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Bilateral multifocal hemangiomas of the orbit in the blue rubber bleb nevus syndrome
Bilateral Multifocal Hemangiomas of the Orbit in the Blue Rubber Bleb Nevus Syndrome Eli L. Chang, MD, Peter A. D. Rubin, MD Purpose: To report the clinical findings and surgical treatment of multifocal, bilateral orbital hemangiomas in a patient with the blue rubber bleb nevus syndrome, a rare vascular disorder characterized by distinctive cutaneous and visceral hemangiomas. Design: Interventional case report. Methods: Review of clinical findings, radiologic studies, and treatment of the patient. Results: A 36-year-old female with multifocal, bilateral orbital lesions was seen with severe proptosis and decreased visual acuity of the left eye. Surgical debulking of multiple cavernous hemangiomas of the orbit resulted in decreased proptosis and an improvement in visual acuity. Subsequent histopathologic analysis and the results of a systemic workup revealing multiple, distinctive, cutaneous and visceral lesions were found to be consistent with the blue rubber bleb nevus syndrome. Conclusions: Although hemangiomas of the orbit are relatively common occurrences, multifocal, bilateral lesions may exist in the setting of underlying systemic hemangiomatosis. Bilateral or multifocal hemangiomas associated with cutaneous or visceral lesions should alert the clinician to the possibility of a number of syndromes that may have life-threatening consequences. Ophthalmology 2002;109:537–541 © 2002 by the American Academy of Ophthalmology. Cavernous hemangiomas are the most common, primary, benign tumor of the orbit in adults.1 Unlike the capillary hemangiomas of childhood, cavernous hemangiomas of adults are composed of large endothelial-lined channels and demonstrate no regressive stage. These lesions are usually readily excisable by orbitotomy when function of the eye is threatened. Bilateral hemangiomas of the orbit are an extremely rare occurrence, with only four reported cases in the modern literature.2– 4 Of these four cases, one of the cases was found to be in a patient diagnosed with Maffuci’s syndrome, a rare nonhereditary disease characterized by hemangiomas and enchondromas.5 We report a case of a patient with bilateral orbital hemangioma with multiple, associated cutaneous and visceral lesions consistent with the manifestations of blue rubber bleb nevus syndrome (BRBNS). The BRBNS is a vascular disorder characterized by multiple, distinctive hemangiomas of the skin and gastrointestinal tract.6 Commonly described as blue or purplish red, thin-walled sacs that contain blood and are easily compressed, these lesions refill slowly when pressure is released. These hemangiomas are usually located on the upper extremities and the trunk but may be found anywhere on the skin and mucous mem-
Originally received: January 18, 2001. Accepted: March 28, 2001.
Manuscript no. 210042.
Harvard Medical School, Massachusetts Eye and Ear Infirmary, Ophthalmic Plastic, Orbital and Cosmetic Surgery Service, Boston, Massachusetts. Reprint requests to Peter AD Rubin, MD, 243 Charles Street, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. © 2002 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
branes. Unilateral, isolated cavernous hemangiomas of the orbit have been previously described to be associated with BRBNS. To our knowledge, this is first report of bilateral lesions found in association with this rare angiomatosis and the second report of bilateral, multifocal, cavernous hemangiomas of the orbit.4
Report of a Case A 32-year-old female was referred to the Ophthalmic Plastic, Orbital and Cosmetic Surgery Service at the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, for evaluation of gradual, painless proptosis of both eyes. The patient first noted proptosis of the left eye in 1994 at the age of 27. She had a partial excision of an orbital mass from the left orbit 1 year later. Histopathologic studies of the lesion at that time reported “cavernous hemangioma.” Proptosis of the left eye recurred shortly after surgery and became progressively worse over time. Three years after the initial debulking surgery, at the age of 31, a follow-up magnetic resonance imaging scan was obtained. It demonstrated bilateral, multifocal, hyperfluorescent lesions of the orbit in the intraconal and extraconal spaces consistent with cavernous hemangiomas. There was extension of these lesions through the superior orbital fissure and into the left cavernous sinus and extension through a defect of the lateral wall into the temporal fossa (Fig 1). At this time the patient was referred for further treatment. Examination revealed visual acuity in the right eye of 20/20, although the left eye had declined to counting fingers at 1 m. There was a left afferent pupillary defect. Hertel readings were 21 mm in the right eye and 26 mm in the left eye at a base of 100 mm. On palpation there was a firm, nontender mass over the medial aspect ISSN 0161-6420/02/$–see front matter PII S0161-6420(01)00989-7
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Figure 1. MRI—axial T2-weighted sequence of orbits showing left proptosis and infiltrating, multiloculated, high-signal, masses present in both orbits, right greater than left. Lesions of the left orbit extend in to the cavernous sinus. Figure 2. Preoperative clinical photograph showing proptosis of the left eye. Figure 3. Photograph of cutaneous, bleblike lesions (arrows) of neck. Figure 4. Preoperative axial computed tomogram of orbits demonstrating contrast-enhancing lobulations of the orbits. On the right, the lobulations are confined to the orbit. Lesions of the left orbit extend the superior orbital fissure into the cavernous sinus and laterally through a prior lateral orbitotomy bony defect, into the left parapharyngeal space, infratemporal fossa, masticator space, parotid space, and left lateral scalp. Figure 5. Intraoperative tumor specimens. Figure 6. Large, blood-filled spaces, lined by endothelium and separated by fibrous septa (stain, hematoxylin– eosin; original magnification, ⫻40).
