Capillary hemangioma (infantile periocular hemangioma)

SURVEY OF OPHTHALMOLOGY VOLUME 38-NUMBERS-MARCH-APRIL 1994

MAJOR REVIEW

Capillary Hemangioma (Infantile Periocular Hemangioma) BARRETT G. HAIK, MD,' ZEYNEL A. KARCIOGLU, MD,' ROBERT A. GORDON, MD,' AND BRYAN P. PECHOUS, MD 2

'Department of Ophthalmology, Tulane University School of Medicine, New Orleans, Louisiana, and 'Dubuque, Iowa Abstract. Capillary hemangiomas are the most common orbital tumors in children . They typically arise early in life, grow rapidly during a proliferative phase and then slowly regress in an involutional phase . The tumors may present as small isolated lesions of minimal clinical significance or as large disfiguring masses that can cause visual impairment and systemic symptomatology, Capillary hemangiomas are managed effectively by establishing a secure diagnosis, outlining the extent of the tumor, and understanding the natural history of the lesion, as well as its response to therapy . The ophthalmic and systemic manifestations of capillary hemangiomas are discussed in detail, as are the histopathology, radiologic findings, differential diagnosis, and therapeutic alternatives . (Sure Ophthalmol 38 :399-426, 1994) Key words . amblyopia • capillary hemangioma • corticosteroids hemangioma • interferon • Kasabach-Merritt syndrome • laser

Capillary hemangiomas are the most common orbital tumors in children 92'172 They are benign neoplasms originating as a result of vasoformative tissue proliferation . Each consists of anastomosing vascular channels having an infiltrative growth pattern and no true encapsulation ." ' Although many other terms have been used to describe the childhood vascular tumors (e .g ., infantile hemangioma, juvenile hemangioma, hemangioblastoma, benign hemangioendothelioma, hypertrophic hemangioma), the term "capillary hemangioma" is most commonly used in the ophthalmic literature because it most accurately describes the tumor's structure of a true capillary unit consisting of endothelial cells surrounded by pericytes . 105 Mulliken alternatively presents a convincing argument that the word "capillary" is a stumbling block to interspecialty

communication about these tumors and prefers to simply utilize the term "hemangioma ." 152 He has provided the medical community with simplified terminology of vascular tumors based on a rational biologic classification . Mulliken divides vascular birthmarks into "hemangiomas" and "malformations," based on a combination of cellular features and clinical behavior . Although we acknowledge the logic of his classification, we found ourselves unable to totally abandon the term "capillary hemangioma," since it is the term utilized throughout the worldwide ophthalmic literature . The tumors may present as small isolated lesions or large disfiguring masses that can cause visual impairment and systemic symptomatology. Although most capillary hemangiomas can be diagnosed readily by clinical inspection, those 399



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that present equivocally may necessitate computed tomography, magnetic resonance imaging, or ultrasound as diagnostic aids . The tumors are managed effectively by establishing a secure diagnosis, outlining the extent of the tumor, and understanding the natural history of the lesion as well as its response to therapy . Here we present an overview of these management concerns as distilled from the ophthalmic and general medical literature . The reader is referred to the extensive landmark text entitled Vascular Birthmarks, by Mulliken and Young, 15' for additional insights into these fascinating lesions .

I. Epidemiology Studies show that capillary hemangiomas are among the most common tumors in infants . 63,98, 107,131,'91 .'96 Jacobs and Walton 108 detected "strawberry" marks in 2 .6% of 1058 newborns, and both Jacobs 106 and Holmdahl" reported that 10% of all children under one year of age have visible hemangiomas . In infants, capillary hemangionias are the most common orbital tumor, although histopathologic series may not reflect this prevalence, because many hemangiomatous lesions do not undergo biopsy . The incidence of orbital capillary hemangiomas is not generally reported to vary by race, ethnicity, or geographic location . A7 However, Mulliken 752 reports hemangiomas to be uncommon in black children seen at his institution . Females are more often affected than males, with a 3 :2 female-to-male ratio most commonly reported 29.48.87,195 This tumor has neither a clear hereditary pattern nor an increased incidence among siblings of affected patients . One-third of all orbital capillary hemangiomas are noted at birth, and virtually all are diagnosed by age six months . 7 .92 .172 Early reports suggested that capillary hemangiomas occurred more frequently in premature, low-birth-weight infants,"' 72 presumably in association with perinatal oxygen exposure and retrolental fibroplasia . Later studies have not supported these associations, which now are not generally accepted .87'98 New interest in this area has arisen following a report that 23% of premature infants weighting less than 1000 grams had hemangiomas .'

II. Natural History A . CLINICAL HISTORY In the early 1900s descriptions first appeared in the medical literature outlining the unique natural history of the capillary hemangioma,

Fig. 1 . Fourteen-month-old infant with extensive superficial hemangioma involving the right periocular and temple region . (Reprinted from Haik BG, Jacobiec FA, Ellsworth RM, Jones IS, 87 with permission of the American Academy of Ophthalmology .)

particularly its tendency toward spontaneous involution in most patients . 24 " 86 Later investigators supported these observations and further de.27.'06,13U37,173. fined the lesion's natural history .2s .6,2'6 . Their consensus has been that capillary hemangiomas typically present in the first few months of life, with one-third clinically obvious at birth . The tumor may be seen first as a flat, circumscribed lesion with telangectatic vessels in the superficial layers of the skin . These vessels appear as tiny macular red spots, also called "herald spots," which may be indistinguishable from other cutaneous vascular anomalies, such as neonatal staining, salmon patch, or port-wine stain ." Within weeks, the affected area becomes raised and comprises finely lobulated smooth nodules . The tumor's increasing nodularity and scarlet-red color results in a strawberry-like appearance (Fig . 1), hence the name, "strawberry nevus ." If the mass begins in the deeper subcutaneous region, one may not see the cutaneous vessels, but rather, a spongy, bluish-purple swelling (Fig . 2) resembling a bruise . Large venous channels may be seen in the subcutaneous region . As Listed . ' pointed out, "when both superficial and deep sites are involved, the naevus may be compared to a poached egg, the yoke being represented by the central, crimson nodular zone of superficial vascularity, which is superimposed on a more extensive base of the deeper type, corresponding to the white of the egg" (Fig . 3). There follows a proliferative phase of variable duration that is often characterized by explosive growth of the tumor, most rapidly within the first 3-6 months after diagnosis .29s7,13','s,'s2 The tu-

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Fig . 2 . Infant with predominantly deep hemangioma displaying a bluish-purple swelling in the inferior right orbit .

Fig . 3 . A large combined superficial and subcutaneous

mor then stabilizes and finally involutes, which is often characterized by a lessening of tension and dulling of color that results in fine, grayish wrinkles on the tumor's surface (Fig . 4) . The involution typically begins in the center of the lesion, spreading outward toward the periphery . Most of the involution will occur by five years of age ; however, regression may continue until the end of the first decade . 152 In many cases, the involution will be complete and have no significant cosmetic sequelae . In Lister's pioneering 1938 report of 93 strawberry nevi in 77 children followed up for seven years, all but one showed nearly complete resolution .'" In the study by Bowers arid associates of 169 hemangiornas in 140 patients, 83 (49%) resolved by five years of age and 122 (72%) by seven years 29 In one of the largest studies to date, Margileth and Muscles examined 210 children with 336 hemangiomas, and found a regression rate of 30% at three years, 60% at four years, and 76% at seven years ."" One should be aware, however,

that in periocular and large facial lesions, especially those with a combined superficial and subcutaneous component, both functional and cosmetically disturbing defects commonly persist . Functional defects include amblyopia, strabismus, and, rarely, optic atrophy . Facial disfigurement may persist 6,79 .87 92 after incomplete regression of vascular tissue and secondary fibrosis, and include proptosis, ptosis, and orbitopalpebral asymmetry (Fig . 5) . Dermatologic sequelae include "crepe paper" scarring, a residual subcutaneous or orbital mass, hair loss, and superficial telangiectasias .

capillary hemangioma causing total pupillary occlusion .

B . BIOLOGICAL PHASES The biological life cycle of the hemangioma parallels its clinical course and can be divided into the "proliferative" and "involutional" phases, with an intermediate stage of varying doration .111,112 During the proliferative phase, endothelial cells multiply quickly and form clusters rather than lining the lamina of well structured

Fig . 4 . Twelve-month-old infant with an extensive cap-

illary hemangioma showing signs of regression in the periocular region . The tumor has become less dense and less erythematous centrally .

Fig . 5 . Child manifesting orbital-palpebral asymmetry

following incomplete regression ofleft superior orbital capillary hemangioma .



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Fig. 6 . Proliferative phase of hemangioma with clusters of endothelial cells, some of which form irregular, thin walled vascular spaces (H & E, original magnification x 100) .

Fig. 7 . Reticulin stain depicting the outlines of endothelial cell groups in capillary hemangioma (reticulin stain, original magnification x 100) .

vascular channels . The lining cells and other well developed endothelial cells incorporate tritiated thymidine into replicating DNA, as shown by autoradiography, and produce Factor VIII, as confirmed by both peroxidase and fluorescein anti53 body techniques .' Glowacki and Mulliken were the first to document the presence of mast cells in hemangiomas . 7 " Within the proliferating hemangioma, mast cells are about 30-fold more than their number in location-matched normal tissues ."' '52.'°o Normally, mast cells are located along the walls of vascular channels and contain serotonin and other vasoactive substances including prostaglandins . 81 Mast cells apparently play a major role in the development of a hemangioma by interacting with macrophages within the tumor during the proliferative and early involution phases . Later the endothelial cell proliferation

III. Histopathology and Ultrastructure

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slows down and the deposition of fibrous tissue begins . The number of mast cells decreases and their orientation to other components of the hemangioma changes as the involution takes place . As involution progresses and fibrosis predominates, many fihrohlasts and macrophages are seen to be close to the mast cells, and, in later stages of involution, cytoplasmic bridges form between the mast cells and fibroblasts . 50 Although the exact roles of the above-mentioned cells are not clearly understood, there is no doubt that the neoplasm's biological evolution, particularly its most unusual characteristic, natural regression, depends on the interaction between its cellular elements . The old involution theory of thrombosis and infarction, first proposed by Watson and McCarthy, does riot seem applicable in the absence of histopathologic or any other evidence for such a mechanism ."'

