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Multimodal management of diffuse neonatal hemangiomatosis
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Multimodal management of diffuse neonatal hemangiomatosis Elizabeth Gardner Stratte, MD, a Whitney D. Tope, MPhil, MD, c Christopher L. Johnson, ]VID, b and Neil A. Swanson, MD a Portland, Oregon, and
Boston, Massachusetts Diffuse neonatal hemangiomatosis is a rare, frequently fatal disorder. We describe the case of a neonate with numerous cutaneous and ocular hemangiomas. Hepatic hemangiomas were noted at 4 weeks of age, ,associated with congestive heart failure resulting from hepatic arteriovenotts shunting. This condition was controlled by treatment with prednisone, interferon alfa-2b and hepatic embolization. Treatment of cutaneus hemangiomas wit}h the tunable dye laser prevented hemorrhage, facilitated routine skin care, and allowed uninhibited intravenous access during hospitalization. (J AM ACAD DERMATOL1996;34:337-42.)
In diffuse neonatal hem,'mgiomatosis (DNI-I), lesions may occur in the skin, liver, lungs, intestines, and central nervous system. 16 Lesions are usually present at birth (70%) or develop within the first weeks of life and may number in the hundreds. 7, 8 D N H c a r i e s a mortality rate of 60% to 90%, with death usually occurring within the first months of life as a result of high- output cardiac failure caused by arteriovenous shunting. 7, 9 W e describe the case of a patient with D N H complicated by congestive heart failure and treated successfully with prednisone, interferon alfa-2b, the flashlamp-pumped tunable dye laser (TDL), and hepatic embolization. CASE REPORT A 2-day-old girl had hundreds of 1 to 3 mm hemangiomas on her skin arid oral and genital mncosae (Fig. 1). Hemangiomas of the irides and retinas, along with retinal hemorrhages, were noted on ophthalmologic examination. The child weighed 2900 gan at birth after a 40-week, term, uncomplicated gestation. Auscultation revealed no intracranial, cardiac, or abdominal bruits. There were no abdominal masses oi"hepatosplenomegaly. The results of neurologic examination were non-hal. A complete blood From the Department.s of Dermatologya and Pediatrics, l' Oregon Health Sciences University, Poit!and, and the Depmment of Dermatology, Wellman Laboratories of Photomedicine and Harvard Medical School, Boston.e Reprint requests: Elizabeth Gardner Stratte, MD, Depm'tments of Pediatrics and Dermatology, The Children's Hospital, 747 52nd St., Oakland, CA 94609. Copyright 9 1996 by the American Academy of Dermatology, Inc. 0190-9622t96 $5.00+0 16/4/65181
cell count demonstrated a hemoglobin level of 22 grrgdl, a platelet count of 249,000 cells/dl, and a normal differential. Magnetic resonance imaging of the brain, chest roentgenoglaphy, and abdominal ultrasono~aphy showed normal features. A biopsy specimen showed numerous thin-walled vessels lined by plump endothelial ceils throughout the dermis. Fibroblasts, maemphages and an increased number of mast cells were present. During the patient's fn'st weeks of life, the hemangiomas enlarged. Pefiorificial lesions and lesions over pressure areas became friable and bled. TDL treatments were begun when the patient was 17 days of age. The TDL (Candela SPTL- 1; Candela Laser Corp., Wayland, Mass.) delivered pulses of 585 nm light over 450 Its at fluences of 7.0 to 8.75 J/cm2. Three or 5 mm spot sizes were used to photocoagulate hemangiomas in periorificial regions, areas of trauma, and potential in~avenous therapy sites. The patient underwent a total of six treatment sessions and received, under general anesthesia, from 600 to 800 pulses per session every 2 to 4 weeks. Lesions completely resolved after two to four treatments; small, macular lesions responded more readily than did larger papules. Single laser pulses occasionally caused rapture of the overlying epidermis with consequent mild bleeding, but TDL u'eatments were not associated with significant blood loss or platelet consumption. When the patient was 4 weeks of age, tachycardia and tachypnea developed. A chest roentgenograna demonstrated cardiomegaly, and an echocardiogram showed biventricular enlargement, volume overioad, and pulmonary hypertension, ,all consistent with cardiac failure. An abdominal ultrasonograna revealed multiple inttahepatic hypoechoic rounded lesions consistent with hemangiomas; the largest measured 1.6 x 1.7 x 1,5 cm (Fig. 2). The patient was treated with oral prednisone (2 mg/kg), 337
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Fig. 1. The patient before treatment. There are numerous hem,'mgiomas on the face (A), the trunk (13), and the Ms (C). digoxin, mad furosemide. This regimen ,alleviated her symptoms, but 3 weeks later, a liver sonogram appeard unchanged. When the patient was 8 weeks of age, severe congestive heart failure developed. Prednisone was continued, and intramuscular interferon alfa-2b (Intron A Schering Corporation, 3 MU/m2/day) was begun. At 10 weeks of age the patient had persistent, severe congestive heart failure ,and failure to thrive Spironolactone was added to her regimen, and the prechfisone dosage was increased to compensate for adrenal suppression.
