of the Pediatric Dermatology Outpatient Clinic, Dermatology Service, Hospital das Clínicas, Faculty of Medicine, UFMG

^IIMasters in Dermatology, UFMG. M.D. at the Pediatric Dermatology Outpatient Clinic, Dermatology Service, Hospital das Clínicas, Faculty of Medicine, UFMG

^IIIAssistant Professor of Dermatology, Faculty of Medicine, UFMG. Masters in Dermatology, UFMG. Member of teaching staff at the Pediatric Dermatology Outpatient Clinic, Dermatology Service, Hospital das Clínicas, Faculty of Medicine, UFMG

Correspondence

SUMMARY

New classifications and availability of modern radiologic diagnostic tools have not only allowed a precise distinction between vascular tumors and vascular malformations but have also significantly modified management and treatment of these vascular anomalies. Hemangioma of infancy, the most common vascular tumor of this age and subject of this review, is approached from its clinical and laboratory features, differential diagnosis and therapeutic options. Although non-intervention remains the treatment of choice for the majority of cases, critical judgement is mandatory to decide whether other therapeutic modalities should be used.

Key words: hemangioma; hemangioma, capillary; review literature.

INTRODUCTION

For many centuries congenital vascular lesions were denominated nevus maternus, reflecting a popular belief that mothers were responsible for their children's lesions. It was believed that emotions and maternal desires could print a mark on the newly born, and, depending on the culture of each region, the mothers were blamed for ingesting or not ingesting certain red fruits or other food types during the pregnancy, hence the terms describing the lesions as strawberry, raspberry, port wine and salmon.¹

Virchow, in 1863, classified the vascular anomalies for the first time, on the basis of their microscopic aspect, into simple, cavernous and racemosum angioma.² He considered that each one of these types could change into another by cellular proliferation or dilation of blood vessels. In 1877, Wegener, a student of Virchow, on the basis of these studies, proposed a similar classification for the lymphatic alterations that was used until the end of the 20th Century: lymphangioma simplex, cavernosum and cysticum. It attributed the genesis of these lesions to lymphatic inflammation and dilation, and to endothelial malformation or proliferation.³

The term hemangioma was used for many years, in a wide and indiscriminate manner, to designate vascular anomalies that were totally different in terms of their genesis, clinical and histopathological characteristics, clinical course and prognostic. Hence, capillary or strawberry hemangioma were the expressions used to designate what is now known as the superficial form of hemangioma of childhood: a tumor, in the meaning of the word, caused by the multiplication of endothelial cells, that may or may not be present at birth, with consecutive phases of growth, stoppage and regression. They are usually of little clinical significance and in the majority of cases the consequences are only cosmetic. At the same time, hemangioma planum was the denomination that today is classified as port wine stain: a vascular malformation, almost always present at birth, with growth proportional to the child's development and with a permanent character that can be associated to several syndromes. Furthermore, adjectives such as cavernous, a histological descriptive term that should be reserved for this finality, referred to clinical characteristics such as the blue coloration suggestive of deep lesions.¹ in this way, lesions that are radically different, as in the case of the deep form of hemangioma of childhood (with spontaneous regression) and the subcutaneous vascular malformations (that are permanent), each presenting no more than a bluish coloration in common, were characterized equally as cavernous. The confusing nomenclature and absence of an appropriate classification were the main cause of the diagnostic and therapeutic difficulties surrounding vascular anomalies.

In 1982, Mulliken and Glowacki proposed a new classification for the vascular lesions based on the clinical manifestations, histopathological picture and natural history (Chart 1), distinguishing them into hemangiomas and vascular malformations.^4,5

The hemangioma of childhood is the most common vascular tumor in this age group. However, other vascular tumors, albeit rarer, have been described. Beacause of this, the classification by Mulliken and Glowacki was reviewed in 1996, and the new classification was adopted as official by the International Society for the Study of Vascular Anomalies - ISSVA. It divides the vascular lesions into two groups: tumors and vascular malformations.6 The vascular tumors are neoplasias of the vasculature (cellular proliferation) and include hemangioma of childhood, rapidly involuting congenital hemangioma, non-involuting congenital hemangioma, tufted angioma, kaposiform hemangioendothelioma and pyogenic granuloma. The vascular malformations consist of errors in the morphogenesis and are classified according to the predominant vein (Chart 2).^6,7,8 As in all classifications, it is not absolute. However, its simplicity and clinical relevance enabled an important advance in the management of vascular anomalies.

This EMC-D (Continuing Medical Education - Dermatology) article specifically approaches hemangioma of childhood. The other vascular tumors will be commented on in summarized form in the differential diagnosis, and the vascular malformations will be the subject of the next chapter of EMC-D in this Journal.

HEMANGIOMA OF CHILDHOOD

This is the most common tumor of childhood, occurring in 10 to 12% of children with one year of age and involving up to 30% of those with very low birth weight (less than 1,000 g).⁹ The risk of hemangioma is 10 times higher in children whose mothers were submitted to biopsy of the chorionic villi during pregnancy,¹⁰ and there is a clear feminine bias with a ratio that varies from 3:1 to 7:1.^11,12 About 80% of the patients present single lesions and the presence of four or more lesions is rare. The skin is the organ most commonly involved, and particularly in areas of the head and neck (60%), and the trunk (25%).^12,13,14 The size can vary from a few millimeters to several centimeters.