The clinical appearance of the lesion changes coincident with histopathologic transformation during growth and involution . 5s . ' is'' 48 In its proliferative phase, the young hemangioma has a characteristic histopathologic pattern with masses of plump endothelial cells with increased mitotic figures, some of which attempt to form vascular spaces with small, irregular lumina (Fig . 6) . Because of the rarity of vascular spaces in early stages of proliferation, the tumor presents a poor differentiation without apparent vascular origin . A reticulin stain may help to identify the hemangioma pattern in a questionable tumor by delineating primitive vascular structures and a network of thin, connective tissue fibers encircling the poorly differentiated cells (Fig . 7) . During the proliferative phase, the endothelial cells produce von Willebrand's factor (Factor VIII), and the localization of this factor with either peroxidase or fluorescent antibody techniques may be valuable in the diagnosis of poorly differentiated tumors (Fig . 8) . Weibel-Palade bodies are rod-shaped intracytoplasmic structures measuring approximately 0 .3 micron in length ."' These structures are found in the normal endothelial cells and occasionally in pericytes . Factor VIII-associated antigen has been demonstrated within Weibel-Palade bodies by immunoelectronmicroscopy . A good correlation between the number of these organelles and increased intensity of staining with Factor VIII-associated antigen is also well established . In better differentiated forms of hemangioma, numerous Weibel-Palade bodies are found within the tumor cells, but these structures tend to be scarce in poorly differentiated tumors (Fig . 9) . Therefore, the demonstration of

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Fig . 8. Darkly stained cells within the hemangioma depict the positive response to Factor VIII marker indicating that the cells are of endothelial origin . The positive control is clearly seen in the endothelial cells of the blood vessel in the upper right-hand corner of the photograph (immunoperoxidase, original magnification x 100) .

these organelles by electron microscopy or Factor VIII-associated antigen are not very helpful to decide on the cell of origin in poorly differentiated tumors . The occasional identification of Weibel-Palade bodies within pericytes may even confuse the issue further, and lead to misdiagnosis of hemangiopericytoma as hemangioma . Other nonspecific inclusions have also been described in capillary hemangioma. l6z In later-stage lesions, the blood-filled vascular structures are better formed but the endothelial cellularity is diminished . The endothelial cells are flat, and the vascular pattern becomes more prominent and interspersed with occasional small nests of poorly differentiated cells . Lobulated groups of endothelial cells are separated by fibrous septae containing feeding and draining vessels (Fig. 10) . Histopathologic examination easily confirms the tumor's vascular nature at this stage. As the lesion involutes, fibrofatty tissue is deposited around the blood vessels and lobules of endothelial cells . The late, regression stage of the hemangioma presents a haphazard histopathologic pattern dominated by fibrosis, which eventually leads to total atrophy of the vascular component of the lesion . The ultrastructural appearance of the hemangioma also depends on the phase of tumor devel."-`61'215 During the proliferative phase, opment endothelial cells present as multilaminated nuclear membrane with clusters of free ribosomes and active, swollen mitochondria . As early involution with fibrosis proceeds, ultrastructural features of endothelial cell proliferation, particu-

Fig . 9 . Electromicrograph of Weibel-Palade body (WP) within an endothelial cell . N : nucleus of the endothelial cell (original magnification : Top : x 22,258 ; bottom : x 5100) . larly the swollen mitochondria are less evident . As noted by Mulliken, "the basement membrane is still multilaminated, although it is thin and disordered ." 1,2 Mast cells diminish in numbers, and cytoplasmic bridges develop between the remaining mast cells and active fibroblasts . Although transmission electronmicroscopy (TEM) is an effective tool for investigating the pathogenesis and evolution of hemangiomas, it is not commonly used in daily patient management (Fig . 11) . Its application is limited to providing additional information in the diagnosis of an occasional poorly differentiated tumor by identifying the cell of origin . Immunohistochemical studies including Factor VIII-related antigen, collagen type-IV laminin, and ULEX EuropaeusAgglutinin I may also be helpful to demonstrate the vascular origin of

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power appearance of hemangioma during the involution phase with many vascular spaces surrounded by fibrous tissue (H & E, original magnification x 25),

HAIK ET AL

Fig. 10. Low

poorly differentiated tumors . In many instances, a panel of imtnunohistochemical markers are required to evaluate the lesion . Compared with electronmicroscopy, the immunohistochemical methods can be applied in a more cost-effective manner . The sensitivity and specificity of many of these methods will likely improve as more specific markers of endothelial differentiation are characterized . 200

IV. Presentation A. CLINICAL FINDINGS As to clinical presentation, periocular capillary hemangioma can be categorized in several ways . One common method describes three distinct clinical presentations : the classic superficial strawberry nevus, the subcutaneous hemangioma that appears dark blue or purple through the overlying skin, and the deep orbital tumor that usually presents as unilateral proptosis with no skin discoloration . In one series," 68% of patients presented with bluish-purple, "spongy" subcutaneous masses in the eyelids or superficial orbit, 25% had a classic strawberry nevus and a subcutaneous mass, and 7% had deep orbital involvement and no skin discoloration or visibly perceptible mass ."7 Whereas the typical strawberry nevus or deep-blue swelling of the lid may immediately suggest the diagnosis, a solitary deep tumor may provide no visual clue and thus require diagnostic testing and often biopsy. Rootman,' 77 on the other hand, categorized his 23 cases of capillary hemangioma as follows : nine cases of combined subcutaneous and deep orbital involvement, seven superficial, consisting

Transmission clectronmicrograph of a capillary unit during the proliferative phase with multilaminated membranes (arrows) . E : endothelial call nucleus; P : pericyte nucleus (original magnification x 13,362) . Fig. 11 .

of the typical strawbery nevus confined to the superficial dermis, and another seven combined superficial (strawberry) hemangiomas with deep or subcutaneous involvement . Regardless of the method of classification, orbital capillary hemangiomas can present at any singular location or combination of locations within the orbit or periorbital tissue - superficial, subcutaneous, or deep orbit - and have various appearances and effects on the globe and ocular adnexa . In 101 patients with orbital capillary hemangiomas, Haik et al" 7 found the tumor present in the superior orbit in 60 patients, inferior orbit in 16, and in both lids in two . The tumor mass can cause blepharoptosis and occlusion of the visual axis (Fig . 12) 87."' Even if the visual axis is not totally obstructed, a large tumor mass in the lid may exert pressure on the globe .",175 Proptosis and/or ocular displacement is a common finding . In one series of 101 patients, many had vertical or horizontal ocular displacement, and 38 had some degree of proptosis8 7 Yroptosis ranged from mild (< 2 .0 mm) to severe (15 mm), and was occasionally associated with disturbing disfigurement, corneal exposure, and optic nerve damage . Displacement caused by tumor pressure on the globe often leads to global distortion and lengthening as well as a refractive abnormality . . "' The direction of ocular displacement often provides a clue to the true location of the orbital tumor 17 .5; the tumor generally dis-

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405 ondary to amblyopia in infants, it may also contribute to the condition when the orbital portion of the tumor infiltrates extraocular muscles or otherwise inhibits ocular motility . Thus, periocular capillary hemangioma serves as a clinical

Fig . 12. Occlusion of the visual axis as a result of hem-

angiomatous involvement of the left upper lid .

places the globe to the opposite side of the orbit . On valsalva maneuver, which raises the intrathoracic pressure of the great vessels, another common clinical finding of orbital capillary hemangioma is seen : enlargement of the mass and a change in its color to a deep blue . These changes are most often observed with the crying child" and are thought to result from the force of deoxygenated blood into the capillary spaces . The changes were seen in 46 of 101 patients in Haik's series 87 ; however, change in size, color, or position is not pathognomonic for capillary hemangiomas, in as much as other types of vascular lesions can show these effects, although usually to a lesser degree . Hemangiomatous involvement of the palpebral or forniceal conjuctiva may be an important diagnostic clue, especially because it is seen in more than one-third of patients on careful inspection of the fornices or everted lids (Fig . 13) . Patients presenting with orbital capillary hemangiomas can also have coexisting capillary hemangiomas on other parts of the body, as did 23 of 80 patients in one study ."

paradigm for all forms of amblyopia . The characteristics of amblyopia that accompany adnexal capillary hemangioma have been studied in several large series .26,87,175,198 In a retrospective study, Robb 175 reported his findings on 37 patients with periocular capillary hemangioma who were old enough to cooperate with recognition visual acuity testing . He found that 46% had amblyopia, and all but one case was associated with astigmatism on the affected side . Astigmatism was seen more often with uppereyelid than with lower-eyelid involvement, and the axis of the astigmatic plus cylinder was generally directed toward the location of the eyelid hemangioma . The induced astigmatism seemed to be permanent in most of his cases and keratometry on five of his older patients confirmed that this component of refractive error resulted from corneal distortion . Robb concluded that early visual deprivation caused by total eyelid occlusion, in concert with asymmetrical refractive errors, resulted in the most severe amblyopia . Conversely, lack of asymmetrical refractive error correlated with a good visual prognosis in the eye on the involved side . Of 17 patients with refractive asymmetry, nine were more myopic on the affected side than on the normal side . Strabismus was detected in 7 of those 17 patients, in contrast to only 5 of 19 patients without refractive asymmetry . Stigmar et al"' reviewed 51 verbal patients having infantile hemangioma of the eyelids and

B. AMBLYOPIA Visual loss from amblyopia is the most common ocular complication of adnexal capillary hemangiomas in infants . Amblyopia affects 4360% of the population, and usually results from anisometropia, visual deprivation, or a combination of the two .87'92 .t75,'98 The anisometropic form usually results from astigmatism caused by massinduced indentation of the highly elastic infant sclera and cornea . 45,145 .175,198 On the other hand, when an infiltrating tumor enlarges the eyelid and obstructs the visual axis, the more severe deprivation amblyopia may easily develop . In addition, although strabismus usually occurs sec-

Fig . 13 . Diffuse hemangiomatosis of the tarsal conjunctiva . (Reprinted from Haik BG, 86 with permission of the Williams & Wilkins Co ., Baltimore, MD .)



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orbit and found 22 patients (43%) with amblyopia . In 15 of these, the amblyopia was thought to have resulted from stimulus deprivation caused by pupillary obstruction, while in seven it occurred secondary to anisometropia or strabismus. It was noted that the longer the visual axis is occluded, the more severe the amblyopia . However, three patients developed severe amblyopia and one moderate amblyopia after only one month of occlusion . Thus, Stigmar and associates suggested that all patients having capillary hemangioma that obstructs the visual axis be carefully monitored by an ophthalmologist to prevent amblyopia . These investigators also recommended surgical excision of tumors that are localized, obscure vision, or induce significant anisometropia . In a later study, Haik et a187 reported a 60% (29 cases) prevalence of amblyopia in 48 verbal patients with hemangioma . In all 29 cases, the visual axis occlusion and anisometropia were present, either separately or in combination, and 17 of these had visual acuity of 20/80 or worse . Six of 12 patients with visual acuity of 20/100 or worse had no evidence of eyelid occlusion but had severe anisometropia ; the other six had histories of partial eyelid closure during infancy . Of those 12 patients, three also had strabismus, which was thought to be secondary to their sensory deprivation . The authors concluded that the longer the duration of eyelid occlusion, the deeper the amblyopia in these patients . Haik et al also found coincident myopia in the eye on the affected side (21 of 49 cases), as did Robb . 177 This myopic propensity is thought to be a direct consequence of axial elongation of the eye, which can result from prolonged unilateral eyelid closure in infants . 101 Began et al evaluated 17 nonverbal infants, aged 1-14 months, with periocular hemangioma . 76 Of those, 14 had 1 .00-5.50 diopters of astigmatism in the affected eye, eight were diagnosed as having definite amblyopia, and five showed anisometropia as the only predisposing factor . Eyelid occlusion was believed to cause the amblyopia in the other three patients, but two of them also had anisometropia . Amblyopia was suspected in three other patients, who were then prescribed spectacles or given intralesional corticosteroid injections which seemed to diminish the astigmatism . The high incidence of amblyopia in reported series of periocular infantile hemangioma undoubtedly reflects the onset of this tumor within the first months of life . According to von Noor-

den, patients are most susceptible to unilateral visual deprivation during the first 5-6 years of age, although their sensitivity is probably greatest during the first several months after birth .""" As suggested by experiments in kittens 226 and infant monkeys,21A even relatively short periods of abnormal visual input during the first months of life may lead to irreversible morphologic and functional abnormalities of the visual portion of the central nervous system . In monkeys, these experimental abnormalities resulted from induced anisometropia and strabismus as well as deprivation from total lid closure . Thus, animal research suggests that any cause of amblyopia that is operative shortly after birth may lead to severe and permanent visual loss . This "visual deprivation syndrome," as termed by Crawford," s can be presumed for human infants as well, as they have been observed to develop severe amblyopia after unilateral visual occlusion for only 1-4 weeks . 212 V . Systemic Associations Rarely are orbital and facial capillary hemangiomas associated with systemic disorders, and then usually only with exceedingly large lesions . In one study of 101 patients with periocular hemangiomas, no systemic complications were found," but reports of associated hematologic, cardiac, respiratory and infectious disorders have been published . Large hemangiomas are subject to superficial ulceration"" 135,137,139,195 and may, rarely, hemorrhage or become secondarily infected, resulting in sepsis . The most noted hematologic abnormality associated with extensive capillary hemangiomas is the Kasabach-Merritt syndrome, first described in 1940 ."' This rare disorder is characterized by a coagulopathy secondary to platelet and/or fibrinogen entrapment and consumption of other clotting factors . More than 100 cases have been reported, but few have been associated with hemangiomas involving the facial region ."-' 10,132 In this syndrome, a critical thrombocytopenia results from platelet entrapment within the vascular channels of the large tumor . Thrombocvtopenic purpura is evident in addition to lower platelet counts . M,0,103J04,189 Large ecchymoses are usually found within the first months of life in and around the hemangiomas, but they may occur anywhere, including the viscera ." Bowles et al" reported a child with significant intrauterine ocular and skin hemorrhage . In their patient, the "right cornea perforated and drained large amounts of serosanguineous fluid ." Life-threat-