The patient then underwent embolization of her right mid left hepatic and phrenic "arteries with polyvinyl alcohol and Geltbam pm'ticles (The Upjohn Company, Kalamazoo, Mich.). Within 6 weeks, alleviation of her congestive heart failure allowed discontinuation of supplemental oxygen, digoxin, furosemide, ,arid spironolactone. Interferon alfa-2b was continued at 3 MU/m2/day, and prednisone was slowly withdrawn over eight weeks. By the time the patient was 6 months of age, all medications had been discontinued except for interferon alfa-
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Fig. 2. Ultrasonogram of the liver before treatment showing multiple intrahepatic hemangiomas (arrows), the largest (cursors) measuring 1.6 cm in diameter.
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Fig. 3. At 6 months of age, most cutaneous hemangiomas have involuted after treatment on the face (A) and trunk (B).
2b. The retinal hemangiomas resolved completely, and the hepatic lesions decreased 30% in size. The cutaneous hemangiomas had improved significantly (Fig. 3), with complete resolution of all TDL-treated lesions leaving soft, atrophic maeules resembling anetoderma (Fig. 4, A). Non-TDL-treated hemangiomas on the back appeared as blanching erythematous macule~s (Fig. 4, B). Results o f liver and thyroid function studies and blood cell
counts were normal ttu'oughout her course of interferon alfa-2b. During her 6-month illness, the infant's length fell from the 90th to the 25th percentile for age, and her weight dropped from the 50th to the 10th percentile. At 12 months of age, the patient had achieved the 25th and 50th percentiles for length and weight, respectively, and she had appropriately met all developmental milestones.