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Chang and Rubin 䡠 Hemangiomas and Blue Rubber Nevus Syndrome of the left upper lid and fullness of the temporal fossa. There was also resistance to retropulsion of the left eye. There were no changes in the degree of the proptosis with a Valsalva maneuver. No lagophthalmos was present, and dilated fundus examination showed myelinated nerve fibers but was otherwise unremarkable. Findings of the remainder of the ocular examinations for both eyes were otherwise unremarkable. There was no demonstrable involvement of the cranial nerves other than compression of the optic nerve in the left eye. Multiple distinctive bluish red, skin lesions, which were easily compressed, were noted on the scalp, neck, and cheek areas at the time of examination (Fig 2, Fig 3). Biopsy of the lesion through a transconjunctival anterior orbitotomy revealed a round cystic orbital mass. Histopathologic studies of the biopsy demonstrated lobules of vascular tissue separated by fibrous septae consistent with cavernous hemangioma. A preoperative computed tomography scan of the orbits demonstrated contrast-enhancing lobulations of the orbits consistent with vascular malformations. On the right, the lobulations were confined to the orbit. On the left, there was extension of these lesions through the superior orbital fissure into the cavernous sinus. There was also extension laterally into the left parapharyngeal space, infratemporal fossa, masticator space, parotid space, and left lateral scalp through her prior lateral orbitotomy bony defect. Additional vascular structures were seen in the region of the scalp, left mandibular gland, and posterior triangle (Fig 4). In an effort to reduce compression of the optic nerve and disfiguring proptosis, a lateral orbitotomy of the left eye was performed to gain access to the tumors. Eight accessible, distinct, red, cystic nodules were excised from the left orbit with the largest tumor measuring 20 ⫻ 18 ⫻ 10 mm (Fig 5). Histopathologic studies of these lesions revealed large, blood-filled spaces lined with endothelium and separated by fibrous septa of varying thickness consistent with cavernous hemangiomas of the orbit (Fig 6). Six months postoperatively, the patient’s visual acuity in the left eye was 20/100, with a 5-mm reduction in proptosis. At that time, a bluish red, slightly raised lesion of the scalp, which was noted to be increasing in size, was biopsied and found to be consistent with a cavernous hemangioma. Because of the diffuse, multifocal involvement of the hemangiomas, a systemic workup was initiated for the possibility of an associated angiomatosis. Plain film x-rays of the long bones of the hands and feet did not reveal abnormalities consistent with Maffucci’s disease. Computed tomography of the body revealed contrast-enhancing lesions of the spleen and liver consistent with hemangiomas. This constellation of findings: multiple, distinctive, bluish red cutaneous nodules, visceral hemangiomas, multiple cavernous hemangiomas of the orbit, is most consistent with a diagnosis of BRBNS. Follow-up of the patient over the course of 1 year has not demonstrated any appreciable change in the orbital lesions by clinical examination. There has been noticeable enlargement of the neck lesions, which has not affected the patient adversely.