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CAPILLARY HEMANGIOMA ening complications of this syndrome include sudden, massive hemorrhage, with resultant cardiovascular collapse and/or the compression of critical structures . One usually treats hemangioma associated with thrombocytopenia (Kasabach-Merritt syndrome) first with systemic corticosteroids and thrombocyte-replacement therapy . About 50% of affected persons will respond to such therapy, Radiotherapy is used alone, or in combination with corticosteroids and blood replacement, in recalcitrant cases . Surgical removal of the hemangioma 152 or embolization has been used in extremely advanced cases where more convervative therapy has failed .", "' Recent reports suggest that interferon alpha-2a therapy is very effective in managing patients with the Kasabach-Merritt syndrome . 22,60 .15z224 Other disorders of coagulation that may occur with capillary hemangiomas include consumption of clotting factors, increased bleeding time, decreased levels of factors V and VII, low fibrinogen level and increased fibrolysis . f3I01•` 94 Tranexamic acid was found to be a valuable adjunct in a patient with a consumptive coagulopathy associated with a massive facial and orbital hemangioma ."" Associations of microangiopathic hemolytic anemia with large hemangiomas of the liver, 16b digestive tract, 25 and periocular region"' have been described . The erythrocyte destruction may occur as a result of coagulation or fragmentation of cells forced, under high pressure, through the abnormally small vascular spaces within the tumor . Park and Ricketts 15' described an infant with facial and neck capillary hemangioma associated with melena and chronic anemia. On systemic evaluation of this patient, they detected extensive gastrointestinal hemangiomatosis . The patient was successfully treated with segmental intestinal resection . The authors stress that "when evaluating anemia in an infant who also has cutaneous hemangiomas, a high index of suspicion should lead to a search for a visceral hemangioma ." High-output congestive heart failure may occur in children having large visceral capillary hemangiomas when the abnormal at teriovenous communication results in a "short circuit" of the systemic circulation . Arterial blood is shunted to a path of least resistance through a systemic vein, thus resulting in increased peripheral resistance . Perfusion of the distal vascular bed can be maintained only by increasing cardiac output and blood volume . Congestive heart failure follows when the infant can no longer compensate for

the increased load by dilatation, tachycardia, and cardiac hypertrophy. This often fatal complication has been reported in patients whose visceral hemangiomatosis involved the liver, lungs, heart, intestines, spleen, and bones, 21 .25, ' 2 s. ' 26.140, 'ss .22v but it rarely occurs with isolated cutaneous hemangiomas, including facial hemangiomas . Cooper and Bolande" reported an unfortunate patient with extensive facial, orbital, and visceral hemangioma responsible for congestive heart failure . Subglottic, paratracheal, oral, and nasal hemangiomas may occur along with orbital capillary hemangiomas .""s' 52 . ' s sss2 These lesions are particularly dangerous because they may compress the adjacent trachea or larynx, causing respiratory distress and asphyxiation, or compress the esophagus, causing secondary aspiration ."' One death has been reported from respiratory arrest after uncontrolled bleeding from an ulcerated hemangioma in the child's nasal passage .'" Because patients with orbital capillary hemangiomas tend to develop noncontiguous hemangiomas of the head and neck regions, the examining physician should take care to identify such abnormalities, especially prior to intubating the patient during general anesthesia . White et al have reported the unusual combination of facial capillary hemangioma, oculomotor nerve palsy, and cerebellar hypoplasia . 225 Deady and Willshaw found two of 26 of their patients had associated abnormalities ." One patient had unilateral microphthalmos and the other had poor vision in both eyes coupled with agenesis of the corpus callosum, Dandy Walker cyst, and the clinical picture of ocular motor apraxia .

VI. Ancillary Diagnostic Testing Many ancillary means are available to aid in establishing the diagnosis and extent of the capillary hemangioma, as well as for monitoring tumor growth and regression . Magnetic resonance imaging with surface coils, gadolinium DTPAenhancement, and fat suppression is our diagnostic modality of choice . Ultrasonography is valuable in that it does not require sedation and is a rapid method of monitoring changes in tumor size after the diagnosis is established . A. PLAIN RADIOGRAPHY Capillary hemangiomas are neither easily nor clearly identified by plain radiography, although rarely a soft tissue mass may be seen ." Plain orbital radiographs or tomograms will often



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HAIK ET AL to fibrous septae separating tumor lobules . Ultrasound is valuable in determining the presence and extent of orbital involvement, and provides safe, noninvasive method for monitoring tumor growth and regression . It is interesting to note that facial hemangiomas have been diagnosed on prenatal sonographic studies C. COMPUTED TOMOGRAPHY Another effective technique for tumor localization and diagnosis is computed tomography (CT) . 202,206,209 It often shows enlargement of the orbit cavity but no erosion of orbital bone . On CT, the capillary hemangioma often appears as an homogeneous soft tissue mass in the anterior orbit or as an extraconal mass with "finger-like" posterior extensions . The tumor often extends into multiple orbital compartments simultaneously (Fig . 15) . The mass configuration may be wellmarginated or irregular and infiltrative, blending with the surrounding soft tissue ."', 180,192 Rarely,

Fig . 14 . B- and A-scan ultrasonograms revealing a dif-

fuse mass which blends into the surrounding retrobulbar fat . On A-scan, variable reflectivity is depicted .

extension back to the cavernous sinus has been reported . With iodinated contrast medium, the capillary hemangioma is enhanced sufficiently so that its border become more apparent from the surrounding tissues, and major feeding vessels supplying the tumor may be depicted . Rapid, uniform enhancement is noted on dynamic computed

show diffuse enlargement of the orbital bone without evidence of bony erosions' The amount of orbital enlargement may be quite striking if the mass is expanding rapidly in the early period of development when the bony orbit has greater plasticity . These findings are not specific, however, because any expanding tumor in the infantile orbit may cause diffuse enlargement of that orbit. B . ULTRASOUND On B-scan ultrasonography, the orbital capillary hemangioma presents as an irregular mass that blends into surrounding orbital structures" (Fig . 14) . Variable internal reflectivity is noted and corresponds to histological variations within the tumor. 18 .148.192 On A-scan ultrasonography, the tumor has regions of low internal reflectivity corresponding to regions of solid, hypercellular endothelial proliferation, areas of sustained, moderate amplitude echoes in regions of ectatic vascular channels, and areas of high reflectivity corresponding

Fig . 15 . Contrast-enhanced axial computed tomogram

revealing contrast enhancing, soft tissue mass involving both intraconal and extraconal tissues .

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J

Fig . 16 . T-l weighted (TR 600 msec/l'E 20 msec) MRI in a patient with a capillary hemangioma displaying a right superior orbital mass which is isointense to brain and hypointense to orbital fat . Several circular hypointensities are seen within the mass corresponding to blood vessels being seen in cross section .

tomography . . "s CT scans can also detect the anatomic relationships of the tumor to important orbital structures, particularly the optic nerve, extraocular muscles, and vascular structures such as the superior ophthalmic vein . D . MAGNETIC RESONANCE IMAGING The tumor is of intermediate intensity on TIweighted studies, hypointense in relation to orbital fat and isointense to muscle' s,74 (Fig . 16) . Capillary hemangioma is hyperintense on T2weighted studies due to slow blood flow within the tumor mass, and thus is well contrasted against a background of orbital fat (Fig . 17) . Major feeding vessels appear as black, serpigenous

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Fig . 17 . T-2 weighted (TR 2000 msec/TE 90 msec) axial MR of patient with predominantly preseptal capillary hemangioma of the left orbit .

structures due to the "flow void" phenomenon on most spin-echo sequences, including those in which gadolinium enhancement was employed (Fig . 18) . The rapidly moving blood in these larger vessels outpaces the stimulation-reception parameters of the MR sequence, therefore not generating a detectable signal . The tumor mass will enhance following gadolinium-DTPA constant administration, therefore fat suppression is advantageous when viewing the tumor on T1weighted enhanced images (Fig . 19) . E . ANGIOGRAPHY Although rarely utilized for establishing the diagnosis, angiography has proven useful in the past and is still sometimes indicated . Orbital venography helps to evaluate orbital masses and disorders of the orbit's venous drainage.47 ''a Venography is not diagnostic in patients with capillary hemangiomas and is technically diffi-

Fig . 18. Left: Oblique T-l weighted (TR 600 msec/TE 20 msec) gadolinium enhanced MRI of a patient with a right orbital capillary hemangioma . Right: Large feeding vessels are depicted as black serpiginous structures arising from the ophthalmic artery .

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Fig. 19 . T-I weighted (TR 600 msec/TE 20 cosec) gadolinium enhanced, fat suppressed axial MR depicting extensive hemangiomatous involvement of the preseptal tissues, however, no significant retrobulbar invo[vement.

cult and at times associated with complications ."' Arteriography, on the other hand, is rarely diagnostic but in extremely rare situations it is useful in the management of orbital capillary hemangioma . 3], .,2,ns.202 .210 Capillary hemangiomas normally have one or more large-caliber feeder vessels and drainage vessels that can be seen by arteriography . Because the blood flow is high within it, the capillary hemangioma is welldelineated from the surrounding, less well-vascularized tissues . The tumor looks like a blush during the capillary phase . A grossly enlarged ophthalmic artery, internal maxillary artery, and frontal branch of superior temporal artery may be found feeding the tumor . The mass often drains to the dilated superior ophthalmic vein into the cavernous sinus . Although the diagnosis of capillary hemangioma is often apparent from other, less invasive examination techniques, the arteriogram delineates the margin giving the exact location of the anterior feeding and draining veins ." Ligation of these major vessels has obvious benefits in the control of bleeding during surgery, but biopsy or excision does not always require identification of the feeding vessels . Knowledge of the detailed vascular anatomy, as supplied by arteriography, is obviously needed in treating the condition with sclerosing agents and arterial embolization ." s Superselective embolization is extremely hazardous and should be reserved for life-threatening hemangiomas unresponsive to other, less risky therapies . F. BIOPSY With the advent of less-invasive diagnostic

HAIK ET AL techniques, biopsy of capillary hemangiomas has become less common . Certain cases, however, still warrant a biopsy, the most common being the infant with rapidly expanding proptosis and no superficial or visible abnormalities or discoloration . The differential diagnosis here can include rhabdomyosarcoma, metastatic neuroblastoma, lymphangioma, inflammatory mass, and other rare conditions . Biopsy should be reserved, however, for cases not easily diagnosed by less invasive techniques . The rare possibility of surgical complications such as infection, hemorrhage, damage to ocular motility, and visual loss must always be kept in mind when biopsy is considered . The surgical approach to the orbit is dictated by the location of the tumor as delineated by CT, MRI, or preoperative arteriography . Judicious use of cautery, compression, or hemostatic agents is usually sufficient for control of bleeding. Although surgery during the hypertrophic stage has been reported to exacerbate the innate growth tendency of the tumor, 109 we have been unable to find convincing documented substantiation of this concept .