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Fig. 4. TDL-treated areas on the abdomen showing residual anetodenna-like lesions (A) and non-TDL-treated hemangiomas on the back that appear as erythematous macules (B). Interferon alfa-2b was gradually discontinued over a 3-month period beginning at the age of 889months. At the age of 12 months the patient had no cutaneous hemangiomas, and by 18 months the hepatic hemangiomas laud resolved completely. DISCUSSION
DNH was first described in the German literature in the nineteenth century l~ and was later redescribed by J',fffe.12Death occurs in 60% to 90% of cases, usually from high-output cardiac failure caused by arteriovenous shunting or from thrombocytopenia caused by hemon'hage from gastrointestinal or respiratory tract hemangiomas. 7-9The average age at death is 11 weeks, with a range from 1 day to 41 months.3' 8 Girls are affected by DNH twice as often as are boys. Cutaneous lesions measure 0.5 to 1.5 cm and may be numerous; our patient had approximately IO00 lesions. DNH: must be differentiated from benign neonatal hemangiomatosis, in which cutaneus lesions are also present at birth but there is
Journal of the American Academy of Dermatology February 1996
no associated visceral involvement or increased mortality, t3 Trealanent of D N H includes systemic steroids, radiation therapy, ligation orembolization of feeding vessels of hemangiomas, and, most recently, interferon alfa-2a.14 Interferon alfa-2a is administered by intrarnuscular or subcutaneous injection beginning at 1.0 MU/m2/day and then advancing as tolerated over the course of a few days to 3 MU/m2/dayJ 4' 15 Interferon alfa may cause transient elevation of liver enzyme levels and neutropenia; appropriate laboratory tests should therefore be performed first weekly (at the onset of therapy) and then monthly. Interferon- induced fever is usually prevented by coadministration of acetaminophen. Reports suggest that v~cular proliferations should regress by 50% or more during an average of 7.8 months of treatment. 16 There have been no reports of long-term toxic effects from interferon alfa use. Indications for interferon alfa therapy include life- or vision-threatening hemangiomas unresponsive to corticosteroids or hemangiomas in locations associated with major morbidity. Although the mechanism of interferon alfa action in the treatment of vascular proliferation is unknown, endothelial cell migration and proliferation and other steps in angiogenesis have been shown in vitro to be inhibited by interferons. 16-21 Vascular proliferative lesions vary in their responses to interferon therapy. 17 Persistent severe congestive heart failure in our patient was treated with hepatic embolization within 3 weeks o f initiation of interferon alfa-2b therapy. This did not 'allow an adequate trial to detect the effect of interferon ,alone in controlling hepatic hemangiomas. By 10 months of age, all of the patient's cutaneous lesions, including those not treated with the TDL, had involuted. This is earlier than would be expected from the natural history of untreated cutaneus hemangiomas, probably because of the therapy with prednisone, interferon zdfa- 2b, or both. Most patients with hemangiomas have been treated with interferon alfa-2a, ts, 17,22-24Two reports discuss the use of interferon alfa-2b. 25, 26 Teillac-Hamel et al.z~ reported the unsuccessful treatment of childhood hemangiomas with interferon alfa-2b, whereas Loughnan et al. 26 successfully treated a massive orbital capillary h emangioma with interferon alfa-2b. Interferon alfa-2a and -2b have sina.ilar clinical and in vitro effects on angiogenesis, suggesting that they should have equivalent efficacies. Interferon alfa-2b was administered to this patient because it was available.
Journal of the American Academy of Dermatology Volume 34, Number 2. Pmt 2
