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Varied Clinical Spectrum of Necrobiotic Xanthogranuloma
Varied Clinical Spectrum of Necrobiotic Xanthogranuloma Wayne T. Cornblath, MD,I·2 Shlomo A. Dotan, MD,I Jonathan D. Trobe, MD,I·2 John T. Headington, MD3
F
our cases are presented that illustrate a wide spectrum of ophthalmologic and systemic features of necrobiotic xanthogranuloma (NXG). Case 1 initially had signs of Cogan syndrome, and then developed chronic lymphocytic leukemia. Case 2, the first case of NXG to undergo autopsy, had progressive cicatricial lid retraction and corneal perforation. Case 3 had a more typical presentation of diplopia and blepharoptosis caused by orbital and periorbital infiltrative masses. Case 4 had non deforming periocular skin lesions over a 6-year period. In all four cases, the diagnosis was made on the basis of characteristic histopathologic and laboratory findings. Although the cause of NXG is still obscure, in many cases it appears to be a forerunner of Iymphoproliferative diseases. Ophthalmology 1992; 99:103-107
The term "necrobiotic xanthogranuloma with paraproteinemia" (NXG) was first used in 1980 to describe an inflammatory subset of normolipemic xanthomas. I Since then, approximately 34 cases have been reported in the medical literature. I- 12 Patients with NXG develop multiple xanthomatous plaques with prominent telangiectasia and bulky subcutaneous nodules that most commonly are found in the periorbital area, trunk, and extremities. The lesions tend to ulcerate and progress. The ophthalmic findings include firm lid nodules and, less frequently, conjunctival hyperemia, episcleral plaques, uveitis, and infiltrative orbital masses. The accompanying paraproteinemia tends to be an IgG monoclonal gammopathy, either kappa or lambda. Neutropenia, hypocomplemen-
Originally received: July 15, 1991. Revision accepted: September 13, 1991. I W. K. Kellogg Eye Center, Department of Ophthalmology, University of Michigan, Ann Arbor. 2 Department of Neurology, University of Michigan, Ann Arbor. 3 Departments of Dermatology and Pathology, University of Michigan, Ann Arbor. Dr. Dotan is currently affiliated with the Department of Ophthalmology, Kaplan Hospital, Rehovot, and the Hebrew University-Hadassah Medical School, Jerusalem, Israel. Presented in part at the Frank B. Walsh Society Meeting, February 1990. Dr. Dotan was supported in part by a grant from the American Physicians Fellowship. Reprint requests to Wayne T. Cornblath, MD, W. K. Kellogg Eye Center, University of Michigan, 1000 Wall St, Ann Arbor, MI 48105.
temia, cryoglobulinemia, hyperlipidemia, and associated malignancies are additional variable features. We report four patients with a spectrum of ocular and systemic manifestations of NXG examined at the University of Michigan (Table 1). In the first patient, signs overlapped with Cogan syndrome, interstitial keratitis with vestibuloauditory dysfunction, an association not previously described. The second patient represents the first reported case of NXG to undergo autopsy. The remaining cases share features of previously reported cases but help to illustrate the wide range of the disease.
Case Reports Case 1. A 45-year-old man with a history of splenomegaly, abdominal lymphadenopathy, and lymphocytosis on bone marrow biopsy noted conjunctival injection without discharge in January 1977. This was followed by two episodes of acute vertigo, bilateral tinnitus, and hearing loss that initially responded to oral prednisone and later to intravenous corticosteroids. A monoclonal IgG kappa spike of 1190 mg/dl was present (normal IgG, 590 to 1581 mg/dl). By 1980, his hearing loss was unresponsive to corticosteroids. Cyclophosphamide was started but later stopped because of side effects. In 1983, visual function was normal in the presence of bilateral annular sclerokeratitis and optic disc edema (Figs lA, I B). Computed tomographic (CT) scans ofthe head and lumbar puncture, including opening pressure, were normal. Xanthomatous lesions on the face, trunk, and extremities were clinically believed to be "dermatofibroma" (Fig 2). Three years later, biopsy of his facial lesions yielded a diagnosis of "necrobiotic xanthogranuloma." The lesions were initially controlled with local injection of triamcinolone acetonide but eventually required cyclophosphamide (750 mg), vincristine (2 mg), and prednisone
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Ophthalmology
Volume 99, Number 1, January 1992
Table 1. Clinical Features of Four Patients with Necrobiotic Xanthogranuloma and Paraproteinemia Patient
(yrs)
Sex
Length of Follow-up
1
45
M
13 yrs
2
64
F
2 yrs
Skin lesions, cicatricial retraction, corneal perforation
3
59 70
F F
1 yr 2 mos
Diplopia, blepharoptosis, skin lesions Skin lesions of eyelids, shoulders, scalp and leg lesions
No.