VII. Therapy A . INDICATIONS

Most capillary hemangiomas regress spontaneously in large amount . Edgerton states, "The choice of optimum method of treatment for a given hemangioma not only depends on the specific variety of hemangiomas under consideration, but also may change with its precise extent, the age of the patient, and the exact anatomical location of the angioma . Both treatment and prognosis of hemangiomas are further complicated by the fact that the congenitally predetermined ultimate extent and pattern of a given hemangioma may be occult and completely indeterminate at the time of initial diagnosis ."" The variability and unpredictability of this tumor's biological behavior makes counseling individual patients difficult and creates difficulty in comparing the effectiveness of various therapies . Unless there are specific ocular, dermatologic, or systemic indications for rapid resolution, treatment should be withheld, in as much as all therapeutic modalities have real or theoretical risks .97"74 '205 Ocular indications for treatment include occlusion of the visual axis by tumor infiltrating the lid and periorbita, compression of the optic nerve by the rapidly growing tumor, or corneal exposure secondary to severe proptosis . Evidence is mounting that tumor-induced anisome-

CAPILLARY HEMANGIOMA tropia is reduced with early therapy . Dermatologic indications for treatment are severe hypertrophy of the epidermal and subcutaneous tissues, leading to maceration and superficial erosion of the epidermis . This superficial breakdown predisposes the skin to secondary infection and disfigurement through scarring . Systemic indications for treatment include : cardiovascular (high-output congestive heart failure), hematologic (thrombocytopenia and hemolytic anemia), and obstructive (nasopharyngeal, oral, or subglottic extensions of the hemangioma) complications . Discussing the natural history of capillary hemangioma with the family and explaining the advantages and disadvantages of administering or withholding therapy is helpful ."' Having parents study photographs of children who have undergone spontaneous regression and speaking to parents of children whose tumors have reached maximal regression can also be helpful . When selecting the treatment, one should know that a number of techniques can be effective, including supportive measures, vascular occlusion, excision, radiation, corticosteroid administration, interferon, and laser therapy . B. AMBLYOPIA THERAPY Our experience corroborates published reports 71,136,143,164,165,204 that severe and permanent visual loss from amblyopia can develop in infants with adnexal capillary hemangiomas . Because patients with capillary hemangioma typically present from birth to two months of age while they are developing their fragile visual sensory system, the threat of deep amblyopia is cause for great concern . The ophthalmologist can monitor visual funciton with fixation-preference or preferential-looking techniques .'-"' 230,236 Visual acuity should be assessed and cycloplegic retinoscopy done at least monthly in these infants until either the hemangioma begins to regress or evidence of amblyopia, refractive asymmetry, or strabismus appears . Once astigmatism of more than 1 .50 to 2D is induced," the visual axis becomes obscured, 212 or the lesion starts to expand rapidly, treatment of the tumor should be considered . 121 In addition to simply shrinking the tumor, early successful treatment of adnexal masses, including dacryoceles as well as hemangiomas, has been shown to reverse the induced astigmatism and thereby avert the development of amblyopia . 3,122 .147 Because the younger the patient at the time of tumor regression the better the chance of diminishing the induced astigma-

411 tism, we repeat intralesional corticosteroid injections 4-8 weeks after the first treatment if significant astigmatism and amblyopia persist . Once amblyopia is suspected, the normal eye should be immediately patched and any indicated optical correction prescribed as treatment of the tumor is planned . The optical correction is usually initiated with spectacles, although contact lenses may be chosen when the size and location of the tumor preclude the fitting of glasses . Aside from the treatment of the tumor, the management of amblyopia caused by capillary hemangioma is not unlike the management of patients with other causes of early visual deprivation, such as unilateral congenital cataract . 3,69,92 In general, occlusion therapy for severe amblyopia in infants less than one year of age will include patching the better eye for all but two waking hours every day . The patients probably should be seen weekly until vision is equal in both eyes, after which the patch time can be reduced to half a day or less, and gradually diminished over several weeks toward the point of discontinuance . If amblyopia is mild or moderate without associated strabismus, optical correction alone and/or combined with only 4-5 hours per day of patching usually suffices to normalize fixation . This partial patching technique should be considered in amblyopic patients with straight eyes who could be rendered strabismic by occlusion therapy since it can disrupt the immature binocular fusional reflexes ." Frequent follow-up during treatment in this extremely young age group is vital for detecting the earliest signs of amblyopia, as well as for preventing occlusion amblyopia in the patched eye . Unfortunately, parental compliance with amblyopia therapy is sometimes poor since patching occludes the normal side of the patient's face and serves to accentuate the cosmetic defects associated with the hemangioma. Management of strabismus in hemangioma patients is usually delayed until amblyopia therapy is completed and the orbital portion of the tumor shows evidence of regressing . Muscle surgery is usually not necessary because the strabisinus may resolve concurrently with regression of the hemangioma . Computerized imaging techniques may help in determining the amount of regression by displaying the anatomic relationship between the tumor and extraocular muscles . By delaying muscle surgery until the tumor shrinks significantly, one avoids potential hemorrhagic operative complications and improves the predictability of the procedure .



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C. SURGERY Surgical procedures can reduce tumor size through (a) compromise of the major arteries feeding the tumor; (b) constriction and sclerosing of the smaller vascular channels ; or (c) primary surgical excision of the mass 85 Ligation of afferent vessels either surgically 21 or through intraarterial embolization 13ss," , u5,184 can effectively decrease blood flow to the tumor mass, thereby stimulating further involution and/or decreasing vascularity before excisional surgery . Accurate radiographic display of the major vessels is necessary for selective interference with the tumor's vascular supply . Such display is often difficult because of the complex configurations and anastomoses assumed by major feeding vessels to the tumors . Adjacent, uninvolved critical ocular, orbital, or intracranial structures may be damaged secondary to inadvertent ischemia after vascular occlusion . Generally, therefore, this therapy is reserved for masses causing significant functional complications that have resisted other forms of therapy . '" Attempts to stimulate the natural involutionary process by destroying smaller vascular channels and stimulating thrombosis include compression, cryotherapy, diathermy, and the injection of either sclerosing solutions or boiling water . 7,42,129,135 .152 .171,231 Each of these methods can certainly speed tumor involution, but they may also lead to more pronounced cosmetic and functional deformities than would have occurred with natural involution or alternative, less destructive forms of therapy . s r•st,r2 Excision is occasionally effective for small, relatively, localized adnexal hemangiomas unresponsive to pharmacologic therapy and causing visual complications and for elimination of fibrovascular remnants after regression . Primary excision of large, actively growing tumors has enjoyed limited popularity because of the diffusely infiltrative nature of these masses, the lack of encapsulation, and the resultant difficulty in differentiating the tumor from critical adjacent orbital structures . When extensive surgery is necessary, we strongly recommend obtaining a preoperative magnetic resonance angiogram, arteriogram, or digital intravenous angiogram to delineate the major vascular channels of the tumor . Blood-typing is advisable in small infants where substantial blood loss is considered a possibility . The risks and benefits of hypotensive anesthesia should be considered since it minimizes blood loss and permits more accurate visualization of orbital structures during surgery . Com-

HAIK ET AL plications of surgery include the inevitable creation of surgical scars and the inadvertent excision of critical vascular, muscular, and neurogenic components of the orbit . Children and infants must be thoroughly evaluated before surgery to rule out other coexisting and even life-threatening abnormalities, such as cardiac and hematologic diseases, and tumors that could compromise the airway during the incubation. The orbit can be approached by any of the standard routes : conjunctival, anterior, or lateral orbital. The skin should be incised in a natural lid or brow crease and rarely should skin be excised . One should carefully identify all critical ocular structures visible in the field, such as the lacrimal gland, lacrimal drainage apparatus, and extraocular muscles, to avoid injuring them during dissection . A canalicular stent is often helpful when dissecting or suturing near to the canaliculus, and a traction suture may be passed under the insertions of the rectus muscles to help localize the muscle bellies during the procedure . When the conjunctiva is involved, care is taken to spare all uninvolved tissue for later closure and reconstruction of the fornices . Sharp and blunt dissection under coaxial illumination and magnification should be meticulous in freeing the tumorous tissue from adjacent critical orbital structures . When the chief intent of the surgery is diagnosis, one can obtain a frozen section and inject corticosteroids under direct visualization during the same procedure . When a highly vascular tumor is isolated for excision, a curved hemostat may be used to crush the base of the tumor, and a razor or scissors used to cut free the distal segment . Diathermy is then applied to the tumor pedicle before the clamp is removed and the tumor retracts posteriorly . This simple maneuver helps prevent immediate and postoperative blood loss . Alternatively, the tumor may be transected utilizing electrocautery or a laser, which coagulates as it cuts . T he orbital incision is then closed in a standard fashion . If the surgery has been done under hypotensive anesthesia, one should raise the blood pressure levels to normal before closing the wound completely, to prevent postoperative orbital hemorrhage . Deans et al recently reported a surgical approach that involves dissection on the tumor's surface without entering its substance .49 Hemangiomas were removed en bloc from five patients with insignificant blood loss and excellent anatomic restoration . Surgical time required ranged from two to eight hours . These authors point out that surgical dissection

CAPILLARY HEMANGIOMA is not appropriate for capillary hemangiomas that extend into the dermis, or for massive, diffuse facial lesions . This approach would also appear potentially hazardous in patients with extensive tumor feeding vessels in the posterior orbit such as in the patient seen in Fig . 18 . D. RADIATION Radiotherapy can be highly effective in the management of capillary hemangioma sas7,18s .w2 . 156,164 .165 Low-level radiation can help create microembolisms in these vascular tumors and speed regression of the mass . Either supervoltage or orthovoltage radiotherapy in the 150-250 rad range is administered in a single treatment, with appropriate shielding of the globe and adjacent uninvolved tissues . An involutionary response usually occurs in I to 2 weeks, and treatment may be repeated to achieve additional resolution . 87 Only rarely should cumulative doses of more than 750 rads be used . Both radioactive needles and seeds can be effective in the treatment of deep-seated hemangiomas,' 8• 92 but they necessitate more complex planning, because shielding of uninvolved structures is impossible . In the past, when large doses of radiation were administered and methods of delivery and shielding were less exact, radiation-induced complications of the skin, orbit, and eye were commonplace . 29,170,234 With present improved delivery precautions and shielding, direct damage from radiation should not occur,"' although it is possible to induce a radiation cataract with 200-600 rads 144 when the anterior segment has not been adequately shielded . Our primary concern in the radiation treatment of these benign tumors in the pediatric population is the potential for radiation oncogenesis . The fear of radiation oncogenesis following therapy for benign pediatric ophthalmic conditions stems primarily from the high rate of thyroid cancer induction observed in patients treated for benign nonophthalmic conditions . A remarkably high incidence of thyroid cancer has been noted after radiation therapy and a long latent period for childhood conditions such as thymic, tonsillar, or adenoid hypertrophy, chronic respiratory disease, tinea capitis, and acne . 19,62 This linkage between irradiation and thyroid carcinoma has been striking, and the statistical indictment against radiation continues to increase with time . One should note, however, that this experience with thyroid cancer should not be extrapolated to the general pediatric patient population, as the thyroid gland is known to be exquisitely sensitive to irradiation and not