Comment Cavernous hemangiomas of the orbit are common lesions of the adult orbit. They are benign, low-flow hamartomas with a fine capsule. These typically manifest in the fourth and fifth decades, with a 60% to 70% female preponderance.7–9 Most patients have gradually increasing, painless proptosis. On rare occasions, patients can also manifest signs of mass effect such as diplopia, pain, choroidal striae, and compressive optic neuropathy. Growth of these lesions may be stimulated by local hemodynamic disturbances, hypoxia,
and hormonal changes during pregnancy, stimulating proliferation of capillaries.6,10 When these lesions are found to be either bilateral or multifocal, they may be associated with an underlying systemic syndrome. Lesions of the skin, visceral system, and skeletal system may be found to exist concurrently with the unusual finding of multiple orbital lesions. On rare occasions when these lesions are found in association with cutaneous, visceral, or skeletal lesions, there are a number of vascular disorders that should be included in the differential diagnosis. Many of these syndromes with multisystemic involvement are hereditary, although others are sporadic in occurrence. BRBNS is a rare syndrome characterized by distinctive bluish red, rubbery, cutaneous lesions in the skin, gastrointestinal tract, and other organs. Originally described in 1860 by Gascoyan, the term “blue rubber bleb nevus syndrome” was coined in 1958 by William B. Bean because of the blue coloration and rubbery texture of the hemangiomas.11 Although few cases have been described with an autosomal dominant pattern of inheritance, most cases are sporadic. The peculiar lesions of BRBNS, which may number up to several hundred, are generally present from birth or early childhood and vary in size from 1 to 30 mm in diameter. With advancing age, some lesions may spontaneously involute, although most lesions persist, and some may enlarge. Visceral lesions are most often found in the small intestine or in the distal part of the colon, although lesions have also been found in the stomach, liver, spleen, and lungs.12 Gastrointestinal bleeding from these lesions can lead to iron-deficiency anemia.13 Other complications of this disease include orthopedic abnormalities and neurologic deficits from central nervous system lesions.14 The lesion that distinguishes BRBNS from other entities is the distinctive appearance of the cutaneous hemangiomas. The characteristic description is a bluish red, thin-walled sac, with a soft, rubbery consistency. Digital compression leaves an empty wrinkled sac that refills slowly. Histopathologic examination, as with other cavernous hemangiomas, reveals large, blood-filled spaces separated by fibrous septa of varying thickness lined by endothelium that reacts strongly for factor VIII–related antigen. Imaging studies are consistent with slow flow vascular lesions that may enhance with contrast. Associated ocular findings include hemangiomas of the conjunctiva, iris, and macula. There are four reported cases of BRBNS with orbital involvement. Rennie and colleagues15 described a 71-year-old woman with BRNBS who had an intraconal mass on computed tomography imaging, causing intermittent episodes of exophthalmos. In 1996 Mojon and colleagues16 described a 47-year-old woman with BRBNS who had ptosis, miosis, and spontaneous ecchymoses. This patient was found to have an intraconal mass with irregular surrounding fibrosis and calcifications, presumed to be a cavernous hemangioma on computed tomography imaging. McCannel et al17 described two cases of BRNBS with unilateral, orbital hemangiomas. The first case was a 28-year-old woman who had spontaneous lid ecchymoses and orbital pain. Diagnosis of the orbital lesions was made by magnetic resonance imaging and computed tomography. The second patient was a 7-year-old girl
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Ophthalmology Volume 109, Number 3, March 2002 who had blurred vision and proptosis of the right eye, which was more noticeable with strenuous activity. Diagnosis of the orbital lesions was based on computed tomography findings consistent with hemangioma of the orbit and a biopsy of a neck lesion with histopathologic findings consistent with cavernous hemangioma. We now report a patient with BRBNS with multifocal, bilateral, orbital hemangiomas. Rapid growth of the lesions of the left orbit caused proptosis and decreased vision. On computed tomography, the orbit showed multifocal lesions with calcifications and contrast enhancement similar to the lesions in the spleen and liver. Biopsy of a scalp lesion and the orbital lesions showed histopathologic findings compatible with cavernous hemangiomas. The characteristic appearance of the lesions of the neck, mandible, and scalp in conjunction with the histopathologic findings consistent with cavernous hemangioma are most compatible with BRBNS. Other systemic angiomatoses, which may be considered in the differential diagnosis of orbital lesions associated with systemic hemangiomas, are described below. Maffuci’s syndrome is a rare, congenital disease, with no familial predisposition, characterized by the development of multiple enchondromas and soft-tissue hemangiomas. Twenty-five percent of patients with Maffucci’s syndrome demonstrate skeletal or vascular manifestations of this disease before the age of 1 and 78% before puberty.18 Cavernous hemangiomas and capillary hemangiomas are the most common vascular lesions of this entity, although lymphangiomas