4
Age
Features
Treatment and Course
Cogan syndrome, optic disc edema, skin lesions, myocardial infarct, chronic lymphocytic leukemia
Initial control with local injection, then systemic chemotherapy; lesions recurred requiring local injection and excision for control Lesions progressed despite multiple chemotherapies and plasmapheresis; eventual death from pneumonia Resolution of lesions with chemotherapy Control with intralesional therapy for 6 years
(100 mg) in monthly cycles. Most recently, excision oflesions has been necessary. During this interval, the patient had a subendocardial infarction and a cardiac arrest. Coronary angiography was normal. A cochlear implant was inserted for severe hearing loss. In March 1990, the patient was diagnosed with chronic lymphocytic leukemia. Case 2. A 64-year-old woman with a history of periorbital xanthomas, hypercholesterolemia and carcinoma of the cervix presented in 1971 with granulomatous uveitis, peripheral neuropathy, and nodular lung lesions. The diagnosis of sarcoidosis was confirmed with liver, skin, and bone marrow biopsies. Additional findings included leukopenia, cryofibrinogenemia, hypersplenism, and IgG kappa monoclonal gammopathy. In 1976, the patient developed severe ulceration of her facial xanthomas followed by cellulitis, which progressed despite skin grafts. Skin biopsy was diagnosed as "xanthohistiolytic granulorna." (This part of her history has been previously reported. I) Ophthalmologic examination disclosed visual acuities of counting fingers in the right eye and 20/100 in the left, bilateral lid retraction, and exposure keratitis with corneal ulceration in the right eye. Treatment consisted of bilateral tarsorrhaphies and topical lubricants. Repeat skin biopsies showed "necrotizing xanthogranulomas." Her xanthomas became more confluent and ulcerated (Fig 3). Bilateral conjunctiVal flaps were done for corneal ulcers. One month later she had a permanent tarsorrhaphy of the left eyelids for persisting keratitis, but, despite this, a corneal perforation developed. Visual acuity was light perception in both eyes with extensive corneal scarring. Dapsone (300 mg per day), cyclophosphamide (100 mg per day), clofazimine, and plasmapheresis failed to improve her skin lesions. She died of pneumonia in May 1978. Autopsy showed ulcerated, xanthomatous lesions ofthe face with less than 10% normal skin remaining and associated scalp and neck lesions. Lesions were present on the arms, chest, abdomen, and legs. The anterior right leg was totally ulcerated, to a depth of 0.3 to 0.5 cm, from the patella to the malleoli. The spleen was enlarged and fibrotic with confluent "xanthohistiocytic granulomata." There was no evidence of vasculitis. The cause of death was bilateral bronchopneumonia and pulmonary edema. Case 3. A 59-year-old woman with a history of hypertension, hypercholesterolemia, xanthelasma, and a benign monoclonal IgG lambda spike of 1775 mg/dl of 3 years' duration presented in March 1989, with complaints of double vision, left blepharoptosis, and swelling ofthe left cheek and both temporal fossae. A CT scan and magnetic resonance imaging 1 month later showed thickening of the left lateral rectus muscle and possibly the right medial rectus (Fig 4). Additional images showed
104
enlargement of the left lacrimal gland. A biopsy of the right temporal fossa showed "annular elastolytic giant cell granulorna." Two weeks later, a left orbital biopsy showed nonspecific inflammation. Prednisone 60 mg every day resulted in improvement of the skin masses, diplopia, and blepharoptosis. In May 1989, visual acuity was 20/20 in both eyes with normal pupils. The left cheek and soft tissues around the left eye were thickened. There was no proptosis, but there was marked resistance to retropulsion in both eyes. Yellowish "xanthelasma-like" lesions were present on the medial portions of both lids. There was 3 mm of blepharoptosis on the left side, and 1 mm on the right. An exodeviation greater than 50 prism diopters was present in primary position (Fig 5). In the right eye, adduction was reduced to 80% and other ductions were full. In the left eye, adduction was absent, elevation was 50%, depression was 50%, and abduction was 100%. Forced ductions were positive. On review, the biopsy of the temporal fossa was diagnosed as NXG. Facial nodules recurred as prednisone was tapered but regressed when prednisone was increased to 20 mg per day. Because of concern about the side effects ofIong-term prednisone therapy, the patient was started on cyclophosphamide 200 mg per day and prednisone 60 mg per day in 5-day cycles. She continues to improve on this regimen. Case 4. A 70-year-old woman with a history ofhypercholesterolemia, hypertension and angina noted a flat, firm lesion on her left shoulder in 1984. Biopsy was "suggestive of granuloma annulare." One year later, similar lesions developed on her scalp and around the left eye. These were removed and said to be granulomas. In 1989, biopsy was performed on lesions around the left eye which were said to be "xanthogranulomas." In 1990, biopsy was performed on a lesion at the right medial canthus and read as NXG. At this time, an IgG of2454 mgfdl (normal, 710 to 1540) was noted. During this same period, the patient underwent intralesional injections of triamcinolone with partial resolution of her lesions. She also had a xanthelasma and a spontaneously waxing and waning lesion on her left lower leg. Her ophthalmologic examination remains normal except for the lesions around the eyes (Fig 6).