413 typical of other body tissues . Furthermore, the radiation-induced hypothyroidism and the circulating level of thyroid-stimulating hormone of the patients is also an important factor in carcinogenesis . With modern delivery and shielding techniques, the thyroid no longer receives radiation for most benign tumors unless those tumors compromise breathing and are in the region of the thyroid gland. The indictment of low-level irradiation oncogenesis in other tissues of the body is much less convincing ; however, some authorities believe the evidence shows that a risk is being taken whenever low-level radiation is used . The Gray hypothesis" suggests that tumor induction increases with dose to a certain level of maximal tumor induction (about 1000 rads), after which the rate of cell death mitigates the induction effect . Experimental and clinical evidence exists that both supports and contradicts that hypothesis, and it is presently not possible to wholly accept or reject it . Scattered case reports of radiation oncogenesis in capillary hemangioma patients exist . Talmi201 and associates examined a patient who developed thyroid carcinoma, cataract, and decreased hearing 35 years after treatment of a large facial hemangioma with 24,000 rads. Ward and Buchanan218 reported on a patient treated with about 1000 rads at five months of age who developed a facial hemangiosarcoma at 18 years of age . Several large studies of the cancer incidence following radiation therapy for skin hemanagiomas have shown conflicting results . In elaborate retrospective studies '69,70 Furst et al found a slightly increased cancer risk in capillary hemangioma patients treated with radium-226 or orthovoltage therapy. Conversely, Li et alts' followed up nearly 5000 children treated with 300-600 rads over 20 years and found no significant excess of malignancies . It seems reasonable, though, that irradiation should be restricted to clinical situations where an alternate therapy is not available and a serious functional deformity is likely to occur without treatment . As in any therapeutic situation, clinical judgment is required to determine whether this small risk of radiation cancer induction is justifiable in terms of potential clinical gains from radiation therapy" E. SYSTEMIC CORTICOSTEROIDS In 1967, Zarem and Edgerton reported on seven infants with large capillary hemangiomas who responded well to treatment with systemic



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corticosteroids . 284 The effectiveness of this therapy in stimulating tumor regression has now been supported in the literature .1 .51,56,57,67,W,197 The most commonly recommended oral corticosteroid dose is either 1-2 mg/kg of prednisone daily, or 2-4 mg/kg on alternate days . Tumor shrinkage is often dramatic and typically noted within two weeks, but the response rate has varied among study groups ." Other investigators have reported disappointing amounts of tumor regression in the orbit 87 .92 and a high incidence of rebound tumor growth when the dosage of corticosteroids is tapered down or discontinued . This tendency for rebound growth has prompted physicians to keep some patients on steroids for many months ."," 94,234 This prolonged steroid use has raised concern as to the risks involved, including growth delays, cushingoid features, and susceptibility to infection . Considerable speculation exists concerning the mechanism of corticosteroid stimulated in234 volution . Zarem and Edgerton found minimal histologic evidence of inflammatory activity in their biopsy specimens of three patients . They proposed, along with others, that steroids may have antianabolic effects on immature vascular tissue . 67 ' 127 De Venecia and Lobeck, however, noted that the anti-inflammatory effect of steroids appeared to fit the dramatic responses and relapses noted in their case and by other authors ." Others believe that the mechanism of steroid action may be secondary to a vasoconstrictive effect . Zweifach"s7 and associates showed that corticosteroids increase vascular sensitivity to circulating vasoconstricting agents . Such sensitivity could result in vascular constriction that stimulates local hypoxia and the cascade of regression . Although the mechanisms of the corticosteroid effect on the proliferation of hemangioma cells is not clear, a considerable amount of research data has accumulated in the literature on the pharmacological inhibition of angiogenesis . Experimentally, corticosteroids have been shown to reduce the rate and extent of blood vessel growth .'' Certain tetrahydrocortisone analogs have been proven to act more potently as inhibitory agents of angiogenesis than the parent hormone, hydrocortisone ." There is also ample evidence that in some cases, steroids have better angiostatic activity in combination with heparinP'' 66 The hexasaccharide component of heparin actively inhibits the angiogenesis when given with corticosteroids 65,66 Corticosteroids may also inhibit activators of

fibrinolysis in the vessel walls, thereby changing the balance in the coagulation-fibrionolysis equation toward incrasing coagulation . Detailed information as to how corticosteroids affect capillary hemangiomas is scant because no acceptable animal model exists, and few histologic studies on recently treated tumors have been undertaken .

414

F. INTRALESIONAL CORTICOSTEROIDS The most promising advancement in the treatment of capillary hemangiomas is the use of intralesional corticosteroids . The rationale for such treatment is to deliver a high concentration of the medication directly to the tumor while minimizing systemic absorption . This technique, first described in patients with nonorbital cutaneous hemangiomas,1i 1a1184h,2s4 was then popularized for periocular lesions by Kushner, 121 who in 1979 reported success in three of four patients injected with triamcinolone and betamethasone sodium phosphate . Subsequent reports 16 .27 .33.48,61, 64,86 .122,121,155 .196233 were generally favorable, and today this technique is the most commonly used form of therapy . Injections may be the primary form of treatment in anterior hemangiomas or after biopsy or partial excision in deeper orbital areas. Computed tomography and ultrasonography may be employed for needle localization and guidance when injecting deep orbital tumors (Fig . 20) . Several therapeutic injection regimens comprising various doses and combinations of shortand long-acting steroids have been successful . Kushner's regimens are most commonly used and he presently recommends separate injections of40 mg of triamcinolone acetate and 6 mg preparation consisting of betamethasone acetate and betamethasone phosphate . 125 The total amount of this mixture injected varies according to the size of the tumor, but it is usually 1-2 m1 . 124 Nelson 1F' uses triamcinolone (80 mg) and dexamethasone sodium phosphate (16 mg) for large tumors and half that amount in smaller masses . Others have utilized triamicinalone (20-40 mg) and lower doses of dexamethasone (4-8 mg) 61,64,147 Apt 12 points out that physicians have given the same dose of intralesional corticosteroid to patients regardless of the size of the hemangioma or the size of the pediatric patient . He warns that the amount of corticosteroid absorbed systemically from injections relative to a patient's size could be excessive and thus lead to troublesome side effects, including adrenal gland suppression . Apt therefore determines his

CAPILLARY HEMANGIOMA dose on the basis of the patient's weight . Initially, he gave four sequential weekly injections of Celestone Soluspan-a commercial preparation that consists of a mixture of 3 mg of betamethasone phosphate and 3 mg of betamethasone acetate in a I ml volume . His dose for pediatric

415 patients was 0 .4 mg of bethamethasone per kg body weight. Apt indicates that the action of this corticosteroid salt combination lasts about one week . Because weekly injections were inconvenient for some patients, Apt more recently has added triamcinolone acetonide, which has an ac-

Three-week-old infant born with capillary hemangioma involving left medial orbit and causing total pupillary occlusion, Patient's refraction on retinoscopy O .D . +0 .50 sphere, OS . -9 .00 +9 .00 x 180 . B . The left globe is noted to be compressed and displaced temporally on contrast enhanced axial computed tomography . C . The anterior portion of the tumor was injected under direct visualization . D . - 1 he deep tumor is injected under ultrasonographic guidance (arrows depict location of needle) . E . Eight weeks after injection an open pupillary axis is noted . On retinoscopy, O .D . + 0 .25 sphere, O .S . -2 .50 +2 .00 x 135 . F. Almost complete regression oftumor at five years of age ; compliance with patching was moderate to good, with a satisfactory visual outcome : O .D . piano=20/25, O .S . -2 .75 +2 .00 x 140, 20/40 . Fig . 20 . A .

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Lion time of 3 to 4 weeks, to the betamethasone preparation . The mixture of these three corticosteroid salts, he points out, permits a continuum of action starting immediately and lasting 3 to 4 weeks (Apt L: Personal communication) . Apt's present plan of treatment is as follows. One ml ofCelestone Soluspan is combined with I ml of Kenalog 40 (40 mg of triamcinolone acetonide) ; this blend provides a corticosteroid dose equivalent to 100 mg of prednisone . In infants, Apt usually starts treatment by injecting into the hemangioma an amount of the mixture equal to a prednisone dose of 6 mg/kg body weight . If a second injection is needed, the dose may be increased up to 9 mg/kg body weight . More than the full 2 ml of the mixture is rarely given to infants . If no response is seen after two, occasionally three, injections, Apt questions the diagnosis or concludes that the hemangioma is a type unresponsive to corticosteroids . Injections are usually given under general anesthesia without intubation . Separate 1-3-cc syringes with 25-27-gauge needles are used for each substance . The medication is evenly distributed throughout the tumor under low injection pressure while the needle is slowly withdrawn . These maneuvers minimize the possibility of retrograde injection into arterial channels and thus the likelihood of deposteroid embolization . Deans et a1 49 have suggested that perilesional, rather than intralesional, administration might limit intravascular dissemination . They, however, do not discuss any patients successfully treated in this fashion . Morrell and Willshaw reported on 27 patients with steroid injections . 141 in their first five patients, the steroid was injected "round the margins of the lesion," and one child developed subcutaneous fat atrophy which resolved over six months . Thereafter, the authors converted to injecting directly into the tumor in 22 patients and no serious complications were seen in these children . Most tumors will require multiple injections to achieve adequate distribution of the steriod . If a hemangioma is massive and requires an unacceptably high dose of corticosteroid, one should limit the injection to the most critical area, such as the upper lid when ptosis is obstructing the pupillary axis . The tumor may enlarge noticeably after the injection because of the bulk of medication and, rarely, hemorrhage, but mild pressure over the area assures hemostasis . The retinal vessels should be examined during and after the injection for possible compromise of the central ret-

inal artery . Ice packs may be valuable in the immediate postoperative period ; however, it is important to avoid firm pressure . This temporary swelling subsides in 24 hours, and within 2 3 days much tumor blanching may be seen . Involution of the tumor may begin several days after injection, and will usually be considerable within 2-4 weeks (Fig . 21) . Additional injections within 4-8 weeks are required in most patients to obtain satisfactory regression . Complications from local steroid therapy may vary according to the frequency, quantity, and method of injection . Although various side effects have been reported after intralesional corticosteroid injections, the incidence of serious complications has been relatively low . 16,33,23.1 Kushner, for example, reported having no serious complications in 25 patients. 121 Serious, potential complications that may result from injection into a vascular tumor include retrobulbar hemorrhage and inadvertent ocular penetration . The most serious reported complication has been central retinal artery occlusion ."' Short speculated that sufficient force from the injection or digital pressure may have resulted in retrograde flow of the steroid particles into the central retinal artery. The particle size of commonly used steroid preparations ranges from IOM to 50M, compared with 6M to 7M for erythrocytes, and may be much larger if the steroid particles aggregate . Aging of the medication, its exposure to air, or an incompatibility between solutions that results in flocculation when mixed36 .134,185 .227.228 may cause the aggregation . Crystal growth with particles measuring 50µm to 200µm may occur during storage of suspensions of hydrocortisone acetate, cortisone acetate, and prednisolone . To avoid these problems, one should use only unopened vials of medication and mix only medications known to be compatible . The bottle of deposteroid and the filled syringe should be thoroughly agitated immediately before injection . Low-pressure injections are best, and funduscopic examination should follow routinely . Rututm et al' s' reported bilateral retinal embolization following intralesional corticosteroid injection in an infant with a periocular capillary hemangioma . Although the authors were unable to provide with certainty the etiology of the reported complication, they state "the most plausible route for corticosteroid particles to reach both the contralateral and ipsilateral ocular circulation from an injection that did not cross the