One proposed model of the natural history of proliferating hemangiomas is hased on the dynamic expression of mediators affecting endothelial cell activity and extracellular matrix compositionY One clinically useful marker in this model is the expression o f basic fibroblast growth factor (bFGF). The proliferation phase is characterized by high bFGF expression, which then slowly falls during involution. Urinary levels of bFGF COlTelate with the proliferative activity of hemangiomas and provide a marker with which to gauge a patient's response to corticosteroid or interferon therapy. Alpha interferons appear to produce their antiangiogenic effect by down-regulating expression o f bFGF. The T D L h~u,; proved efficacious ,as a primary Ireatment for both proliferative and nonproliferative pediatric vascular lesions. 2s-34 We found T D L photocoagulation therapy of selected hemangiomas to be beneficial and associated with minimal side effects in the treatment of DNH. T D L therapy prevented potential impairment of vision, feeding, intravenous access, and diaper care by enlarging hemangiomas. T D L treatment clearly decreased the number ,and overall volume of hemangiomas, possibly decreasing platelet trapping and blood shunting as well. W e suggest that T D L therapy be considered as adjunctive therapy in the treatment of DNH. To our knowledge, no published reports have implicated photocoagulation therapy in precipitating platelet trapping (Kasabach-Merritt syndrome). Although photocoagulation does cause inWavascular hemolysis in irffants with large port-wine stains, the resultant hemoglobinemia does not appear to reach harmful levels, even if large areas are Ireated. 35 The superficial hemangiomas in our patient responded well to T D L treatment before her other cutaneus hemangiomas responded to systelnic medications. The TDL-treated lesions on the Irunk healed with soft promtsions resembling anetoderma, whereas the non-TDL-treated lesions resolved into erythematous macules. Whether this difference was scarring caused by the T D L or represents the redundant skin fiequently seen as the perm,'ment end result of natural involution in fibrosing hemangiomas is unknown. D N H is a life-threatening disorder that requires a multimodal, interdisciplinary approach. In this patient we cannot differentiate with certainty the therapeutic effects of prednisone from those of interferon al.fa. Although interferon is usutdly recommended for tumors that fail to respond to high-dose prednisone, interferon alfa should be considered, because
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of its effectiveness and paucity of side-effects, as ,an importantfirst-li~w agent in treating life- and visionthieatening vascular proliferative lesions, z3, 36 REFERENCES 1. Held JL, Haber RS, Silvers DN, et al. Benign neonatal hemangiomatosis: review ,anddescriptionof a patient with unusually persistent lesions. Pediau"Dermatol 1990;7:63-6. 2. Goz~flD, Saad, N, Bader D, et ,'ft.Diffuseneonatalhaemangiomatosis: successfld management with high dose corticosteroids. Eur J Pediatr 1990;149:321--4. 3. Byard RW, Burrows PE, Izakawa, T, et al. Diffuse infmltile haemangiomatosis: clinicopathoiogical [eattu'es and management problems in five fatal cases. Eur .I Pediatr 1991; 150:224-7. 4. Haik BG, Clancy P, Ellsworth RM, et al. Ocular manifestations in diffuse neonatal hemangiomatosis.J PexliatrOphthahnol Strabismus 1983;20:101-5. 5. Geller JD, Topper SF, Hashimoto K. Diffuse neonatal hemangiomatosis: a new constellation of findings. J AM ACADDERMATOL1991;24:816-8. 6. Golitz LE, Rudikoff J, O'Meara OP. Diffuse neonatal hemangiomatosis. Pediatr Dermatol 1986;3:145-52. 7. BurlnanD, Mansell PWA, W;u-inRP. Milimyhemangiomata in the newborn. Arch Dis Child 1967;42:193-7. 8. Holden KR, Alexander F. Diffuse neonatalhemangiomatosis. Pedialaics 1970;46:411-21. 9. McLean RH, Moiler JH, Warwick WJ, et al. Multinoduh'u" hemangiomatosis of the liver in infancy. Pediatrics 1972; 49:563- 73. 10. R,'u-ndohrM. Ein fall yon angebomem angios,'u'com. Virchows Arch A Pathol Anat HistoI 1878;73:459-60. 11. Stature C. Beitrage zur Lehre die Gel~issgeschwulsten UDissertationl.G/3ttingen,Germany:Gtttingen University, 1891. 12. J,~fe RH. Multiple hemangiomas of the skin and of intern,'d organs. Arch Pathol 1929;7;44-54. 13. Stern J-K,Wolf JE Jr, Jan-.attM. Benign neonatal hemangiomatosis. J AM ACAD DnRMXrOL1981;4:442-5. 14. Enjolras MD, Mulliken JB. The current management of vascular birthmarks. Pedlatr Dennatol 1993;10:311-33. 15. EzekowitzRA, Mulliken JB, FolkmanJ. Interferonalfiv2a therapy for fife-threatening hemangiom~ of infancy. N Engl J Med 1992;326:1456-63. 