Discussion Robertson and Winkelmann5 reported the ophthalmic manifestations in 15 patients from a series of 16 cases of NXG. Firm lid nodules or plaques were by far the most
Top, Figure 1. Bilateral disc edema in case 1. Left, A, right eye. Right, B, left eye. Second row left, Figure 2. Case 1 with lesions of NXG prominently on lower lids bilaterally and also on medial upper lids (arrows). Second row right, Figure 3. Case 2 with necrotic skin lesions of NXG.
Third row left, Figure 4. CT of case 2 shows enlarged recti muscles. Third row right, Figure 5. Case 2 with blepharoptosis, skin lesions, and exophoria. Bottom, Figure 6. Right eye of case 4 with skin lesions ofNXG (arrows).
Ophthalmology
Volume 99, Number 1, January 1992
frequent symptom, seen in 13 patients. Scleritis or episcleritis and anterior uveitis were each seen in three patients. Extensive destruction of periorbital tissue with loss of vision occurred in two patients. Conjunctival infiltration, cicatricial symblepharon, and keratoconjunctivitis sicca were each seen in one patient. Since this report,5 a number of other patients with varying ophthalmic presentations have been reported. 6- 12 Our case 1 had conjunctival hyperemia and papular skin lesions typical ofNXG and additional symptoms not previously described that overlap with Cogan syndrome. Cogan syndrome is a disease of young adults characterized by episodes of acute interstitial keratitis with vestibuloauditory dysfunction progressing to deafness. 14,15 Aortic insufficiency and aortitis develop in 10% of cases and, in rare cases, are associated with myocardial infarction due to coronary vasculitis or emboli. Variants of Cogan syndrome have been described with optic disc edema, vasculitis, and in association with rheumatologic syndromes such as Wegener's granulomatosis or rheumatoid arthritis.14 The cause of Cogan syndrome is unknown but possibly autoimmune in nature. Our case 1 had progressive sensorineural hearing loss, chronic optic disc edema, and cardiac disease, all consistent with Cogan syndrome. To our knowledge, neither NXG, monoclonal gammopathy, nor chronic lymphocytic leukemia have been described before with Cogan syndrome. Even the association of NXG and chronic lymphocytic leukemia is rare, with only one previous report. 3 This case raises the possibility of an underlying autoimmune disorder causing both Cogan syndrome and NXG. Our case 2 had a clinical course characterized by aggressive periocular ulcerative skin lesions, lid retraction, and corneal exposure, leading to corneal perforation and blindness. Eventually, lesions spread over most of the face and involved the rest ofthe body to varying degrees. Autopsy showed "xanthohistiocytic granulomata" in the spleen, suggesting internal involvement with NXG. No surgical procedure or systemic treatment was of any benefit throughout her course of treatment. Only two patients have been previously reported with orbital soft tissue destruction by NXG, both resulting in blindness. 10 However, the details of their cases were not reported. This patient demonstrates the potential for a devastating visual and systemic outcome in a rare form of NXG. Our case 3 is similar to a number of previous cases, with ophthalmic symptoms and periocular involvement dominating her course. Codere et al 3 described a similar patient, presenting with restricted ocular motility due to thickened extraocular muscles and infiltrative orbital masses. Spontaneous ulceration of the periocular plaques also developed, as in our case. Bullock et al8 reported a case of bilateral orbital infiltration by a yellowish indurated mass, which was found on histopathologic examination to be NXG. Scupham and Fretzin l2 described a 57-yearold woman with NXG who presented with diplopia, mild blepharoptosis, yellow plaques on her eyelids, and firm cutaneous nodules on her face. Three additional cases overlap with our patient, for a total of six similar cases.