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CAPILLARY HEMANGIOMA

417

midline would be to travel in a retrograde direction through distal branches of both ophthalmic arteries that were involved as feeding vessels in the capillary hemangioma ." They thus stated, "based on the mechanism we have proposed, it would seem prudent to avoid altogether or to use extreme caution with corticosteroid injection of any portion of a capillary hemangioma approaching the midline of the face ." It is important to note that although this is an important case report, numerous patients with medial orbital hemangiomas have been treated with intralesional corticosteroid injections to date, and this is the only reported patient with such a complication . Eyelid necrosis following an intralesional corticosteroid injection was reported by Sutula and Glover .' They speculate that the "vasoconstrictive effect would seem to be more potent in a rapidly expanding capillary hemangioma that is outstripping its blood supply ." Jakobiec and Jones also noted this phenomenon in untreated hemangiomas consequent to spontaneous thrombosis or necrosis ."' Minor complications are more common, especially the presence of white or yellow subcutaneous deposits representing the deposteroid complexes . 16,s6,122 These deposits resolve during several months ; however, focal areas of hypopigmentation in the overlying skin may persist, especially in patients with darkly pigmented skin ." Local fat atrophy is a well-known complication of corticosteroid injections and has been reported in the periocular region ." The putative mechanisms include localized lipolysis from direct action of steroid crystals, vasoconstriction with hypoxia and resultant tissue necrosis, and allergic reaction to the medication . Although local fat atrophy is not uncommon, linear subcutaneous atrophy along lymphatic channels was not reported until 1988 by Droste et alb" The corticosteroid apparently migrates along the route of normal lymph channels, causing the adjacent fat atrophy and producing a linear facial depression . Linear subcutaneous atrophy has shown a variable tendency to resolution as the deposteroid dissipates ."-"'.208 Transient adrenal suppression and cushin.17,"1-'93,222 goid symptoms have been reported These findings underscore the importance of avoiding immunizations with live attenuated viruses for four weeks before and after injections of corticosteroids . Weiss 122 diagnosed growth retardation in two patients having adrenal suppression after corti-

Fig. 21 . Top: Infant with right lower lid and inferior

orbital hemangioma at two months of age . Center: Following intralesional corticosteroid injection, the tumor has dramatically decreased in size over a one month period, and the pupillary axis is no longer obstructed . Bottom: At two-and-one-half years of age, the tumor continues to show signs of regression and the patient is responding well to amblyopia therapy .



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costeroid injection into periocular hemangiomas . He reports that this suppressive effect was mediated by intravascular absorption of the corticosteroid, with feedback inhibition of adrenocorticotropic hormone secretion . Glatt et al also reported two patients with growth suppression, and therefore stressed the importance of monitoring adrenal function in such patients." Romano 15b et al reported death ofan 11-month-old girl who developed Cushing's syndrome after routine topical and periocular dosages of fluorinated corticosteroids following corneal homografts for sclerocornea . Topical betamethasone valerate cream has been used in combination with external compression to speed resolution of an extremity hemangioma . 22°

have reported that interferon-associated retinopathy is occurring in adults with increasing frequency, and they emphasize the importance of monitoring patients who are receiving interferon alfa therapy for these retinal complications, which may rarely be associated with permanent loss of vision secondary to closure of retinal capillaries .' The incidence of interferonassociated retinopathy in infants is unknown .

G. INTERFERON Interferon alpha-2a was initially developed as an antiviral agent but subsequently was found to have antiangiogenic activity in vitro and in a few studies involving small groups of patients ." , ` 60,224 The mechanism of action is unclear ; however, interferon inhibits both endothelial cell and fibroblast proliferation, as well as production of endothelial prostaglandins in experimental studies. Encouraging clinical results have been observed although treatment has been generally reserved for life- or sight-threatening corticosteroid resistant hemangiomas . 22.1 $3 Dosage and administration regimens are being refined continually . Ezekowitz et a160 utilized daily subcutaneous injections of interferon alfa2a (up to 3 million units per square meter of body surface area) . In 18 of their 20 patients, the hemangiomas regressed by 50% or more after an average of 7 .8 months of treatment . The response to interferon therapy may be slow, thus often not rapid enough to alleviate impending amblyopia . Since daily visits to the physician for weeks or months may be required and the effect of interferon therapy is often mild, this treatment has enjoyed limited popularity for orbital lesions . Side effects are common and both time and dose dependent ; thus, patients must be closely monitored . The severity and reversibility of these adverse reactions are variable, but, usually mild (fever, neutropenia) in children . Ezekowitz noted no longterm toxicity after a mean follow-up of 16 months .' Other side effects of interferon therapy include retinal vasculopathy, fatigue, nausea, vomiting, elevated levels of liver enzymes, leukopenia, neurotoxicity, and EEG abnormalities . 22 .111 .1°"914 Guyer et al

H. LASER THERAPY Laser therapy has been advocated for the treatment of capillary hemangioma . The carbon dioxide, argon, neodymium YAG, and flashlamp pumped-dye laser have all been utilized . The carbon dioxide laser has been used to treat eyelid hemangiomas ." This laser is in the infra-red range and has the advantage of coagulating small blood vessels while cutting through the vascular tumor . 22 s Unfortunately, large vessels are not easily coagulated, and surgical landmarks are obscured by tissue charring. The argon laser produces intense light in the blue-green (480-521 nm) spectrum . This laser light is selectively absorbed by red hemoglobin pigment and converted into heat that then coagulates blood vessels in the upper dermis ." Preliminary results were positive ."" Hobby utilized argon laser to treat six children with capillary hemangiomas with generally favorable results ." This author felt that argon laser could be most effective if used when the lesion is first noted, before it has time to grow .' Histopathological analysis demonstrates obliteration of the large ectatic vessels to a depth of the outer 1 mm of dermis and replacement by a diffuse collagenous deposition and reconstitution of a normal epidermis .' The noncontact neodymium YAG laser produces a continuous-wave power output at 1064 nm and penetrates to a depth of 5-7 mm . " The near infrared, invisible light scatters within the tissue and is converted into heat, resulting in thermal coagulation of the adjacent blood vessels . Favorable therapeutic results have been reported in patients with capillary hemangiomas of the head and neck . 10,179,[87 Achauer compared argon and neodymium YAG laser treatment in 55 patients treated over a six-year period .' Argon laser was generally superior, although it was utilized for smaller, more superficial tumors . The neodymium YAG laser permitted treatment of massive and deep hemangiomas, but was associated with a high incidence of scarring and delayed healing. Apfelberg used YAG laser photo-

CAPILLARY HEMANGIOMA coagulation and direct steroid instillation in the treatment of infantile hemangiomas, and reported that cessation of growth and immediate institution of color blanching was achieved in all patients . Five of 13 patients experienced dramatic shrinkage, and two patients experienced significant complications .' Most of the aforementioned authors suggest that tumors should be treated early, before they can spread to surrounding tissue . However, Bilyk et a1 22 note several potential flaws in this approach . First, they point out, "hemangiomas begin as a field transformation, in a wide area, and in deeper tissues than initially surmised . Second, the small and superficial lesions, more amenable to laser ablation, usually do not cause amblyopia and do not require intervention . Third, larger, more problematic lesions are thicker than those described in current laser reports . Furthermore, there is no evidence that laser treatment to the superficial layer of a hemangioma initiates regression of the adjacent untreated tumor ." 22 They concluded that laser therapy must be considered as experimental procedure and not advocated as routine treatment . Mulliken reported earlier that thermal damage within the skin usually causes ulceration of the hemangiomatous tissue, the papillary dermis, and epidermis, resulting in scarring. 112 He suggested that, for the present, argon laser should be viewed as a sophisticated form of thermocautery and should not be recommended for cutaneous hemangiomas . More promising results have been reported with the flash lamppumped pulsed dye laser . '4145' 188 That laser emits yellow light, which is highly specific for the beta peak of oxyhemoglobin, permitting selective destruction of dermal vessels . Selective thermal damage may be induced in dermal capillaries if the emitted wavelength is tuned to 577 not and the pulse duration is less than 10 milliseconds .' In other recent clinical studies, a wavelength of 585 nm was used to allow deeper penetration into the tumor while maintaining vascular selectivity . These early reports describe accelerated tumor regression with less scarring ."" Mulliken advocates limited use of laser therapy in infants with hemangiomas, suggesting that if we knew more about the cellular mechanism of proliferation and involution of hemangioma, a specific laser might be designed to treat the l esion . 149 I. THERAPEUTIC CONCLUSIONS Capillary lemangiomas have been treated with multiple modalities over the past century .

419 The risk/benefit ratio of each modality must be carefully considered . Because the natural growth history of capillary hemangiomas is quite variable, it is often difficult to fully access the therapeutic response in an individual patient . At times, multiple modalities may be utilized in a synergistic fashion during the treatment of complex tumors not responsive to a single therapy . Rarely, a tumor will be extremely resistant to all resonable therapeutic modalities, resulting in an extremely frustrating situation for the patients's family and the treating physician . VIII . Differential Diagnosis The differential diagnosis of orbital capillary hemangioma includes rhabdomyosarcoma, lymphangioma, chloroma, neuroblastoma, dermoid cysts, cellulitis, and various inflammatory conditions ." . 77 The common thread uniting all of these entities is that each can present with a rapidly expanding orbital mass in infancy or early childhood . Of course, the typical capillary hemangioma with the superficial strawberry nevus and proptosis is usually not a diagnostic challenge . The diagnostic dilemma arises with cases of deep or, occasionally, subcutaneous capillary hemangiomas . Obviously in this situation, the explicit differentiation of an orbital malignancy from a hemangioma can be crucial . A. R.HABDOMYOSARCOMA Rhabdomyosarcoma is the most common malignant orbital tumor of childhood ." .88,"9,177,20% It is a rapidly growing tumor that arises from mesenchynral elements of the orbital tissue . It can be present at birth and has been reported in all age groups ; however 70% present within the first decade of life . There is a male predominance in contrast to the female predominance for capillary hemangiomas . Rhabdomyosarcomas usually present as a rapidly expanding orbital mass with proptosis . Radiographic studies may show a discrete mass present in the orbit, and often with erosion of orbital bone . Diffuse orbital enlargement is not typically noted because this rapidly growing tumor invades bone easily, rather than molding it. On CT, the soft tissue mass appears somewhat similar to capillary hemangioma in radiographic density, but enhances slightly less . On MR, the tumor is mildly less intense on T2weighted studies . The management of rhabdomyosarcoma generally includes immediate biopsy and metastatic work-up, followed by combination chemotherapy and external-beam irradiation . Recently, however, some surgeons have



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favored extensive debulking of the tumor followed by chemotherapy and no irradiation . In any case, treatment obviously differs greatly from that of capillary hemangioma ; thus, any orbital tumor showing a reasonable chance of being a rhabdomyosarcoma must undergo biopsy .

enhances following gadolinium-DPTA adminis-

B . LYMPHANGIOMA (MICRO- AND MACROCYSTIC LYMPHATIC MALFORMATIONS)

C . CHLOROMA

420

A cystic lymphatic malformation that may occur in the orbit of infants and small children, lymphangioma, like the capillary hemangioma, can present as a superficial or a deep tumor or as a combination of the two . 102 .1 .2.178 Approximately 20% of patients will have extension of tumor into the palate or maxillary region . Histologically, these tumors consist of dilated, thin-walled vascular chambers lined with endothelium and filled with a proteinaceous material suggestive of lymph . They are surrounded by a fibrous stroma containing connective tissue septae, blood vessels, and lymphocytic infiltrates including lymphoid follicles. When hemorrhage occurs into the tumor, these cystic spaces and the stroma can fill with blood . Depending on the age of the hemorrhage, these spaces could contain anything from fresh blood to organized, vascularized thrombus . Again, it is usually the isolated, deep tumor that may come into question when considering the differential diagnosis in an infantile orbital mass . Proptosis usually develops in an orbit with a lymphangioma that has undergone a spontaneous hemorrhage, a common presenting occurrence with lymphangioma . Fortunately, the spontaneous hemorrhage often provides a unique radiographic or ultrasonic condition that can help differentiate it from other orbital tumors . The hemorrhage creates large cystic cavities that can be identified on ultrasound, CT, and MRI . These large cystic spaces are not seen in capillary hemangiomas . On contrastenhanced CT, the border of the lyniphangioma is often the only component that enhances, as compared with the overall filling of a capillary hemangioma . Also, if arteriography were done, the lymphangioma would show essentially no arterial feeding of the lesion, in effect demonstrating that the fluid-filled channels are essentially isolated from the circulating blood . By contrast, the capillary hemangioma usually shows more arterial feeder vessels having drainage into the venous system . On MR, lymphatic cysts are hypointense on T,-weighted studies and by perintense on T,-weighted studies, while most blood cysts are bright on both sequences .YB Neither cyst

tration . The stroma is typically isointense to extraocular muscle on both sequences and enhances moderately . Often the clinical examination alone can differentiate the combined lymphangioma from the capillary hemangioma .