have been described, as well as one patient with associated BRBNS.19 Visceral hemangiomas of the gastrointestinal tract may occur, with lesions of the esophagus, ileum, and oral mucosa being common. The bone lesions are most commonly enchondromas that affect the small bones of the hands, feet and the long bones. These lesions are readily apparent on plain films from early childhood. The possibility of this disease in cases of bilateral orbital hemangiomas must be explored, because 30% of patients with this disease will eventually develop malignant neoplasm develop.20 One case of Maffucci’s syndrome has been described with bilateral orbital hemangiomas and multiple enchondromas.5 Diffuse neonatal angiomatosis is a rare, often fatal, condition characterized by multiple cutaneous and visceral hemangiomas. Despite therapy with corticosteroids, mortality rates of 60% to 90% in the first few months of life have been reported.21–23 Complications include high-output cardiac failure, gastrointestinal bleeding, hydrocephalus, and consumption coagulopathy. Death is usually a result of high-output cardiac failure caused by arteriovenous shunting. The organs most commonly affected are the gastrointestinal tract, brain, liver, and lung.11 Ophthalmic examination of patients with this syndrome can reveal a number of abnormalities. Hemangiomas may involve the iris, ciliary body, and ciliary processes, leading to complications such as hyphema and vitreous hemorrhage. In addition, conjunctival hemangiomas and bilateral eyelid hemangiomas have also been described.23 Klippel-Trenaunay syndrome consists of a triad of nevus flammeus (port-wine stain), hypertrophy of the underlying soft tissue and bone, and venous varicosities. This condition
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shows no familial pattern of inheritance and no sexual preponderance. The nevus flammeus, which is present in 75% of patients, is usually noted at birth. Other vascular malformations manifesting during infancy are usually unilateral and involve the lower extremity, including capillary and cavernous hemangiomas, angiokeratomas, and lymphangiomas.24 Hemihypertrophy of the lower extremity often leads to compensatory scoliosis, whereas venous varicosities may result in cutaneous ulcerations, edema, and stasis changes. Other associated lesions include cavernous hemangiomas of the bladder25 and colon.26 Ophthalmic features occasionally seen in association with the syndrome are similar to those seen in the SturgeWeber syndrome. These features include retinal varicosities, choroidal angiomas, iris heterochromia, and glaucoma.6 Orbital manifestations associated with Klippel-TrenaunayWeber syndrome include regional hypertrophy of the orbital contents,27 a case of bilateral optic nerve sheath meningioma that was diagnosed by fine-needle aspiration biopsy28 and an orbital varix.29 Rendu-Osler-Weber syndrome (hereditary hemorrhagic telangiectasia) is an autosomal dominant disorder characterized by the development of mucocutaneous and visceral telangiectasias associated with recurrent episodes of hemorrhage. Skin lesions that appear as punctate telangiectasias or spider telangiectasias usually become evident during puberty and increase in both size and number with advancing age. Vascular lesions may occur anywhere on the skin, although the mucosa of the lips, tongue, nasal septum, and buccal mucosa are the most frequently involved sites. Visceral lesions, which require endoscopies or arteriographic procedures for visualization, are usually found in the upper gastrointestinal tract and liver.30 Recurrent epistaxis and bleeding from the gastrointestinal tract associated with severe iron-deficiency anemia requiring repeated transfusions are related to hemorrhage from telangiectatic vessels in the nasal mucosa and gastrointestinal tract. Dyspnea on exertion, clubbing, or cyanosis may be seen as a result as a sequelae of the pulmonary arteriovenous shunts, which are seen in 20% of patients with Rendu-Osler-Weber syndrome.31 Ocular findings, which are present in 45% of patients with this syndrome, include conjunctiva telangiectasias and small retinal arteriovenous malformations.32 Occasionally, bloody tears may be noted because of the presence of the conjunctiva telangiectasias. No orbital lesions have been described associated with this entity in our review of the modern literature. Although cavernous hemangiomas of the orbit are common lesions of the adult, bilateral lesions are extremely rare. Of the five lesions described in the literature, one was described in a case of Maffuci’s syndrome, whereas our case occurred in the setting of BRBNS. A number of other entities with cutaneous and visceral lesions have also been described, including diffuse neonatal hemangiomatosis, Klippel-Trenaunay-Weber syndrome, and Osler-RenduWeber syndrome. Diffuse neonatal hemangiomatosis has also been associated with bilateral hemangiomas of the lids.23 The other two entities have not been described in association with orbital cavernous hemangiomas, although
Chang and Rubin 䡠 Hemangiomas and Blue Rubber Nevus Syndrome they certainly merit consideration in the differential diagnosis of any patient with diffuse systemic hemangiomas of the orbit, skin, and visceral system. Because many of these diseases can be complicated by life-threatening gastrointestinal hemorrhage or cardiac failure, the diagnosis of bilateral or multifocal hemangiomas should prompt a thorough workup for the possibility of one of these syndromes.
16. 17. 18. 19.