CLINICAL PICTURE

The clinical presentation varies according to the size of the lesion, location, depth and stage of clinical course. In general absent at birth, hemangioma of the childhood becomes apparent within the first days of life. An initial lesion, known as a precursory lesion (Figure 1), is present in a percentage that varies from 30 to 50% of the cases at birth and can present clinically in the form of an anemic stain, erythematous and/or ecchymotic patch, a small group of bright-red papules or even telangiectasia that may or may not be surrounded by an anemic halo.¹⁵ The growth is fast, and over 90% of the hemangiomas are very evident by the end of the first month of life.^1,15,16,17 More profound hemangiomas (subcutaneous) become apparent later, generally several months after birth.^8,12,13 In rare situations, the hemangioma presents at birth as an ulcerated lesion whose angiomatous component appears later or as a partially developed tumoral lesion and that also presents fast post-natal growth.^16,18,19,20

They can be divided into superficial, profound or combined according to their clinical appearance.^21,22 The superficial form (50-60% of the cases)^15,23 have well-defined borders, with a bright red color and nodular or in plaques, with normal surrounding skin, often with an aspect similar to a strawberry (Figure 2). They are usually restricted to the papillary and reticular dermis, on palpation they have a firm, only slightly compressible mass that can present a localized increase in temperature. With regression of the lesion, the red color becomes lighter, from the center to the edges and acquires a grayish-blue tone.^9,24 They can sometimes have a macular appearance, with slightly raised skin, that can be mistaken by capillary malformation. The deep hemangiomas (15% of cases),^15,23 previously denominated cavernous, are nodular lesions, either presenting the skin color or of a bluish tone, sometimes with telangiectasia in the surface, it is occasionally possible to observe drainage veins in the periphery. They involve the lower dermis and subcutaneous tissue.^8,25 Mixed or combined lesions (Figure 3) account for the remaining 25 to 35% of cases.^15,23

The rapid phase of growth usually lasts from six to 10 months of life. It can be a little more prolonged in the deep hemangioma, however it rarely exceeds two years of age.²⁶ In general the maximum size is reached by the end of the first year of life, although a few cases present in a fray form, with very discreet growth, and remain almost indistinguishable from the precursory lesion.⁸ Later the hemangioma enters a quiescent phase that persists for several months, followed by a slow involution. It is considered that 50% of the lesions regress either totally or partially by up to five years of age and 90% by 10 years of age.^13,23 Involution and proliferation can be observed simultaneously in different parts of the same lesion or in different hemangiomas of a child with multiple lesions.⁹ The regression is considered esthetically acceptable - with discreet alterations of the skin - in more than 50% of the cases. Residual lesions observed include telangiectasia, atrophy, redundant skin, retraction of the skin and hypopigmentation, among others.^{1,8,9,12,13,16} The complete resolution of the hemangioma is not influenced by size of the lesion, ulceration, depth, the child's sex or age at onset, but appears to be related to an early beginning of the involution process.^9,15

ETIOPATHOGENESIS

Although the physiopathogenesis is not well understood, it is now considered that the hemangiomas are the result of an imbalance in the angiogenesis that allows an uncontrolled proliferation of vascular elements.^1,8,27,28 During the proliferative phase of the tumor, several markers of angiogenesis are increased, such as the basic fibroblast growth factor (bFGF), vascular endothelium growth factor (VEGF), metalloproteinase, proliferating cell nuclear antigen (PCNA), collagenase type IV, urokinase, proteases and E-selectin. These factors decrease when there is involution of the tumor, except for bFGF that remains high in the beginning of the regression, but eventually reaches normal levels when the hemangioma completes its involution. The urinary level of bFGF can be used as a parameter for the effectiveness of the treatment of hemangiomas. Factors bFGF and VEGF have an important role in the differentiation of the endothelial cells in the phase of rapid proliferation of the tumor. These differentiated endothelial cells, in turn, besides attracting a great number of mastocytes, express the tissular inhibitor of metalloproteinase type 1 (TIMP-1), a potent blocker of the formation of new blood vessels. It has been speculated that mastocytes possibility secrete substances such as interferon, that reduce the angiogenesis and also promote the involution. Other markers of the involution phase of hemangiomas are angiostatin, endostatin, platelet factor 4, interleukin-12, interferon -a and glycocorticoid.^8,29-33

An anomaly in the fetal development in the first three months of pregnancy or a genetic alteration are just two of the theories proposed to explain this imbalance in the angiogenesis.^27,28

The hypothesis of a genetic alteration is based on the existence of affected siblings and in reports of a higher incidence of hemangiomas in certain family groups. The possibility of an autosomal dominant inheritance is speculated in the transmission of these tumors.^8,24,27,28

HISTOPATHOLOGY

The biopsies of superficial and deep lesions present similar histopathological pictures. In the growth phase of the hemangioma, aggregations of endothelial proliferative cells are observed constituting solid strings and masses, sometimes with a lumen formation. These cells tend to group together forming delicate lobules separated by fine bands of connective tissue. None of the lobules are encapsulated or fibrotic, and many contain normal tissue and an alimentary artery. The thrombosis and hemosiderin deposits are rare and limited to areas of ulceration or acute inflammation. Pericytes, fibroblasts and especially mastocytes are numerous in the late phase of the proliferation. In the involution phase the endothelial cells become flattened and there is a formation of progressively prominent and ectatic channels, leading to the formation of major veins with thin walls. The islands of fatty and fibrous tissue gradually substitute the tumoral cells.^1,15,34,35

The immunohistochemistry is positive for CD31 antigen, Von Willebrand factor and urokinase, confirming its vascular origin.^8,32,33 The antigen erythrocyte-type glucose transporter protein (GLUT1), a glucose transporter usually expressed in the endothelium of the microvasculature of the brain, retina, placenta and endoneurium, but not in the normal skin, was described recently as a specific marker of hemangioma of childhood, being present in all of the clinical phases.³⁴ Hemangioma of childhood also presents intense immunoreactivity with several vascular markers of the placenta, such as merosina and Lewis Y (LeY).^8,36,37