The chloroma, or granulocytic sarcoma, is another rare malignant orbital tumor that can be confused with capillary hemangioma . 551n 2s ' Like rhabdomyosarcoma, it has a male predominance (3 :2) . This tumor often undergoes a rapid proliferative phase with early development of proptosis, and there may be obvious involvement of the orbital bone on radiographic studies. The chloroma is usually an extramedullary extension or precursor of acute myelogenous leukemia ; however, because the tumor is often the first sign of the developing leukemia, biopsy is usually necessary to confirm the diagnosis . D. NEUROBLASTOMA Neuroblastoma is the most common metastatic orbital tumor of early childhood . 15477 Although the lesion often has systemic manifestations of the disease by the time orbital signs appear, 8% of neuroblastomas will have orbital disease as the presenting symptom . Overall, 20% of neuroblastoma patients will have ophthalmic manifestations . The age of onset is similar to that of capillary hemangioma, with 50% occurring before the age of two years . The disease is characterized by a sudden onset ofproptosis and ptosis, with ecchymosis, not usually seen in capillary hemangioma patients, being a distinguishing factor . Neuroblastoma is bilateral in 40% of cases, which would be an unusual finding in capillary hemangioma . CT scan of the orbit often shows destruction of the orbital bone, in constrast to what is seen with capillary hemangioma . Necrosis of the tumor or evidence of cranial metastases may also be seen . Chemotherapy, radiation therapy, and occasionally excision are all used in attempts to treat this disease . E . OTHER NEOPLASMS Other less common neoplasms may also occur in early childhood and may present with a sudden proptosis, and often with inflammatory signs . These include Swing's sarcoma, medulloblastorna, and Wilms' tumor ."" F. ORBITAL CYSTS Although dermoids, rnucoceles, and encepha-

CAPILLARY HEMANGIOMA loceles can all cause proptosis in early childhood, radiographic or ultrasonic studies should be able to distinguish those lesions from capillary hemangioma . 9° ' 17 On CT, the dermoid is usually spherical or ovoid and well demarcated, often showing in the lateral orbit with mixed internal densities reflecting keratin and sebaceous material . In large cysts, the orbital bone may be focally expanded or the orbital cavity may be enlarged . On CT, the mucocele will have a homogeneous fluid or tissue density, and is seen arising from one of the paranasal sinuses and extending into the orbit from the sinus cavity . Encephaloceles can present in early childhood, occasionally enlarging slowly to cause proptosis . On CT, one will often see a cyst-like structure that appears to arise from the cranial cavity and to extend through a bone defect into the orbit . G. CELLULITIS Acommon disease of childhood, orbital cellulitis can present in any age group . 10° .12° .177 Proptosiss and ocular displacement can occur along with lid edema and erythema . Often, a history of trauma or upper respiratory infection is obtained . Often, there are systemic signs of infection, with fever and leukocytosis . These findings rarely occur with capillary hemangioma . On CT, the cellulitis often shows a diffuse edema without a discrete mass, unlike that of the capillary hemangioma . In addition, sinus opacification and subperiorbital abscess formation is commonly seen in patients with orbital cellulitis and not in those with capillary hemangioma . Treatment of orbital cellulitis consists of appropriate systemic antibiotics and surgical drainage of abscess formation . IX. Summary Capillary hemangiomas are the most common orbital tumors in infants . Although the overwhelming majority of these lesions can be diagnosed on clinical inspection of the child, ancillary diagnostic tests are valuable in establishing a secure diagnosis and outlining the tumor's extent . A thorough understanding of the tumor's natural history and response to available therapeutic modalities are critical to appropriately managing this disorder . References 1 . Achauer BM, Vander Kam VM : Capillary hemangioma (strawberry mark) of infancy : comparison of argon and Nd :YAG laser treatment . Piasl Reconstr Surg 84:60-69, 1989 2 . .Al-Rashid RA, Griffiths J : Induced resolution of orbital hemangioma with prednisone therapy . J Pediatr Ophthalmol 7 :167-170, 1970

421 3 . American Academy of Ophthalmology: Ambhupia, Preferred Practice Pattern . San Francisco, American Academy of Ophthalmology, 1992 4- Amir J, Metzker A, Krikler R, Reiser SH : Strawberry hemangioma in preterm infants . Pediatr Dernatol 3:131, 1986 5 . Anderson RR, Parrish JA : Selective photothermolysis : precise microsurgery by selective absorption of pulsed radiation . Science 220:524-527, 1983 6 . Andrews CC, Domonkos AN, Post CF : Treatment of angiomas: summary of twenty years experience at Columbia Presbyterian Medical Center . Am J Roenigenol 67273-285, 1952 7 . Andrews CC, Domonkos AN, Torres-Rodriguez VM, Bemhenista j K : Hemangiomas - treated and untreated, J.AMA 165: 1114-1117, 1957 8 . Apfelberg DR, Greene RA, Maser MR, et al : Results of argon laser exposure of capillary hemangiomas of infancy - preliminary report . Plant Reconsf Surg 67: 188-193,1981 9 . Apfelberg DB, Maser MR, White DN, et al : A preliminary study of the combined effect of neodymium : YAG laser photocoagulation and direct steroid instillation in the treatment of capillarylcavernous hemangiomas of infancy . Ann Plastic Surg 22:94-104, 1989 10 . Apfelberg DB, Maser MR, White DN, et al : Benefits of contact and noncontact YAG laser for periorbital hemangiomas . Ann Plait Surg 24 :397-408, 1990 11 . Appelbaum FR: Introduction and overview of interferon alfa in myeloproliferative and hemangiomatous diseases . Semis Hematol fSufipl 4) 3 :1-5, 1990 12 . Apt L : Intralesional corticosteroid therapy for infantile hemangioma . Audiadige_sl, Ophthalmology, Vol . 20, No . 7, April 8, 1982 13 . Argenta LC, Bishop E, Cho KJ, et al : Complete resolution of life-threatening hemangioma by emholization and c orticosteriods . PMa.s i Recon,l Surg 70 :739-744, 1982 l4 . Ashinoff R, Geronemus RG : Capillary hemangiomas and treatment with the fash lamp-pumped pulsed dye laser . Arch Dermatol 127:202-205, 1991 15 . Ashton N, Cook C : In vivo observations of the effects of cortisone upon the blood vessels in rabbit ear chatnhers . Rr J F'xp Pathol 33 :445-450, 19 .52 16. Assaf A, Amin N, Johnson T : Corticosteroids in the management of adnexal hemangiomas in infancy and childhood . Ann Ophthalmol 24 :12-18, 1992 17 . Azzolini A, Nouvenne R: Nuove prospecttive nella terapia degli angiomi immaturi dell' infanzia, 115 lesion trattate con infiltrazioni di triamcinolone acetone . Aria Bio-Medica Ateneo Pannensa 41 :51-73, 1970 IS. BastaLL,AndersonLS,AcersTE :Regressionoforbital hemangioma detected by echography . Arch Ophthalmol 95:1383-1386, 1977 19. Becker FO, Enonomou SG, Southwick HW, Eisenstein R : Adult thyroid cancer after head and neck irradiation in infancy and childhood Ann Intern Med 83:: 347-351, 1975 20 . Bek V, Zahn K : Cataract as a late sequel of contact roentgen therapy of angiomas in children . Arta Radiol 54 :443--448, 1960 21 . Berdon WE, Baker DH : Giant hepatic hemangioma with cardiac failure in the newborn infant : Value of high-dosage intravenous urography and umbilical angiography. Radiology 92 :1523-1528, 1969 22 . Bilyk JR, Adamis AP, Mullikcn JB : Treatment options for periorbital hemangioma of infancy, in Shore JW (ed) : Orbital Disease, Vol 32, Number 3, Boston, Little, Brown and Company, 1992, pp 95-109 23 . Bingham HG: Predicting the course of congenital hemangioma . Plast Ret-orwlr Surg 63 :161-166, 1979 24 . Bland-Sutton .J : Tumours innocent and Malignant . London, 1912, ed 5

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25 . Bloch A, Lupo I, Rosen H, Vardy PA : Intestinal hemangiomas causing severe chronic gastrointestinal bleeding. Israel J Med Sci 7 :1286-1288, 1971 26 . Began S, Simon JW, Krohcl GB, Nelson LB : Astigmatism associated with adnexal masses in infancy . Arch Ophthalmol 105:1368-1370, 1987 27 . BonavolantA G, Vassallo P, Uccello C, Tranfa F : Our experience with intralesional corticosteroid injection therapy for infantile adnexal hemangioma . Orbit 4:177181, 1985 28 . Bond JB, Hails BC, Taveras JL, et al : Magnetic reso nance imaging of orbital lymphangioma with and without gadolinium contrast enhancement . Ophthalmology 99 .1318-1324, 1992 29 . Bowers RE, Graham EA, Tomlinson KM : 'The natural history of the straw berry nevus . Arch Dermata182:59-72, 1960 30. Bowles LJ, Kostopoulos-Farri E, Papageorgiou AN : Perinatal hemorrhage associated with the KasabachMerritt syndrome . Clin Pediatrics 20:428-429, 1981 31 . Bradac GB, Simon RS, Bunte M, Stellmach R : Angiography in vascular malformations of the face . Am .1 Roentgenol 129:469-475, 1977 32 . Brady LW, Cooper MR, Cummings CW, et al : Hemangioma : When to wait, when to act (Roundtable discussion) . Patient Care, June 30, 1984, pp 141-147 33 . Brown BZ, Huffaker G : Local injection of steroids for juvenile hemangiomas which disturb the visual axis . Ophthalmic Surg 13 :630-633, 1982 34 . Bulas DI, Johnson D, Allen J F, Kapur S : Fetal hemangioma : sonographic and color flow doppler findings . J Ultrasound Med 11 :499-501 . 1992 35 . Burrows PE, Lasjaunias PL, TerBrugge KG . Flodmark 0 : Urgent and emergent embolization of lesions of the head and neck in children : indications and results . Pediatrics 80:386-394, 1987 36 . Byers B : Blindness secondary to steroid injections into the nasal turbinates . Arch Ophthalmil 97: 79-811, 1979 37 . Chamot L, Zografos L, Micheli JL : Ocular and orbital complications after sclerosing injections in a case of a frontal cutaneous angioma . Ophthalmologico 182 :19:3198, 1981 38 . Chopdar A: Carbon-dioxide laser treatment of eye lid lesions . Trans Ophthalmil Soc UK 104:176-180, 1985 39 . Cogen MS, Elsas FJ: eyelid depigmentation following corticosteroid injection for infantile ocular adnexal hemangioma . J Pediatr Opiathatmol Strabismus 26:35-38, 1989 40 . Coleman DJ, Jack RL., Franzen LA : Hemangiomas of the orbit . Arch Ophthalmil 88:368-374, 1972 41 . Cooper AG, Bolande RP : Multiple hemangiomas in an infant with cardiac hypertrophy : Postmortem angtographic demonstration of the arteriovenous fistulae . Ped2'alrics 35:27-35, 1965 42 . Crawford GM : Injection therapy for angiomas . /AMA 137519-527, 1948 43 . Crawford MLJ : The visual deprivation syndrome . Ophthalmology 85 :465-477, 1978 44 . Crum R, Szaho S, Folktrtan J : A new class of steroids inhibits angiogenesis in the presence of Heparin or a Heparin fragment . Science 230 :1375-1378, 1985 45 . Cuttone JM, Durso F, Miller M, Evans LS : The relationship between soft tissue anomalies around the orbit and globe and astigmatic refractive errors : a Preliminary Report . J Pedialr Ophthalmol Strabismus 17: 29-36, 1980 46 . David-['J, Evans DI K, Stevens RE : Haemangioma with thrombocytopenia (Kasabach-Merritt syndrome) . Arch Do Child 58:1022-1023, 1983 47- Dayton GO : Orbital venography : anatomy, rechnique, and diagnostic use . Tr Am Ophthalmol Soc 75 :459-504, 1977 48. DeadyJP, Willshaw HE : Vascular hamartonsas in childhood . Trans Ophtholmol .Soc UK 105 :712-716, 1986