16. Brouty-BoyeD, Zetter BR. Inhibition of cell motility by interferon. Science 1980;208:516-8. 17. White CW, Wolf SJ, Korones DN, et al. Treatment of childhood angiornatous diseases with recolnbinant interferon alfa-2a. J Pediatr 1991; 118:59-66. 18. Ffiesel R, Komoriya A, Maciag T. Inhibition of endothelial cell proliferation by gamma interiimm. J Celt Bid 1987;104:68% 96. 19. Feldmtm D, Goldstein AL, Cox DC, ctal. Cultured human endothelial cells treated with recombinantleukocyteA interferon: tubuloreticuhwinclusion formation,antiproliferalive effect, and 2'5' oligoadenylate synthetase induction. Lab Invesl 1988;58:584-9. 20. Folkrnma1. Successful treatmentof an angiogenicdisease. N Engl J Med 1989;320:1211-2. 21. Tsuruoka N, Sugiyama M, Tawm'agiY, et al. Inhibitionof in vitro angiogenesis by lymphotoxin and interferongamma. Biochem Biophys Res Commun 1988;155:42935. 22. Ezekowitz A, Mulliken J, Folkman J. Interferon alpha
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therapy of haemangiomas in newborns and infants. Br J Haematol 1991;79(Suppl 1):67-8. Blei F, Orlow SJ, Geronemus RG. Supraumbilical midabdominal raphe, sternal atresia, and hemangioma in an infant: response of hemangioma to laser and interferon alfa2a. Pediatr Dermatol 1993;10:71-6. Harley RM, Sabio H, HoweU CG, et al. Successful management of an infant with a giant hemangioma of the retroperitoneum and Kasabach-Merritt syndrome with alphainterferon. J Pediatr Surg 1993;28:1356-7. Teillec-Hamel D, De Prost Y, Bodemer C, et al. Serious childhood angiomas: unsuccessful alpha-2b interferon treatment. A report of four cases. B r J Dermato11993; 129:473-6. Loughnan MS, Eider J, Kemp A. Treatment of a massive orbital- capillary hemangioma with interferon alfa-2b: short-term results. Arch Ophthomol 1992; 110:1366-7. Takahashi K, Mulliken J'B, Kozakewich HPW, et al. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest 1994;93:235764. Tan OT, Carney M, Margolis R, et al. Histologic responses of portwine stains treated by argon, carbon dioxide and dye lasers: apreliminaryreport.Arch Dermato11986;122:101622.
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29. Tan OT, Sherwood K, GilchristBA. Treatment of children with port-wine stains using the flashlamp-pumped tunable dye laser. N Engl J Med 1989;320:416-21. 30. Ashinoff R, Geronemus RG. Flashlamp-pumped pulsed dye laser for port-wine stains in infancy: early versus later treatment. J AM ACADDF_~MATOL1991;24:467-72. 31. Morelli JG, Tan OT, Weston WL. Treatment of ulcerated hemangiomas with the pulsed tunable dye laser. Am J Dis Child 1991;145:1062-4. 32. Tan OT. Lasers for vascular lesions in pediatric dermatology. Pediatr Derrnatol 1992;9:358-60. 33. Sherwood KA, Tan OT. Treatment of a capillary hemangioma with the flashlamp pumped-dye laser. J AM ACAD DF_maATOL 1990;22:136-7. 34. Garden JM, Bakus AD, Paller AS. Treatment of cutaneous hemangiomas by the flashlamp-pumped pulsed dye laser: prospective analysis. J Pediatr 1992;120:555-60. 35. Eppley BL, Sadove AM. Systemic effects of photothermolysis of large port-wine stains in infants and children. Hast Reconstr Surg 1994;93:1150-3. 36. Blei F, Orlow SJ, Geronemus RG. Interferon alfa-2a therapy for extensive perianal and lower extremity hemangioma. J AM ACAD DERMATOL1993;29:98-9.
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Multimodal management of diffuse neonatal hemangiomatosis Elizabeth Gardner Stratte, MD, a Whitney D. Tope, MPhil, MD, c Christopher L. Johnson, ]VID, b and Neil A. Swanson, MD a Portland, Oregon, and
Boston, Massachusetts Diffuse neonatal hemangiomatosis is a rare, frequently fatal disorder. We describe the case of a neonate with numerous cutaneous and ocular hemangiomas. Hepatic hemangiomas were noted at 4 weeks of age, ,associated with congestive heart failure resulting from hepatic arteriovenotts shunting. This condition was controlled by treatment with prednisone, interferon alfa-2b and hepatic embolization. Treatment of cutaneus hemangiomas wit}h the tunable dye laser prevented hemorrhage, facilitated routine skin care, and allowed uninhibited intravenous access during hospitalization. (J AM ACAD DERMATOL1996;34:337-42.)