References 20. 1. Reese AB. Tumors of the Eye, 3rd ed. Hagerstown, MD: Harper & Row, 1976;272. 2. Fries PD, Char DH. Bilateral orbital cavernous hemangiomas. Br J Ophthalmol 1988;72:871–3. 3. Shields JA, Hogan RN, Shields CL, et al. Bilateral cavernous haemangiomas of the orbit [letter]. Br J Ophthalmol 2000;84: 928. 4. Sullivan TJ, Aylward GW, Wright JE, et al. Bilateral multiple cavernous haemangiomas of the orbit. Br J Ophthalmol 1992; 76:627–9. 5. Johnson TE, Nasr AM, Nalbandian RM, Cappelen-Smith J. Enchondromatosis and hemangioma (Maffucci’s syndrome) with orbital involvement. Am J Ophthalmol 1990;110:153–9. 6. Limaye SR, Doyle HA, Tang RA. Retinal varicosity in Klippel-Trenaunay syndrome. J Pediatr Ophthalmol Strabismus 1979;16:371–3. 7. Harris GJ, Jakobiec FA. Cavernous hemangioma of the orbit. J Neurosurg 1979;51:219 –28. 8. McNab AA, Wright JE. Cavernous haemangiomas of the orbit. Aust N Z J Ophthalmol 1989;17:337– 45. 9. Ruchman MC, Flanagan J. Cavernous hemangiomas of the orbit. Ophthalmology 1983;90:1328 –36. 10. Zauberman H, Feinsod M. Orbital hemangioma growth during pregnancy. Acta Ophthalmol (Copenh) 1970;48:929 –33. 11. Bean WB. Vascular Spiders and Related Lesions of the Skin. Springfield, IL: CC Thomas, 1958;178 – 85. 12. Moodley M, Ramdial P. Blue rubber bleb nevus syndrome: case report and review of the literature. Pediatrics 1993;92: 160 –2. 13. Yacoub M, Gnaoui A, Abroug S, et al. [The “blue rubber bleb nevus” (Bean’s syndrome): uncommon cause of gastrointestinal bleeding]. Ann Pediatr (Paris) 1993;40:157– 61. 14. Garen PD, Sahn EE. Spinal cord compression in blue rubber bleb nevus syndrome [letter]. Arch Dermatol 1994;130: 934 –5. 15. Rennie IG, Shortland JR, Mahood JM, Browne BH. Periodic
21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
exophthalmos associated with the blue rubber bleb naevus syndrome: a case report. Br J Ophthalmol 1982;66:594 –9. Mojon D, Odel JG, Rios R, Hirano M. Presumed orbital hemangioma associated with the blue rubber bleb nevus syndrome [letter]. Arch Ophthalmol 1996;114:618 –9. McCannel CA, Hoenig J, Umlas J, et al. Orbital lesions in the blue rubber bleb nevus syndrome. Ophthalmology 1996;103: 933– 6. Paller AS. Vascular disorders. Dermatol Clin 1987;5:239 –50. Sakurane HF, Sugai T, Saito T. The association of blue rubber bleb nevus and Maffucci’s syndrome. Arch Dermatol 1967; 95:28 –36. Lewis RJ, Ketcham AS. Maffucci’s syndrome: functional and neoplastic significance. Case report and review of the literature. J Bone Joint Surg Am 1973;55:1465–79. Golitz LE, Rudikoff J, O’Meara OP. Diffuse neonatal hemangiomatosis. Pediatr Dermatol 1986;3:145–52. Stratte EG, Tope WD, Johnson CL, Swanson NA. Multimodal management of diffuse neonatal hemangiomatosis. J Am Acad Dermatol 1996;34:337– 42. Haik BG, Clancy P, Ellsworth RM, et al. Ocular manifestations in diffuse neonatal hemangiomatosis. J Pediatr Ophthalmol Strabismus 1983;20:101–5. Gloviczki P, Hollier LH, Telander RL, et al. Surgical implications of Klippel-Trenaunay syndrome. Ann Surg 1983;197: 353– 62. Klein TW, Kaplan GW. Klippel-Trenaunay syndrome associated with urinary tract hemangiomas. J Urol 1975;114:596 – 600. Ghahremani GG, Kangarloo H, Volberg F, Meyers MA. Diffuse cavernous hemangioma of the colon in the KlippelTrenaunay syndrome. Radiology 1976;118:673– 8. Good WV, Hoyt CS. Optic nerve shadow enlargement in the Klippel-Trenaunay-Weber syndrome. J Pediatr Ophthalmol Strabismus 1989;26:288 –9. Spoor TC, Kennerdell JS, Maroon JC, et al. Pneumosinus dilatans, Klippel-Trenaunay-Weber syndrome, and progressive visual loss. Ann Ophthalmol 1981;13:105– 8. Rathbun JE, Hoyt WF, Beard C. Surgical management of orbitofrontal varix in Klippel-Trenaunay-Weber syndrome. Am J Ophthalmol 1970;70:109 –12. Reilly PJ, Nostrant TT. Clinical manifestations of hereditary hemorrhagic telangiectasia. Am J Gastroenterol 1984;79:363–7. McCue CM, Hartenberg M, Nance WE. Pulmonary arteriovenous malformations related to Rendu-Osler-Weber syndrome. Am J Med Genet 1984;19:19 –27. Brant AM, Schachat AP, White RI. Ocular manifestations in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease). Am J Ophthalmol 1989;107:642– 6.
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Originally received: January 18, 2001. Accepted: March 28, 2001.
Manuscript no. 210042.