DIAGNOSIS

In almost all cases, diagnosis can be reached exclusively on the basis of the physical findings and clinical history. However, some hemangiomas can be mistaken by vascular malformations or with other types of tumors.^1,8,16,23

The radiological evaluation can be useful in the differential diagnosis and in the evaluation of the size, type and extension of the lesion. It can also be used in the follow-up of the response to a systemic treatment.^1,38,39

The Doppler ultrasonography (US) continues to be used as an exam for screening because of its low cost, easy availability and lack of risk, and since it can be performed with little or no sedation. In the proliferative phase, a well-defined homogeneous solid mass is observed, with high flow blood vessels (low arterial resistance with increased arterial and venal speeds). These characteristics enable the differentiation between hemangiomas and those due to low flow such as the venous capillary and lymphatic malformations, but they do not allow its distinction from the malformations of high flow, for example when arteriovenous. US is also useful in the differential diagnosis with other common tumors of childhood, such as dermal cyst, lipoma or meningocele. The limitations of US are its small field of vision, restricted visibility in deep lesions, difficulty in evaluating superficial flat lesions and in detecting very small vessels with low flow.^8,39,40,41

The magnetic resonance test (MR) is considered the best exam to confirm the tissular characteristics of the lesion, its extension into the deeper anatomical levels and to evaluate associated adjacent anomalies. Computed tomography (CT) scans with contrast can be substituted for MR, but it is less precise in the evaluation of tissular characteristics and of blood flow. In the proliferative phase, both CT and MR reveal well-defined lesions that are uniform, densely lobulated, with alimentary and drainage vessels in the center or in the periphery. The MR test shows evidence of an isointense or hypointense homogeneous mass in relation to the muscle tissue in the weighted sequence in T1 and hyperintense when weighted in T2. An intense and uniform condition is also brought out by using the gadolinium contrast. The use of the contrast is an important aid in the differential diagnosis between the hemangiomas and malignant tumors or other masses that may resemble a hemangioma.^8,38,42,43

The angiography is not used for diagnosis, but it can be useful for atypical lesions in which surgery or embolization is planned.^8,9,13

A biopsy is recommended in those cases in which there is a diagnostic uncertainty or when it is necessary to rule out the possibility of a malignant tumor. An immunohistochemical study of the lesion facilitates the diagnosis considerably.^1,8,11

DIFFERENTIAL DIAGNOSIS

Hemangiomas should be distinguished from the vascular stains or salmon patch, from vascular malformations and from other vascular tumors of childhood, a description of the characteristics of which is provided below. The distinction can be done in most cases based upon the clinical history and on the physical examination.

Vascular stains or salmon patches are the most common vascular anomalies at birth. They are pink or red, flat lesions, seen in 40% of newborns, mainly on the glabella, eyelids, upper lip, forehead and area of the nape. In spite of the unknown etiology, they are considered to be a physiological alteration that disappears spontaneously in most cases. But about 50% of the salmon patches located on the nape persist indefinitely.^9,24

Vascular malformations present a natural history totally different from that of the hemangiomas. They are congenital anomalies, although some of them cannot be recognized immediately at birth. They grow in proportion to the child's physical development and without involution. They are sensitive to hormonal modulations and present growth during puberty and pregnancy, as well as after episodes of infection or trauma.^8,9

Congenital hemangiomas are rare vascular tumors, previously considered variants of the hemangioma of childhood because they share several clinical, radiological and histological characteristics. Advances in the science of microscopy and immunohistochemistry now permit distinguishing them from the hemangioma of childhood. The lesions, completely developed at birth, are oval or round, in plaques, exophytic or lobulated, with shades of color that run from pink to purple. The skin involved may present telangiectasia with a central or peripheral paleness. One or more drainage vessels may be observed in the periphery and there is increased temperature in that location. They are classed as two distinct tumors: congenital hemangioma with rapid involution (or non-progressive congenital hemangioma) and congenital hemangioma without involution.⁸ The first does not present growth after birth and recedes rapidly in the first months of life (from six to 14 months).⁶ In the histology, lobulation is observed along with fibrotic stroma, hemosiderin deposits, focal thrombosis and sclerosis of the capillary lobules, a reduced number of mastocytes and a proliferation of capillaries with thick walls. The immunohistochemistry shows an absence of reactivity to the antigens GLUT1 and LeY.^8,19 A conservative approach is the most suitable therapeutic modality, since the regression begins to occur in the first months of life.^6,19 On the other hand, non-involuting congenital hemangioma increases proportionally as the child grows, without any tendency toward regression. Its treatment is surgical excision. Histologically, it differs from the hemangioma of childhood by presenting the following characteristics: large lobules of small vessels separated by fibrous tissue, containing abnormal veins and arteries. The basal membranes of the channels are thin, not hyalinized or multilamellated; the endothelial cells have large, dark, round nuclei; the intralobular blood vessels are large with a starlike appearance and fine walls with microscopic arteriovenous fistulae. The immunohistochemistry does not present reactivity to GLUT1.^8,44

The pyogenic granuloma or capillary lobular hemangioma is an acquired vascular lesion, it is clinically and histologically similar to the hemangioma of childhood, however, in general, with smaller dimensions. It tends to occur in the mucous membranes and skin of children and young adults. The mean age affected is six years, but 12% of the cases occur in infants less than a year old. It may appear suddenly and usually without any previous history of trauma. It is located mainly in the cheeks, eyelids, extremities and within capillary malformations. It may be sessile or pedunculated and presents repeated episodes of bleeding with the formation of superficial ulceration. The treatment is the removal of the lesion by surgical excision, electrocauterization, chemical cauterization or cryotherapy.^1,9