In diffuse neonatal hem,'mgiomatosis (DNI-I), lesions may occur in the skin, liver, lungs, intestines, and central nervous system. 16 Lesions are usually present at birth (70%) or develop within the first weeks of life and may number in the hundreds. 7, 8 D N H c a r i e s a mortality rate of 60% to 90%, with death usually occurring within the first months of life as a result of high- output cardiac failure caused by arteriovenous shunting. 7, 9 W e describe the case of a patient with D N H complicated by congestive heart failure and treated successfully with prednisone, interferon alfa-2b, the flashlamp-pumped tunable dye laser (TDL), and hepatic embolization. CASE REPORT A 2-day-old girl had hundreds of 1 to 3 mm hemangiomas on her skin arid oral and genital mncosae (Fig. 1). Hemangiomas of the irides and retinas, along with retinal hemorrhages, were noted on ophthalmologic examination. The child weighed 2900 gan at birth after a 40-week, term, uncomplicated gestation. Auscultation revealed no intracranial, cardiac, or abdominal bruits. There were no abdominal masses oi"hepatosplenomegaly. The results of neurologic examination were non-hal. A complete blood From the Department.s of Dermatologya and Pediatrics, l' Oregon Health Sciences University, Poit!and, and the Depmment of Dermatology, Wellman Laboratories of Photomedicine and Harvard Medical School, Boston.e Reprint requests: Elizabeth Gardner Stratte, MD, Depm'tments of Pediatrics and Dermatology, The Children's Hospital, 747 52nd St., Oakland, CA 94609. Copyright 9 1996 by the American Academy of Dermatology, Inc. 0190-9622t96 $5.00+0 16/4/65181
cell count demonstrated a hemoglobin level of 22 grrgdl, a platelet count of 249,000 cells/dl, and a normal differential. Magnetic resonance imaging of the brain, chest roentgenoglaphy, and abdominal ultrasono~aphy showed normal features. A biopsy specimen showed numerous thin-walled vessels lined by plump endothelial ceils throughout the dermis. Fibroblasts, maemphages and an increased number of mast cells were present. During the patient's fn'st weeks of life, the hemangiomas enlarged. Pefiorificial lesions and lesions over pressure areas became friable and bled. TDL treatments were begun when the patient was 17 days of age. The TDL (Candela SPTL- 1; Candela Laser Corp., Wayland, Mass.) delivered pulses of 585 nm light over 450 Its at fluences of 7.0 to 8.75 J/cm2. Three or 5 mm spot sizes were used to photocoagulate hemangiomas in periorificial regions, areas of trauma, and potential in~avenous therapy sites. The patient underwent a total of six treatment sessions and received, under general anesthesia, from 600 to 800 pulses per session every 2 to 4 weeks. Lesions completely resolved after two to four treatments; small, macular lesions responded more readily than did larger papules. Single laser pulses occasionally caused rapture of the overlying epidermis with consequent mild bleeding, but TDL u'eatments were not associated with significant blood loss or platelet consumption. When the patient was 4 weeks of age, tachycardia and tachypnea developed. A chest roentgenograna demonstrated cardiomegaly, and an echocardiogram showed biventricular enlargement, volume overioad, and pulmonary hypertension, ,all consistent with cardiac failure. An abdominal ultrasonograna revealed multiple inttahepatic hypoechoic rounded lesions consistent with hemangiomas; the largest measured 1.6 x 1.7 x 1,5 cm (Fig. 2). The patient was treated with oral prednisone (2 mg/kg), 337
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Jotmlrd of t~le American Academy of Dermatology February 1996
Fig. 1. The patient before treatment. There are numerous hem,'mgiomas on the face (A), the trunk (13), and the Ms (C). digoxin, mad furosemide. This regimen ,alleviated her symptoms, but 3 weeks later, a liver sonogram appeard unchanged. When the patient was 8 weeks of age, severe congestive heart failure developed. Prednisone was continued, and intramuscular interferon alfa-2b (Intron A Schering Corporation, 3 MU/m2/day) was begun. At 10 weeks of age the patient had persistent, severe congestive heart failure ,and failure to thrive Spironolactone was added to her regimen, and the prechfisone dosage was increased to compensate for adrenal suppression.