Harvard Medical School, Massachusetts Eye and Ear Infirmary, Ophthalmic Plastic, Orbital and Cosmetic Surgery Service, Boston, Massachusetts. Reprint requests to Peter AD Rubin, MD, 243 Charles Street, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. © 2002 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
branes. Unilateral, isolated cavernous hemangiomas of the orbit have been previously described to be associated with BRBNS. To our knowledge, this is first report of bilateral lesions found in association with this rare angiomatosis and the second report of bilateral, multifocal, cavernous hemangiomas of the orbit.4
Report of a Case A 32-year-old female was referred to the Ophthalmic Plastic, Orbital and Cosmetic Surgery Service at the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, for evaluation of gradual, painless proptosis of both eyes. The patient first noted proptosis of the left eye in 1994 at the age of 27. She had a partial excision of an orbital mass from the left orbit 1 year later. Histopathologic studies of the lesion at that time reported “cavernous hemangioma.” Proptosis of the left eye recurred shortly after surgery and became progressively worse over time. Three years after the initial debulking surgery, at the age of 31, a follow-up magnetic resonance imaging scan was obtained. It demonstrated bilateral, multifocal, hyperfluorescent lesions of the orbit in the intraconal and extraconal spaces consistent with cavernous hemangiomas. There was extension of these lesions through the superior orbital fissure and into the left cavernous sinus and extension through a defect of the lateral wall into the temporal fossa (Fig 1). At this time the patient was referred for further treatment. Examination revealed visual acuity in the right eye of 20/20, although the left eye had declined to counting fingers at 1 m. There was a left afferent pupillary defect. Hertel readings were 21 mm in the right eye and 26 mm in the left eye at a base of 100 mm. On palpation there was a firm, nontender mass over the medial aspect ISSN 0161-6420/02/$–see front matter PII S0161-6420(01)00989-7
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Figure 1. MRI—axial T2-weighted sequence of orbits showing left proptosis and infiltrating, multiloculated, high-signal, masses present in both orbits, right greater than left. Lesions of the left orbit extend in to the cavernous sinus. Figure 2. Preoperative clinical photograph showing proptosis of the left eye. Figure 3. Photograph of cutaneous, bleblike lesions (arrows) of neck. Figure 4. Preoperative axial computed tomogram of orbits demonstrating contrast-enhancing lobulations of the orbits. On the right, the lobulations are confined to the orbit. Lesions of the left orbit extend the superior orbital fissure into the cavernous sinus and laterally through a prior lateral orbitotomy bony defect, into the left parapharyngeal space, infratemporal fossa, masticator space, parotid space, and left lateral scalp. Figure 5. Intraoperative tumor specimens. Figure 6. Large, blood-filled spaces, lined by endothelium and separated by fibrous septa (stain, hematoxylin– eosin; original magnification, ⫻40).
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Chang and Rubin 䡠 Hemangiomas and Blue Rubber Nevus Syndrome of the left upper lid and fullness of the temporal fossa. There was also resistance to retropulsion of the left eye. There were no changes in the degree of the proptosis with a Valsalva maneuver. No lagophthalmos was present, and dilated fundus examination showed myelinated nerve fibers but was otherwise unremarkable. Findings of the remainder of the ocular examinations for both eyes were otherwise unremarkable. There was no demonstrable involvement of the cranial nerves other than compression of the optic nerve in the left eye. Multiple distinctive bluish red, skin lesions, which were easily compressed, were noted on the scalp, neck, and cheek areas at the time of examination (Fig 2, Fig 3). Biopsy of the lesion through a transconjunctival anterior orbitotomy revealed a round cystic orbital mass. Histopathologic studies of the biopsy demonstrated lobules of vascular tissue separated by fibrous septae consistent with cavernous hemangioma. A preoperative computed tomography scan of the orbits demonstrated contrast-enhancing lobulations of the orbits consistent with vascular malformations. On the right, the lobulations were confined to the orbit. On the left, there was extension of these lesions through the superior orbital fissure into the cavernous sinus. There was also extension laterally into the left parapharyngeal space, infratemporal fossa, masticator space, parotid space, and left lateral scalp through her prior lateral orbitotomy bony defect. Additional vascular structures were seen in the region of the scalp, left mandibular gland, and posterior triangle (Fig 4). In an effort to reduce compression of the optic nerve and disfiguring proptosis, a lateral orbitotomy of the left eye was performed to gain access to the tumors. Eight accessible, distinct, red, cystic nodules were excised from the left orbit with the largest tumor measuring 20 ⫻ 18 ⫻ 10 mm (Fig 5). Histopathologic studies of these lesions revealed large, blood-filled spaces lined with endothelium and separated by fibrous septa of varying thickness consistent with cavernous hemangiomas of the orbit (Fig 6). Six months postoperatively, the patient’s visual acuity in the left eye was 20/100, with a 5-mm reduction in proptosis. At that time, a bluish red, slightly raised lesion of the scalp, which was noted to be increasing in size, was biopsied and found to be consistent with a cavernous hemangioma. Because of the diffuse, multifocal involvement of the hemangiomas, a systemic workup was initiated for the possibility of an associated angiomatosis. Plain film x-rays of the long bones of the hands and feet did not reveal abnormalities consistent with Maffucci’s disease. Computed tomography of the body revealed contrast-enhancing lesions of the spleen and liver consistent with hemangiomas. This constellation of findings: multiple, distinctive, bluish red cutaneous nodules, visceral hemangiomas, multiple cavernous hemangiomas of the orbit, is most consistent with a diagnosis of BRBNS. Follow-up of the patient over the course of 1 year has not demonstrated any appreciable change in the orbital lesions by clinical examination. There has been noticeable enlargement of the neck lesions, which has not affected the patient adversely.