49 . Deans RM, Harris GJ, Kivlin JD : Surgical dissection of capillary hemangiomas : an alternative to intalesinnal corticosteroids . Arch Ophthalmol 110 : 1748-1747, 1992 50 . Dethlefsen SM, Mulliken jB, Clowacki J : An ultrastructural study of mast cell interactions in hemangiomas . Uitrastruct Pathol 10. 175-183, 1986 51 . de Venecia G, Lobeck CC : Successful treatment of eyelid hemangioma with prednisone . Arch Ophthalsnot 84 : 98-102,1970 52 . Dilenge D : Arteriography in angiomas of the orbit . Radiology 113 :355-361, 1974 53 . Donaldson SS, Chassagne D, Sancho-Gamier H, Beyer Hp : Hemangiomas of infancy : results of 90Y interstitial therapy : a retrospective study . lnl JRadiation Oncol Biol Phvs 5: I-11, 1979 54 . Droste PJ, Ellis FD, Sondhi N, Helveston EM : Linear subcutaneous fat atrophy after corticosteroid injection of periocular hemangiomas . Am J Ophthalmol 105:6569, 1988 55 . Edgerton AE : Choloroma : report of a case and a review of the literature . Trans Am Ophthalmol Soc 45:376-414, 1947 56 . Edgerton MT: The treatment of hemangiomas: with special reference to the role of steroid therapy . Ann Surg 183:517-532, 1976 57 . Enjorlas 0, Riche MC, Merland JJ, Escande JP : Management of alarming hemangiomas in infancy : a review of 25 cases . Pediatrics 85 :491-498, 1990 58 . Enzinger FM, Weiss SW : Benign tumors and tumorlike lesions of blood vessels, in Enzinger FM (ed) : Soft Tissue Tumors . St Louis, CV Mosby, 1988, pp 489-49 .5 59 . Eurvilaichit C, Kraiphibul P, Notitasut S : KasabachMerritt syndrome treated by trans arterial embolism and radiotherapy .,/ Meet Ass Thailand 70 :431-435, 1987 60 . Ezekowitz RAB, Mulliken JB, Folkman J : Interferon alfa 2a therapy for life-threatening hemangiomas of infancy . N Engl J bled 326 :1456-1463, 1992 61 . Famiglietti PJ : Intralesional corticosteroid injection for capillary hemangioma of the eyelid . Trans PA Acad Ophtlmlmol0tolmyngol 38_371-373, 1986 62 . Favus MJ, Schneider AB, Stachura ME, et al : Thyroid cancer occurring as a late consequence of head and neck radiation : Evaluation of 1056 patients . N Engl J Med 294: 1019-1025, 1976 63 . Finn MC, Glowacki J, Mulliken LB : Congenital vascular lesions : Clinical application of a new classification . J Pediatr Sung 18:894-900, 1983 64 . Fitzsimons R : Intralesional corticosteroid injection of infantile adnexal haemangioma . Trans Ophthalmic Soc NZ 36 :74-75, 1984 65 . Folknian J : Toward a new understanding of vascular proliferative disease in children . Pediatrics 74 :850-856, 1984 66 . Folkman J, Langer R, Linhardt RJ, et al : Attgiogenesis inhibition and tumor regression caused by Heparin or a Heparin fragment in the presence of cortisone . Science 22 :719, 1983 67 . Fost NC, Esterly NB : Successful treatment of juvenile hemangiomas with prednisone . / Pediatrics 72 :351-357, 1968 68 . France 'I D : Amblyopia, in Isenberg SJ (ed) : The Eye in Infancy . Chicago, Yearbook Medical Publishers, 1989, pp 100-109 69 . Furst Cl, Lundell M . Holm LE : Radiation therapy of hemangiomas, 1909-1959 : A cohort based on 50 years of clinical practice at Radiumhemmet, Stockholm . Aria Oncologico 26 :33-36, 1987 70 . Furst CJ, Lundell M, Holm LE, Silh'crsward C : Cancer incidence after radiotherapy for skin hemangioma : a retrospective cohort study in Sweden . j Nall Cancer Inst 801387-1392, 1988 71 . Garcia RL, Dixon SI . : Occlusion amhlynpia secondary to a mixed capillary-cavernous hemangioma . / Am Arad

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423 J Ophthalmol 71 :1003-1008, 1971 95 . HiIIJH,MafeeMEChowJM,ApplebaumEL :Dynamic computerized tomography in the assessment of hemangioma . AmJ Otolaryngol 6 :23-28, 1985 96. Hobby LW : Further evaluation of the potential of the argon laser in the treatment of strawberry hemangiomas. Plastic Reconstr Surg 71 :481-489, 1983 97 . Holland VG : Hamangiome der Lider . KlinMonatsbl Augenheilkd 152:365-373, 1968 98 . Holmdahl K : Cutaneous hemangiomas in premature and mature infants . Acta Paediatrics 44 :370-379, 1955 99. Hopfel-Kreiner I : Histogenesis of hemangiomas an ultrastructural study on capillary and cavernous hemangiomas of skin . Path Res Pract 170 :780, 1980 100. Hornblass A, Herschorn BJ, Stern K, Grimes C : Orbital abscess . Sun- Ophthalmil 29 :169-178, 1984 101 . Hoyt CS, Stone RD, homer C, Billson FA : Monocular axial myopia associated with neotonal eyelid closure in human infants . AmJ Ophthalmol 91 :197-206, 1981 102 . Iliff WJ, Green WR : Orbital lymphangiomas . Ophthalmology 86 :914 929, 1979 103 . Inceman S, Tagun Y : Chronic defibrination syndrome due to giant hemangioma associated with microangiopathic hemolytic anemia . AmJ Med 46:997-1001, 1969 104. Inglefield J1', Tisdale PD, Fairchild JP : A case of hemangioma with thrombocytopenia in the newborn infant treated by total excision . j Pediatrics 59:238-242, 1961 105 . Iwamoto T, Jakobiec FA : Ultrasound comparison of capillary and cavernous hemangiomas of the orbit . Arch Ophthwlmol 97 :1144-1153, 1979 106. Jacobs AH : Strawberry hemangiomas : The natural history of the untreated lesion . California Med 86:8-10, 1957 107 . )acobs AH : Vascular Nevi . Pehatr Clin North America 30:465-481, 1983 108 . Jacobs AM, Walton RG : The incidence of birthmarks in the neonate, Pediatrics 58 :218-222, 1976 109. Jakobiec FA, Jones IS : Vascular tumors, malformations, and degenerations, in Duane TD, Jaeger EA (eds): Clinical Ophthalmology Vol2 . Philadelphia : JB Lippincott, 1988, chapter 37, p 6 110 . James DH, Tuttle AH : Congenital hemangioma with thrombocytopenia . J Pediatrics 59:234-237, 1961 111, Jones GJ, Itri L : Safety and tolerance of recombinant interferon alfa-2a (Roeferon-A) in cancer patients . Cancer 57 :1709-1715, 1986 112 . Jones IS : Lymphangiomas of the ocular adnexa : an analysis of 62 cases . Trans Am Ophthalinol Society 57 : 602-665, 1959 113 . Karcioglu ZA :'I issue diagnosis : Orbit, in Karcioglu Z .4 (ed) : Laboratory Diagnosis in Ophthalmology . New York: MacMillan, 1987, pp 33-34 114 . Kasahach HH, Merritt KK : Capillary hemangioma with extensive purpura : report of a case . AmJ Dis Child 59: 1063-1070, 1940 115 . Kennedy RE : Arterial embolization of orbital hemangiomas . Trans Am Ophthalmol Sot 76:266-277, 1978 116 . Kiehn CL, Desprez JD, Kaufman B : Cavernous hemangiomas of the head and neck : Indications for arteriography and surgical treatment . Plastic Reconstr Surg 33 : 338-348, 1964 117 . Knochel JQ, Osborn AG, Wing SD : Differential diagnosis of lateral orbital masses . C'h: J Computed Toning, 5 : 11-15,1981 118 . Kopf AW, Bart RS : Tumor conference #9 : Massive hemangioma with pharyngeal involvement . j Dermalol Surg 2:373-377, 1976 119 . Kopf AW, Bart RS : Tumor conference #48 : Massive congenital hemangioma resulting in death . J Dennalol Snrg Orrcol 9 :509-512, 1983 120 . KroheI GB, Krauss HR, Winnick J : Orbital abscess : presentation, diagnosis, therapy . and sequelae . Ophthalmol-



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I3AIK ET AL tions of granulocytic sarcoma (myeloid sarcoma or cholortna) . Am J Ophthalmol 80:975-990, 1975 236 . Ziph RF : Binocular fixation pattern . Arch Ophthalmal 94 :401-405, 1976 237 . Zweifach B W, Shoot E, Black MM : The influence of the adrenal cortex on behavior of terminal vascular bed . Ann NYAcad Sci 56.:626-633, 1953 Outline I . Epidemiology II . Natural history A. Clinical history B . Biological phases 111, Histopathology and ultrastructure IV . Presentation A. Clinical findings B . Amblyopia V . Systemic associations VI . Ancillary diagnostic testing A . Plain radiography B . Ultrasound C . Computed tomography D . Magnetic resonance imaging E . Angiography F . Biopsy VII . Therapy A . Indications B . AMttblyopia therapy C . Surgery D . Radiation E . Systemic corticosteroids F . Intralcsional corticosteroids G . Interferon H . Laser therapy I . Therapeutic conclusions VIII . Differential diagnosis A . Rhabdomyosarcoma B . Lymphangioma C . Chloroma D . Neuroblastoma E . Other neoplasms F . Orbital cysts G . Cellulitis IX . Summary

The authors gratefully acknowledge the assistance of Leonard Apt, M .D ., Robert M . Ellsworth, M .D ., and Ira S . Jones, M .D . in the preparation of this manuscript . This study was supported by unrestricted grants from the St . Giles Foundation, New York, New York, and Research to Prevent Blindness, Inc., New York, New York . Reprint requests to Barrett G . Haik, M .D ., Tulane University School of Medicine, Department of Ophthalmology, 1430 Tulane Avenue, New Orleans, LA 70112-2699.