Kaposiform hemangioendothelioma (Figure 4) is an aggressive vascular tumor of infancy, frequently associated with serious thrombocytopenia (Kasabach-Merritt syndrome). Present at birth or appearing in early infancy, without sex bias, it involves other areas besides the cervicofacial segment, such as the extremities, the trunk and the retroperitoneal region. The lesion is hardened, red-violet and grows rapidly. Histologically it is a more invasive tumor than the common hemangioma. Lobules and bands of cells that infiltrate the dermis and the subcutaneous fatty tissue may be observed, as well as fusiform endothelial cells, microthrombi, hemosiderin deposits and blood vessels or lymphatic channels (Chart 3).^1,9,21,35,45

Another benign vascular tumor that may appear in infancy or is sometimes present at birth is tufted angioma (angioblastoma or Nakagawa's angioblastoma). It presents a slow growth but in some patients it can affect large areas of the trunk and neck. The principal histological characteristic is the presence of aggregated, circumscribed angiomatoses, some of which are small and elongated, forming tufts, while others form larger, round or irregular lobules. It may present the Kasabach-Merritt syndrome, especially when associated with lymphatic channels (Chart 3).^9,21,35

Other masses and neoplasias can simulate a hemangioma, especially the deep or combined hemangioma: angiosarcoma, infantile myofibromatosis, eccrine angiomatous hamartoma, fibrosarcoma, rhabdomyosarcoma, neurofibroma, teratoma, nasal glyoma and dermoid cyst. Exams such as US, TC, RM or biopsy aid in the differential diagnosis.^8,9,16,35

COMPLICATIONS

Ulceration: it is the most frequent complication, occurring in 5 to 13% of cases.^9,23,46 It is more common in the phase of rapid proliferation and usually causes pain and discomfort, especially when it involves the lips, the perianal, genital or flexural areas.^8,23,46 Once established, resolution may require a period between one week to 12 months, the mean time for cicatrization being 86 days.⁴⁶ The area most frequently affected is the perineum, evidence to the fact that maceration and friction are contributory factors in its formation. On rare occasions the ulceration may be present even before the angiomatous component of the lesion is clinically visible.^18,20 Secondary infection is common and usually restricted to the skin, but it may involve deeper structures, leading to conditions such as erysipelas, cellulitis or septicemia. Bleeding of low intensity may occur but this usually responds well to direct compression. More serious cases that might demand surgical intervention and/or transfusions are rare.¹⁵ There is no evidence that the ulceration in itself propitiates a faster involution of the hemangioma.

Congestive Heart Failure (CHF): is a rare complication and may be associated with the hemangiomas of greater dimensions or multiple hemangiomas. There is a fundamental need for investigation into lesions occurring in other organs, principally the liver, since they represent the most common cause of CHF.^13,15 It would be thoughtful to remember that hepatic hemangioma may occur alone, with no association with cutaneous hemangiomas.⁸ Infants present CHF and hepatomegaly already in the first weeks of life, and this could coexist with anemia and thrombocytopenia. CHF is caused by high deficits and therefore may respond to treatment with digitalis and diuretics. However, it is fundamental that the blood volume be reduced, thus promoting the regression of the hemangioma, whether by use of medications or methods of ablation.^8,9,15

Hypothyroidism: it may be associated with the larger hemangiomas. The enzyme 3-iodothyronine deiodinase, usually present in the brain and placenta, can also be found in the formative tissues of the hemangioma. This enzyme catalyzes the conversion of the thyroxin into reverse triiodothyronine and the conversion of triiodothyronine into 3.3'-diodothyronine, both biologically inactive. It is believed that in a very large hemangioma, due to its high vascularity and size, there may be excessive inactivation of the thyroid hormone by the enzyme 3-iodothyronine deiodinase, it cannot then be sufficiently supplanted by synthesis of the hormone through the infant's thyroid gland. However in smaller hemangiomas, which represent the majority of cases, the infant's thyroid gland compensates for that degradation by producing a larger quantity of hormones. Until prospective studies are developed to evaluate the real risk of hypothyroidism, investigation of the thyroid function is recommended for all of the children with large and/or hepatic hemangiomas, together with periodic check-ups during the entire proliferation phase.^8,47

Visual alterations: this may occur when a hemangioma in the periorbital area causes obstruction of the visual axis, compression of the eyeball or if it should expand within the retrobulbar space.⁸ It is estimated that 80% of the periorbital hemangiomas, mainly those located in the area of the upper eyelid, present visual complications. The most common alteration is astigmatism, but other disturbances may occur, such as amblyopia, ptosis, imperfections in refraction, squint and keratitis. A prolonged obstruction of the vision or compression of the optical nerve can lead to blindness. Early and periodic ophthalmologic evaluation is fundamental in these cases. Either CT or MR are indicated when involvement is suspected of the retrobulbar space.^8,9,17,23

Compromising of the breathing: it is the result of the obstruction of the airways due to a hemangioma located in the nasal passages, in the oropharynx or in the tracheolaryngeal area.^9,15 The area most frequently involved is the subglottis. It is estimated that from 10 to 20% of the cases are symptomatic and put the infant's life at risk. Usually the clinical situation is of an afebrile infant, with between six and 12 weeks of life and presenting two-phase strident breathing (inspiration and expiration).^1,16,17 The voice is normal and there is usually no difficulty in deglutition. A cough may occur similar to that observed in laryngitis.⁸ The symptoms are progressive. The diagnosis is obtained by the clinical history and by the finding of a red or bluish lesion by endoscopy. The infants with the greatest risk of subglottic attack are those that present hemangiomas in the "beard" area, especially if the lesion is located in four or more of the following areas: right or left preauricular, inferior lip, chin and the front of the neck.⁴⁸ Asymptomatic infants should be monitored with caution, since the obstruction continues to grow in more than 60% of the cases.^1,17,26,49