The patient then underwent embolization of her right mid left hepatic and phrenic "arteries with polyvinyl alcohol and Geltbam pm'ticles (The Upjohn Company, Kalamazoo, Mich.). Within 6 weeks, alleviation of her congestive heart failure allowed discontinuation of supplemental oxygen, digoxin, furosemide, ,arid spironolactone. Interferon alfa-2b was continued at 3 MU/m2/day, and prednisone was slowly withdrawn over eight weeks. By the time the patient was 6 months of age, all medications had been discontinued except for interferon alfa-
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Fig. 2. Ultrasonogram of the liver before treatment showing multiple intrahepatic hemangiomas (arrows), the largest (cursors) measuring 1.6 cm in diameter.
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Fig. 3. At 6 months of age, most cutaneous hemangiomas have involuted after treatment on the face (A) and trunk (B).
2b. The retinal hemangiomas resolved completely, and the hepatic lesions decreased 30% in size. The cutaneous hemangiomas had improved significantly (Fig. 3), with complete resolution of all TDL-treated lesions leaving soft, atrophic maeules resembling anetoderma (Fig. 4, A). Non-TDL-treated hemangiomas on the back appeared as blanching erythematous macule~s (Fig. 4, B). Results o f liver and thyroid function studies and blood cell
counts were normal ttu'oughout her course of interferon alfa-2b. During her 6-month illness, the infant's length fell from the 90th to the 25th percentile for age, and her weight dropped from the 50th to the 10th percentile. At 12 months of age, the patient had achieved the 25th and 50th percentiles for length and weight, respectively, and she had appropriately met all developmental milestones.
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Fig. 4. TDL-treated areas on the abdomen showing residual anetodenna-like lesions (A) and non-TDL-treated hemangiomas on the back that appear as erythematous macules (B). Interferon alfa-2b was gradually discontinued over a 3-month period beginning at the age of 889months. At the age of 12 months the patient had no cutaneous hemangiomas, and by 18 months the hepatic hemangiomas laud resolved completely. DISCUSSION
DNH was first described in the German literature in the nineteenth century l~ and was later redescribed by J',fffe.12Death occurs in 60% to 90% of cases, usually from high-output cardiac failure caused by arteriovenous shunting or from thrombocytopenia caused by hemon'hage from gastrointestinal or respiratory tract hemangiomas. 7-9The average age at death is 11 weeks, with a range from 1 day to 41 months.3' 8 Girls are affected by DNH twice as often as are boys. Cutaneous lesions measure 0.5 to 1.5 cm and may be numerous; our patient had approximately IO00 lesions. DNH: must be differentiated from benign neonatal hemangiomatosis, in which cutaneus lesions are also present at birth but there is
Journal of the American Academy of Dermatology February 1996
no associated visceral involvement or increased mortality, t3 Trealanent of D N H includes systemic steroids, radiation therapy, ligation orembolization of feeding vessels of hemangiomas, and, most recently, interferon alfa-2a.14 Interferon alfa-2a is administered by intrarnuscular or subcutaneous injection beginning at 1.0 MU/m2/day and then advancing as tolerated over the course of a few days to 3 MU/m2/dayJ 4' 15 Interferon alfa may cause transient elevation of liver enzyme levels and neutropenia; appropriate laboratory tests should therefore be performed first weekly (at the onset of therapy) and then monthly. Interferon- induced fever is usually prevented by coadministration of acetaminophen. Reports suggest that v~cular proliferations should regress by 50% or more during an average of 7.8 months of treatment. 16 There have been no reports of long-term toxic effects from interferon alfa use. Indications for interferon alfa therapy include life- or vision-threatening hemangiomas unresponsive to corticosteroids or hemangiomas in locations associated with major morbidity. Although the mechanism of interferon alfa action in the treatment of vascular proliferation is unknown, endothelial cell migration and proliferation and other steps in angiogenesis have been shown in vitro to be inhibited by interferons. 