Comment Cavernous hemangiomas of the orbit are common lesions of the adult orbit. They are benign, low-flow hamartomas with a fine capsule. These typically manifest in the fourth and fifth decades, with a 60% to 70% female preponderance.7–9 Most patients have gradually increasing, painless proptosis. On rare occasions, patients can also manifest signs of mass effect such as diplopia, pain, choroidal striae, and compressive optic neuropathy. Growth of these lesions may be stimulated by local hemodynamic disturbances, hypoxia,
and hormonal changes during pregnancy, stimulating proliferation of capillaries.6,10 When these lesions are found to be either bilateral or multifocal, they may be associated with an underlying systemic syndrome. Lesions of the skin, visceral system, and skeletal system may be found to exist concurrently with the unusual finding of multiple orbital lesions. On rare occasions when these lesions are found in association with cutaneous, visceral, or skeletal lesions, there are a number of vascular disorders that should be included in the differential diagnosis. Many of these syndromes with multisystemic involvement are hereditary, although others are sporadic in occurrence. BRBNS is a rare syndrome characterized by distinctive bluish red, rubbery, cutaneous lesions in the skin, gastrointestinal tract, and other organs. Originally described in 1860 by Gascoyan, the term “blue rubber bleb nevus syndrome” was coined in 1958 by William B. Bean because of the blue coloration and rubbery texture of the hemangiomas.11 Although few cases have been described with an autosomal dominant pattern of inheritance, most cases are sporadic. The peculiar lesions of BRBNS, which may number up to several hundred, are generally present from birth or early childhood and vary in size from 1 to 30 mm in diameter. With advancing age, some lesions may spontaneously involute, although most lesions persist, and some may enlarge. Visceral lesions are most often found in the small intestine or in the distal part of the colon, although lesions have also been found in the stomach, liver, spleen, and lungs.12 Gastrointestinal bleeding from these lesions can lead to iron-deficiency anemia.13 Other complications of this disease include orthopedic abnormalities and neurologic deficits from central nervous system lesions.14 The lesion that distinguishes BRBNS from other entities is the distinctive appearance of the cutaneous hemangiomas. The characteristic description is a bluish red, thin-walled sac, with a soft, rubbery consistency. Digital compression leaves an empty wrinkled sac that refills slowly. Histopathologic examination, as with other cavernous hemangiomas, reveals large, blood-filled spaces separated by fibrous septa of varying thickness lined by endothelium that reacts strongly for factor VIII–related antigen. Imaging studies are consistent with slow flow vascular lesions that may enhance with contrast. Associated ocular findings include hemangiomas of the conjunctiva, iris, and macula. There are four reported cases of BRBNS with orbital involvement. Rennie and colleagues15 described a 71-year-old woman with BRNBS who had an intraconal mass on computed tomography imaging, causing intermittent episodes of exophthalmos. In 1996 Mojon and colleagues16 described a 47-year-old woman with BRBNS who had ptosis, miosis, and spontaneous ecchymoses. This patient was found to have an intraconal mass with irregular surrounding fibrosis and calcifications, presumed to be a cavernous hemangioma on computed tomography imaging. McCannel et al17 described two cases of BRNBS with unilateral, orbital hemangiomas. The first case was a 28-year-old woman who had spontaneous lid ecchymoses and orbital pain. Diagnosis of the orbital lesions was made by magnetic resonance imaging and computed tomography. The second patient was a 7-year-old girl
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Ophthalmology Volume 109, Number 3, March 2002 who had blurred vision and proptosis of the right eye, which was more noticeable with strenuous activity. Diagnosis of the orbital lesions was based on computed tomography findings consistent with hemangioma of the orbit and a biopsy of a neck lesion with histopathologic findings consistent with cavernous hemangioma. We now report a patient with BRBNS with multifocal, bilateral, orbital hemangiomas. Rapid growth of the lesions of the left orbit caused proptosis and decreased vision. On computed tomography, the orbit showed multifocal lesions with calcifications and contrast enhancement similar to the lesions in the spleen and liver. Biopsy of a scalp lesion and the orbital lesions showed histopathologic findings compatible with cavernous hemangiomas. The characteristic appearance of the lesions of the neck, mandible, and scalp in conjunction with the histopathologic findings consistent with cavernous hemangioma are most compatible with BRBNS. Other systemic angiomatoses, which may be considered in the differential diagnosis of orbital lesions associated with systemic hemangiomas, are described below. Maffuci’s syndrome is a rare, congenital disease, with no familial predisposition, characterized by the development of multiple enchondromas and soft-tissue hemangiomas. Twenty-five percent of patients with Maffucci’s syndrome demonstrate skeletal or vascular manifestations of this disease before the age of 1 and 78% before puberty.18 Cavernous hemangiomas and capillary hemangiomas are the most common vascular lesions of this entity, although lymphangiomas have been described, as well