Impairment of audition: this can take place when there is an obstruction in the external hearing conduit, which usually occurs when there is a hemangioma of the parotid gland. There is a reduction in the auditory conduction that can in turn lead to delay in the development of language, above all if there is bilateral involvement. There are no reports of deafness. Another complication is the occurrence of repetitive otitis.^9,13,17

Disfigurement: this complication can be a consequence of large hemangiomas, principally those that involve the face and neck. Some places are more critical, such as the nose, mouth and external ears. Residual lesions can leave deformities that are difficult to correct, and there is evidence that it is in these very locations that the hemangiomas regress slowly and incompletely.^11,15,23 The mammary area in the female sex is a locus of both aesthetic and functional risk.¹¹

SPECIAL CLINICAL MANIFESTATIONS

Hemangiomatosis: on rare occasions a child may present multiple cutaneous hemangiomas, with or without visceral involvement. When the lesions are limited to the skin, the condition is known as benign neonatal hemangiomatosis (BNH). When there is visceral involvement, it is denominated disseminated or diffuse neonatal hemangiomatosis (DNH). Children with BNH (Figure 5) present rapid involution of their lesions, usually within the first two years of life, with an excellent prognosis. However, DNH presents an unfavorable prognosis, with a mortality rate between 29% and 81%.^8,15,17,23 Three criteria are necessary for the diagnosis of DNH: onset in the neonatal period, absence of malignancy in the hemangiomas and involvement of three or more organs.⁵⁰ At the present time, the tendency is to consider BNH and DNH as two extremes of the same disease. Hemangiomatosis of the liver, composed of hepatic hemangioma, cutaneous manifestations and CCI, is an intermediate position in that spectrum.

The typical clinical picture of DNH is comprised of multiple hemangiomas, varying from 2mm to 2cm in diameter, bright red or bluish in color, these are present at birth or develop during the neonatal period.^1,17 About 83% of the children with hemangiomatosis present more than five cutaneous lesions, but visceral involvement can occur with a low number of cutaneous hemangiomas or even in their absence.²³ The most frequently involved extracutaneous organs are the liver (64%), central nervous system (52%), gastrointestinal tract (52%), lungs (52%), eyes (32%), mouth and tongue (44%).^15,51 In 2001, Herszkowicz et al.⁵² reported the first case of BNH with lesions of the oral mucous membrane, demonstrating that such involvement is not exclusive to DNH. Most of the infants with significant hepatic involvement will present hepatomegaly, CHF and anemia, usually beginning in the first 16 weeks of life. CHF is the most common cause of mortality. Other complications vary in seriousness relative to the location of involvement (gastrointestinal hemorrhage, obstructive jaundice and hydrocephaly).¹⁷

Early and periodic clinical attendance of all of the patients with hemangiomatosis is essential due to the possibility of DNH. Infants less than three months old with multiple hemangiomas are considered at risk.¹ In that group, the routine performance of an abdominal US exam is recommended in order to evaluate the possibility of hepatic involvement. Other exams should be done according to the clinical history and to the physical findings: a blood count with a screening for coagulation for research of anemia and coagulopathy, routine exam of urine for the detection of hematuria, testing for traces of blood in the feces, ophtalmological evaluation, chest x-ray, electrocardiogram and echocardiogram; and in the event of CHF, lumbar puncture for evaluation of possible bleeding, CT or MR exams of the cephalic sector when there is suspicion of cerebral hemangioma and hepatic function tests in the presence of hepatomegaly and/or jaundice.^8,15,23

Phace syndrome: This neurocutaneous syndrome is composed of malformations of the posterior cerebellar fossa, a large hemangioma on the face, arterial anomalies, cardiac anomalies and coarctation in the aorta and ocular abnormalities (eyes). This can be referred to as Phaces syndrome when associated with a flaw in the ventral development including alterations of the breastbone (sternum) and/or of the supraumbilical raphe.^8,15,17 The cause is due to a defect in the fetal development that appears between six and ten weeks of pregnancy. There is a prevalence in the female gender of 9:1. Facial lesions, whether unilateral or bilateral, are usually seen as large and segmented plaques. In some patients, however, the distribution pattern suggests the involvement of dermatomas, and the area of the ophthalmic branch of the trigeminal nerve is the most affected. There seems to be a correlation between the extension and/or distribution of the hemangiomas and the severity of the complications. Bilateral lesions in the full extent of the three areas of the trigeminal present a greater association with cerebral involvement.⁵³

About 70% of the children with Phace syndrome present only a single extracutaneous manifestation of this, the most common being Dandy-Walker syndrome in the brain and coarctation of the aorta. The former includes: a cyst in the posterior cerebellar fossa, hypoplasia of the cerebral vermis and cystic dilation of the fourth ventricle, leading to hydrocephaly and an increased cephalic circumference.⁵³

The possibility of Phace syndrome should always be considered in a child with a large sized hemangioma on the face. Those patients should be examined carefully in search of ocular, cardiac and neurological alterations, as well as symptoms of obstruction of the respiratory passages.8 Infants less than six months old with fontanelles still open can be submitted to the transfontanelle US exam in order to detect more important anomalies. MR is the most sensitive exam for the evaluation of the posterior cerebellar fossa.^15,16