16-21 Vascular proliferative lesions vary in their responses to interferon therapy. 17 Persistent severe congestive heart failure in our patient was treated with hepatic embolization within 3 weeks o f initiation of interferon alfa-2b therapy. This did not 'allow an adequate trial to detect the effect of interferon ,alone in controlling hepatic hemangiomas. By 10 months of age, all of the patient's cutaneous lesions, including those not treated with the TDL, had involuted. This is earlier than would be expected from the natural history of untreated cutaneus hemangiomas, probably because of the therapy with prednisone, interferon zdfa- 2b, or both. Most patients with hemangiomas have been treated with interferon alfa-2a, ts, 17,22-24Two reports discuss the use of interferon alfa-2b. 25, 26 Teillac-Hamel et al.z~ reported the unsuccessful treatment of childhood hemangiomas with interferon alfa-2b, whereas Loughnan et al. 26 successfully treated a massive orbital capillary h emangioma with interferon alfa-2b. Interferon alfa-2a and -2b have sina.ilar clinical and in vitro effects on angiogenesis, suggesting that they should have equivalent efficacies. Interferon alfa-2b was administered to this patient because it was available.
Journal of the American Academy of Dermatology Volume 34, Number 2. Pmt 2
One proposed model of the natural history of proliferating hemangiomas is hased on the dynamic expression of mediators affecting endothelial cell activity and extracellular matrix compositionY One clinically useful marker in this model is the expression o f basic fibroblast growth factor (bFGF). The proliferation phase is characterized by high bFGF expression, which then slowly falls during involution. Urinary levels of bFGF COlTelate with the proliferative activity of hemangiomas and provide a marker with which to gauge a patient's response to corticosteroid or interferon therapy. Alpha interferons appear to produce their antiangiogenic effect by down-regulating expression o f bFGF. The T D L h~u,; proved efficacious ,as a primary Ireatment for both proliferative and nonproliferative pediatric vascular lesions. 2s-34 We found T D L photocoagulation therapy of selected hemangiomas to be beneficial and associated with minimal side effects in the treatment of DNH. T D L therapy prevented potential impairment of vision, feeding, intravenous access, and diaper care by enlarging hemangiomas. T D L treatment clearly decreased the number ,and overall volume of hemangiomas, possibly decreasing platelet trapping and blood shunting as well. W e suggest that T D L therapy be considered as adjunctive therapy in the treatment of DNH. To our knowledge, no published reports have implicated photocoagulation therapy in precipitating platelet trapping (Kasabach-Merritt syndrome). Although photocoagulation does cause inWavascular hemolysis in irffants with large port-wine stains, the resultant hemoglobinemia does not appear to reach harmful levels, even if large areas are Ireated. 35 The superficial hemangiomas in our patient responded well to T D L treatment before her other cutaneus hemangiomas responded to systelnic medications. The TDL-treated lesions on the Irunk healed with soft promtsions resembling anetoderma, whereas the non-TDL-treated lesions resolved into erythematous macules. Whether this difference was scarring caused by the T D L or represents the redundant skin fiequently seen as the perm,'ment end result of natural involution in fibrosing hemangiomas is unknown. D N H is a life-threatening disorder that requires a multimodal, interdisciplinary approach. In this patient we cannot differentiate with certainty the therapeutic effects of prednisone from those of interferon al.fa. Although interferon is usutdly recommended for tumors that fail to respond to high-dose prednisone, interferon alfa should be considered, because
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