as one patient with associated BRBNS.19 Visceral hemangiomas of the gastrointestinal tract may occur, with lesions of the esophagus, ileum, and oral mucosa being common. The bone lesions are most commonly enchondromas that affect the small bones of the hands, feet and the long bones. These lesions are readily apparent on plain films from early childhood. The possibility of this disease in cases of bilateral orbital hemangiomas must be explored, because 30% of patients with this disease will eventually develop malignant neoplasm develop.20 One case of Maffucci’s syndrome has been described with bilateral orbital hemangiomas and multiple enchondromas.5 Diffuse neonatal angiomatosis is a rare, often fatal, condition characterized by multiple cutaneous and visceral hemangiomas. Despite therapy with corticosteroids, mortality rates of 60% to 90% in the first few months of life have been reported.21–23 Complications include high-output cardiac failure, gastrointestinal bleeding, hydrocephalus, and consumption coagulopathy. Death is usually a result of high-output cardiac failure caused by arteriovenous shunting. The organs most commonly affected are the gastrointestinal tract, brain, liver, and lung.11 Ophthalmic examination of patients with this syndrome can reveal a number of abnormalities. Hemangiomas may involve the iris, ciliary body, and ciliary processes, leading to complications such as hyphema and vitreous hemorrhage. In addition, conjunctival hemangiomas and bilateral eyelid hemangiomas have also been described.23 Klippel-Trenaunay syndrome consists of a triad of nevus flammeus (port-wine stain), hypertrophy of the underlying soft tissue and bone, and venous varicosities. This condition
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shows no familial pattern of inheritance and no sexual preponderance. The nevus flammeus, which is present in 75% of patients, is usually noted at birth. Other vascular malformations manifesting during infancy are usually unilateral and involve the lower extremity, including capillary and cavernous hemangiomas, angiokeratomas, and lymphangiomas.24 Hemihypertrophy of the lower extremity often leads to compensatory scoliosis, whereas venous varicosities may result in cutaneous ulcerations, edema, and stasis changes. Other associated lesions include cavernous hemangiomas of the bladder25 and colon.26 Ophthalmic features occasionally seen in association with the syndrome are similar to those seen in the SturgeWeber syndrome. These features include retinal varicosities, choroidal angiomas, iris heterochromia, and glaucoma.6 Orbital manifestations associated with Klippel-TrenaunayWeber syndrome include regional hypertrophy of the orbital contents,27 a case of bilateral optic nerve sheath meningioma that was diagnosed by fine-needle aspiration biopsy28 and an orbital varix.29 Rendu-Osler-Weber syndrome (hereditary hemorrhagic telangiectasia) is an autosomal dominant disorder characterized by the development of mucocutaneous and visceral telangiectasias associated with recurrent episodes of hemorrhage. Skin lesions that appear as punctate telangiectasias or spider telangiectasias usually become evident during puberty and increase in both size and number with advancing age. Vascular lesions may occur anywhere on the skin, although the mucosa of the lips, tongue, nasal septum, and buccal mucosa are the most frequently involved sites. Visceral lesions, which require endoscopies or arteriographic procedures for visualization, are usually found in the upper gastrointestinal tract and liver.30 Recurrent epistaxis and bleeding from the gastrointestinal tract associated with severe iron-deficiency anemia requiring repeated transfusions are related to hemorrhage from telangiectatic vessels in the nasal mucosa and gastrointestinal tract. Dyspnea on exertion, clubbing, or cyanosis may be seen as a result as a sequelae of the pulmonary arteriovenous shunts, which are seen in 20% of patients with Rendu-Osler-Weber syndrome.31 Ocular findings, which are present in 45% of patients with this syndrome, include conjunctiva telangiectasias and small retinal arteriovenous malformations.32 Occasionally, bloody tears may be noted because of the presence of the conjunctiva telangiectasias. No orbital lesions have been described associated with this entity in our review of the modern literature. Although cavernous hemangiomas of the orbit are common lesions of the adult, bilateral lesions are extremely rare. Of the five lesions described in the literature, one was described in a case of Maffuci’s syndrome, whereas our case occurred in the setting of BRBNS. A number of other entities with cutaneous and visceral lesions have also been described, including diffuse neonatal hemangiomatosis, Klippel-Trenaunay-Weber syndrome, and Osler-RenduWeber syndrome. Diffuse neonatal hemangiomatosis has also been associated with bilateral hemangiomas of the lids.23 The other two entities have not been described in association with orbital cavernous hemangiomas, although
Chang and Rubin 䡠 Hemangiomas and Blue Rubber Nevus Syndrome they certainly merit consideration in the differential diagnosis of any patient with diffuse systemic hemangiomas of the orbit, skin, and visceral system. Because many of these diseases can be complicated by life-threatening gastrointestinal hemorrhage or cardiac failure, the diagnosis of bilateral or multifocal hemangiomas should prompt a thorough workup for the possibility of one of these syndromes.
16. 17. 18. 19.
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