Spinal dysraphism: this is the defective or incomplete fusion of the spinal raphe, although the term may be used to include a variety of anomalies, such as meningocele, myelomeningocele, mieloquisia, spina bifida occulta, lethered cord intraspinal lipoma, lipomyelomeningocele and dermoid cyst. Hemangiomas of the lumbosacral area are very frequently associated with spinal dysraphism, which suggests the need for a broad investigation of neurological alterations in children suffering from such vascular anomalies in that area. An examination of the rectum and of the genitalia is equally important, given the possibility of the coexistence of malformations such as hypospadias, agenesis of the labia minora and unperfurated or anteriorized anus. The radiological evaluation can be done before six months of age with high resolution US or with MR, which is considered the most appropriate exam.^8,15,16

Kasabach-Merritt syndrome (KMS): in 1940 Kasabach and Merritt⁵⁴ described the association between a vascular neoplasia and a thrombocytopenic coagulopathy. Since the tumor was classified by them as "capillary hemangioma", the erroneous interpretation was perpetuated that this phenomenon was a complication of the hemangiomas of infancy. It is known today that the phenomenon occurs in other vascular tumors, especially in kaposiform hemangioendothelioma and in tufted angioma.^55-58

Infants with KMS present, at birth or in the first weeks of life, red-violet, firm infiltrated masses that involve the head, trunk or limbs. The lesion grows rapidly and acquires a hardened, woody consistency and becomes hemorrhagic and shiny. (Chart 3). Initially the hemorrhage is limited to the area of the hemangioma, but soon afterwards it may become disseminated.¹⁵ The thrombocytopenia is serious, usually with platelets less than 20,000/mm³. The infant appears pale, with prolonged bleeding in the umbilical stump or after minimal traumas, with ecchymosis and spontaneous petechiae, hematuria, epistaxis and hematochesia.^1,59 There is also a reduction in the levels of fibrinogen. In spite of the fact that the etiopathology has not been totally clarified, it is thought that there is a capturing and destruction of platelets inside the tumor.^55,57,59 The most common complications are hemorrhages, CHF because of the high deficit, shock and death. If the infant survives, the residual lesions are more disfiguring than those of the typical hemangioma and usually leave sequelae. The mortality rate may reach 30%.²¹

TREATMENT

It is estimated that only 10 to 20% of the hemangiomas require treatment.^8,60 These include the cases in which the vision is involved, those that produce an obstruction of the respiratory passages, of the auditory conduit or of the rectum, those that cause CHF and hemorrhages, those that are ulcerated or infected and those lesions that, after involution, leave esthetically compromising results. The treatment should take into account the age of the patient, the size, number and location of the lesions, the disease duration and the presence of other associated symptoms.⁶¹

The conservative management, adopted in most cases, demands a solid relationship of trust between the doctor and the relatives, who are frequently under stress due to the child's lesion. It is fundamentally essential to have a wide and detailed discussion dealing with the advantages and eventual disadvantages of this therapeutic option. Attendance of the patient should be regular and periodic, preferentially with photographic documentation. A study done among parents of children with facial hemangiomas showed a high degree of dissatisfaction with the medical service received. Among the complaints presented were: inadequate or insufficient information (53%) and lack of emotional support (36%).⁶²

Treatment of ulceration: most of the ulcerations can be treated with basic care alone, such as cleaning, use of compresses moistened with saline solution for softening and topical antibiotics to prevent or to treat infections.^8,17,46,61 Systemic antibiotics may be used in the resistant or more extensive cases of infection, the most used being: first generation cephalosporin or amoxacillin and clavulanic acid in association.⁴⁶ Bio-occlusive dressings have also been used with success. The use of superabsorbent disposable diapers, when frequently changed, and applications of barrier creams are recommended.¹⁷ Control of pain can be reached with oral analgesics and/or with the cautious use of local anesthetics for short periods. The use of prilocaine in association with lidocaine should be avoided due to the risk of methemoglobinemia caused by the prilocaine. Other treatment forms include laser therapy and systemic corticotherapy.^1,8,17,46

Systemic Corticotherapy: this is the most widely employed option, especially for the large or aggressive hemangiomas that place the function of an organ at risk.⁶³ Although the specific mechanisms are still unclear, it is believed that the corticoids promote the interruption of the growth or induce the reduction of the hemangiomas by its effects as a vasoconstrictor and inhibitor of the angiogenesis.^15,64 For this reason, the best results are observed when the treatment is instituted in the proliferative phase of the tumor, or in other words, during the first year of life.¹⁶

The recommended dosage is from 2 to 3 mg/kg/day prednisone or prednisolone orally in a single dose in the morning. Alternatively, when is unable to swallow the medication, parenteral administration may be used, with hydrocortisone or methylprednisolone in equivalent dosages. Higher dosages may occasionally be employed in more serious cases, but they may implicate a considerable increase in side effects.^8,26,65,66 These dosages should be maintained for a period between three to eight weeks, followed by a gradual reduction to avoid the rebound effect (Figures 6A and ^B). In most cases the treatment extends until the infant reaches 10 months of life, an age at which the tumor usually has already ceased to grow.

Hemangiomas sensitive to corticoids present a rapid response, already evident in the first two or three weeks of treatment. If at the end of the first month the lesion remains unaffected or with only a minimum reduction, the medication should be withdrawn, and other therapeutic options be considered. A recent review of the literature showed that an adequate response to corticoid therapy (reduction or cessation of the growth of the hemangiomas) may be expected in 84 to 90% of the cases.^8,9,17

The most common side effects are Cushing's syndrome (moon face) (71%), retarded growth (35%), irritability (29%), gastric symptoms (21%) and Candida sp. infection (6%).⁶⁷ In all of the children with growth retardation, the recovery of their development curves is observed, after the suspension of the corticotherapy, by two years of age.^9,17,67

Hypertension and myopathy are rare events. Vaccination with attenuated live virus should be suspended during the period of the treatment and retaken one month after the withdrawal of the medication.^1,9,17,23 Children under treatment and exposed to varicella-zoster virus should receive specific immunoglobulin within 72 hours after contact for the prevention of a disseminated infection.^8,17,23

Intralesional and topical corticotherapy: the basis for use of this therapy is the attempt to reduce the side effects of systemic corticoids. Usually employed in the treatment of periocular hemangioma, they may also be applied on smaller lesions in other locations. The effectiveness of triamcinolone (slow action) is recognized, associated or not with betamethasone or dexamethasone (fast action). The most used combination is 3 to 5 mg/kg/dose of triamcinolone with a 0.5-1 mg/kg/dose of betamethasone.⁶⁸ The infiltrations, with an interval of four to six weeks, should be done separately (different syringes for each drug) in order to avoid the formation of precipitated solids and may require sedation or even a general anesthesia.^8,9,26,68

The application for intralesional corticoids is controversial, and those that are opposed to their use argue that the effect of the drug is possibly systemic, and not local. That hypothesis is based on reports of the regression of hemangiomas at a distance from the infiltrated lesion and on the occurrence of suprarenal suppression.^9,15 The side effects vary from cutaneous atrophy in the locus treated to transitory or even permanent blindness due to the occlusion of the central retinal artery.

Few works in the literature have demonstrated a gradual reduction of a periocular hemangioma with the topical utilization of clobetasol propionate. Nevertheless, the reduction was less than that produced by intralesional corticoid and was unable to avoid ophthalmological complications. It is considered that, in locations other than the periocular and depending on the size of the lesion, a topical corticoid can eventually be considered a therapeutic alternative.^8,17,64

Interferon alpha (IFN-a): endowed with an inhibitory action of the angiogenesis, IFN-a2a and 2b have been employed during the growth phase (first year of life) of hemangiomas resistant to corticoids (Figures 7A and B). The response is considered satisfactory in a percentage that varies from 75 to 80% of cases, and, because it presents a slower action than the corticoids, the drug should be administered subcutaneously for a period of six to 14 months in a dose of one to three million units/m²/day.^6,11

The most common side effects are fever, irritability and symptoms similar to the flu picture. Neutropenia, anemia and an elevation of the hepatic enzymes, are discreet and transitory. The most feared adverse reaction is spastic diplegia, reported in up to 20% of the cases, the risk being apparently proportional to the dosage and duration of the treatment. Although most of the time it is reversible, there are reports of cases in which the neurological condition was permanent. For this reason IFN- a should be carefully reserved for hemangiomas that represent a serious threat to the function of a vital organ and that do not respond to conventional therapy with the corticoids.^1,8,9,69

The hematological functions, hepatic, renal and thyroidal (the major risk being the formation of auto-antibodies leading to hypothyroidism)^17,70 should be monitored during the entire period of treatment. Neurological attendance is recommended, and should be extended well beyond the termination of the treatment.^17,71 The use of IFN-a does not interfere in the child's development, and there is no need to suspend vaccinations during its use.^9,64

Chemotherapy: antineoplasic agents have been used with success due to the proliferative nature of hemangioma. Vincristine and cyclophosphamide present good results in the treatment of Kasabach-Merritt syndrome^8,9,72 and can be an alternative in the rare cases of hemangiomas of infancy that do not respond to corticoids or INF- a . The recommended dosage of vincristine is 0.05 mg/kg for children weighing less than 10kg, or 1.5 mg/m² for children over 10kg, intravenously in weekly sessions.⁸ The number of sessions varies according to the response to the treatment, but on average two to five are necessary.⁷³

Surgery: it is usually indicated in emergencies, in those in which there is no response to the systemic treatments or even for cosmetic reasons. It may be done by means of embolization, selective arterial connection or simple exeresis, with or without plastic reconstruction.^8,74 Voluminous hemangiomas on the tip of the nose that produce the deformity known as Cyrano-nose, periocular lesions affecting the vision and small hemangiomas, with easy excision that present bleeding and repeated infections, are all good candidates for surgery.⁷⁵ Embolization is particularly useful in the hemangiomas, such as the hepatic types, that cause CHF or those refractory to systemic drugs.^1,13

The surgical repairing of defects resulting from the regression of a lesion should be deferred until after 10 years of age, by which time the hemangioma has already reached its maximum point of involution. In those cases in which the hemangioma regresses slowly and the risks of unaesthetic scars are considerable, the date of surgery may be moved forward to be done at four or five years of age. In that age group children are already aware of their own body and can suffer from embarrassment in social contexts, especially when the lesions are in visible places such as the face.^1,9,74

Laser: this is the treatment indicated during the proliferative phase, for ulcerated hemangiomas and for residual telangiectasies. The main restriction in its use is the fact that the deeper component of the hemangioma is not affected by the treatment. The type of laser most frequently utilized is PDL (pulsed dye laser), and sedation of the patient is usually necessary, especially when very young.^1,8,76

Cryotherapy: it is recommended for lesions of small dimensions, but usually more than one session is necessary. The closed tip should be placed in direct contact with the lesion, and the crusts should not be removed postoperatively. The results are inconsistent and largely dependent on the ability of the operator, such that the risk of permanent dyschromia should be considered.^9,16,74

Radiotherapy: this was much used in the past, but is practically abandoned today because of its long-term sequelae. It is now reserved for life-threatening cases and those that do not respond to other treatments.^9,16,72,77

REFERENCES

Received in October, 03^rd of 2003

Approved by the Consultive Council and accepted for publication in October 08^th of 2003.

* Work done at the Pediatric Dermatology Outpatient Clinic, Dermatology Service of the Hospital das Clínicas, Faculty of Medicine, UFMG

QUESTIONS AND ANSWERS TO QUESTIONS

1. Em relação ao hemangioma da infância, assinale a alternativa incorreta.

a) Acomete predominantemente cabeça e pescoço

b) Apresenta predileção pelo sexo feminino

c) Evolução e regressão podem ser observadas simultaneamente na mesma lesão

d) O período de crescimento atinge seu ponto máximo aos dois anos

e) Pode estar presente ao nascimento

2. Em relação às malformações vasculares, assinale a alternativa incorreta.

a) Apresentam regressão espontânea

b) Associam-se com freqüência a síndromes

c) Crescem proporcionalmente ao crescimento do paciente

d) Estão presentes ao nascimento na maioria dos casos

e) São classificadas conforme o componente vascular predominante

3. Em relação ao hemangioma da infância, assinale a alternativa incorreta

a) As alterações histológicas são semelhantes nos hemangiomas superficiais e profundos

b) As ulcerações representam a complicação mais comum

c) Lesões volumosas podem associar-se à insuficiência cardíaca congestiva

d) O diagnóstico é eminentemente clínico

e) O hipotireoidismo associado ocorre por mecanismos auto-imunes

4. Qual dos seguintes marcadores imuno-histoquímicos é específico do hemangioma da infância?

a) CD 31

b) Fator de Von Willebrand

c) GLUT 1

d) S-100

e) Uroquinase

5. Assinale a alternativa incorreta:

a) As manchas salmão constituem a anomalia vascular mais comum ao nascimento

b) As manchas salmão localizadas na nuca podem ser permanentes

c) Hemangiomas congênitos apresentam negatividade para o antígeno GLUT 1

d) O granuloma piogênico é freqüentemente precedido por trauma.

e) O granuloma piogênico assemelha-se histologica mente ao hemangioma da infância

6. Em relação aos hemangiomas congênitos, assinale a alternativa incorreta.

a) As lesões encontram-se totalmente desenvolvidas ao nascimento

b) Apresentam características clínicas e histológicas bem distintas do hemangioma da infância

c) Podem crescer proporcionalmente ao crescimento do paciente

d) Podem regredir durante o primeiro ano de vida

e) São tumores vasculares raros

7. Em relação ao hemangioendotelioma kaposiforme, assinale a alternativa incorreta.

a) Associa-se com freqüência ao fenômeno de Kasabach-Merritt

b) É tumor de crescimento lento

c) Histologicamente é mais invasivo do que o heman gioma da infância

d) Não apresenta predileção por sexo

e) Pode estar presente ao nascimento

8. Em relação ao angioma em tufos, assinale a alternativa incorreta.

a) Associa-se com freqüência ao fenômeno de Kasabach-Merritt

b) É tumor de crescimento lento

c) Pode acometer grandes áreas do tronco

d) Seu nome deriva de suas características histológicas

e) Surge geralmente na adolescência

9. Em relação às ulcerações dos hemangiomas da infância, assinale a alternativa incorreta.

a) Acometem comumente o períneo

b) Constituem a complicação mais comum

c) Induzem resolução mais rápida da lesão

d) Podem estar presentes antes de o hemangioma tornar-se clinicamente detectável

e) São mais comuns durante a fase de proliferação do hemangioma

10. Em relação às complicações do hemangioma da infância, assinale a associação incorreta.

a) Alteração da visão - hemangioma da pálpebra superior

b) Comprometimento da respiração - hemangioma subglótico

c) Deformidades estéticas - hemangioma da região da mama

d) Insuficiência cardíaca congestiva - hemangiomas múltiplos

e) Surdez - hemangioma da parótida

11. Em relação à hemangiomatose neonatal disseminada, assinale a alternativa incorreta.

a) Acomete três ou mais órgãos

b) Apresenta prognóstico reservado

c) O acometimento hepático implica maior risco de insuficiência cardíaca congestiva

d) O acometimento visceral pode ocorrer na ausência de lesões cutâneas

e) Os pulmões são o órgão extracutâneo mais afetado

12. Em relação ao fenômeno de Kasabach-Merritt, assinale a alternativa incorreta.

a) A trombocitopenia é geralmente grave

b) As lesões residuais são mais desfigurantes do que as do hemangioma da infância

c) Associa-se classicamente ao hemangioma comum da infância de grandes dimensões

d) Há redução dos níveis de fibrinogênio

e) Não há predileção por sexo.

13. Em relação à corticoterapia nos hemangiomas da infância, assinale a alternativa incorreta.

a) A fácies cushingóide é o efeito colateral mais comum

b) A vacinação deve ser suspensa até um mês após o término do tratamento

c) Deve ser empregada apenas na fase proliferativa do tumor

d) O retardo do crescimento é reversível após os dois anos de idade

e) Os resultados são lentos, em geral após o segundo mês de tratamento

14. Os seguintes efeitos colaterais podem ser atribuídos ao interferon alfa, exceto:

a) Anemia

b) Diplegia espástica

c) Febre

d) Neutropenia

e) Retardo do crescimento

15. Em relação às indicações terapêuticas mencionadas abaixo, assinale a associação incorreta:

a) Corticoterapia sistêmica - hemangiomas em fase de crescimento

b) Exérese cirúrgica - lesão de pequenas dimensões

c) Laser - lesões ulceradas

d) Interferon alfa - hemangiomatose neonatal benigna

e) Vincristina - hemangiomas resistentes aos cor ticóides e ao interferon alfa

GABARITO

Cicatrização: conceitos atuais e recursos auxiliares -Parte II

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Publication Dates

• Publication in this collection
  10 Feb 2004
• Date of issue
  Dec 2003

History

• Received
  03 Oct 2003
• Accepted
  08 Oct 2003