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Our case 4 had a very benign course without significant disfigurement or visual dysfunction. Her management over 6 years has required only local therapy. This case is in sharp distinction to case 2 and illustrates the varying intensity of the disease. Histopathologically, the lesion ofNXG is characterized by granuloma formation throughout the layers of dermis, consisting of inflammatory histiocytes, foam cells, and Touton and foreign body giant cells, surrounded by eosinophilic changes in dermal collagen. 13 Case 2 is the only reported case of NXG to have undergone autopsy. Although the brain was excluded, there was involvement of NXG over a large area of skin and in the spleen, with no evidence of vasculitis. In the differential diagnosis of NXG, one should consider necrobiosis lipoidica, juvenile xanthogranuloma, granuloma annulare, foreign body granuloma, subcutaneous rheumatoid nodules, xanthoma disseminatum, plane normolipemic xanthoma, primary and secondary amyloidosis, and Erdheim-Chester disease. 1,5,9 Necrobiosis lipoidica, the principal entity to be considered, is usually confined to the pretibial areas in patients with diabetes mellitus. In two of our cases, the diagnosis was initially granuloma annulare. In the third case, it was xanthohistiocytic granulomata, and, in the fourth case, it was dermatofibroma. Patients with benign monoclonal gammopathy have a 10% risk of later developing multiple myeloma, macroglobulinemia, amyloidosis, or malignant lymphoproliferative diseases. 16 From previously reported cases with NXG, multiple myeloma developed in five patients, a plasmaproliferative disorder developed in eight, and a lymphoproliferative disorder and lymphocytic leukemia each developed in one patient. 1,5,7,8,10 This is equivalent to a 47% risk of later malignancy. With a longer followup period, this incidence might be even greater. On the basis of this observation, patients with NXG with paraproteinemia should be repeatedly investigated for myeloma or other lymphoproliferative disorders. Although two of our patients had normal bone marrow biopsies on several occasions, the third patient was diagnosed with chronic lymphocytic leukemia 13 years after splenectomy revealed a nonspecific lymphocytosis. In our cases, the paraproteinemia preceded the diagnosis ofNXG by 3,5, and 6 years, respectively. In the fourth patient, the paraproteinemia was discovered after the pathologic diagnosis of NXG was made. Interestingly, the multiple myeloma in three ofthe patients with NXG described by Finan and Winkelmann9 was somewhat unusual in being low grade, generally asymptomatic, and having a prolonged course after chemotherapy. Myeloma associated with NXG may be of the "smoldering" variety. Treatment ofNXG has involved a number of different modalities, including excision, local injection, plasmapheresis, and chemotherapy. The chemotherapeutic agents used in NXG have included methotrexate, azathioprine, melphalan, chlorambucil, cyclophosphamide, nitrogen mustard, and prednisone. 1,3,5,6,8,9,11,12 The response to therapy has varied, but low-dose chemotherapy has generally been beneficial. Response to chemotherapy
Cornblath et al . Necrobiotic Xanthogranuloma also varied in our patients: case 3 had a favorable response to cyclophosphamide and prednisone, case 1 had only a partial response to the combination of cyclophosphamide, vincristine, and prednisone, whereas case 2 failed to respond to dapsone, cyclophosphamide, clofazimine, or plasmapheresis. Case 4 has required only excision and intralesional triamcinolone. Because of the small numbers of reported cases, no firm conclusions as to the efficacy of therapy can be made. The cause ofNXG is unknown. Bullock et al8 suggested that serum immunoglobulins complex with lipids and deposit in the skin, eliciting a giant cell foreign reaction. Venencie et alii hypothesized that the paraproteinemia is the primary phenomenon and that NXG represents a secondary proliferation of the macrophages that have receptors for the Fc portion of IgG. Our first patient, with symptoms of Cogan syndrome, provides further evidence for the likelihood of a dysimmune cause for NXG. It seems plausible that the skin lesions of NXG are an additional manifestation, along with the paraproteinemia, of an underlying hematopoietic or lymphoproliferative disorder of an unusually benign nature. We still lack good understanding of the pathophysiology of this rare disease, for which ophthalmologists can contribute to an early diagnosis. Acknowledgments. The authors thank Dr. W. Carter Lowe, Dr. Thimmiah Ramesh, and Dr. David Reifler for their kind referral of patients.
References 1. Kossard S, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia. JAm Acad Dermatol 1980; 3:25770.
2. Kossard S. Xantogranuloma necrobiotico con paraproteinemia. G Ital Dermatol Venereol 1983; 118:219-22. 3. Codere F, Lee RD, Anderson RL. Necrobiotic xanthogranuloma of the eyelid. Arch Ophthalmol 1983; 101:60-3. 4. Smith SA, Alexander RA, Stasko T, et al. Necrobiotic xanthogranuloma. J Assoc Mil Dermatol 1983; 9:78-83. 5. Robertson DM, Winkelmann RK. Ophthalmic features of necrobiotic xanthogranuloma with paraproteinemia. Am J Ophthalmol 1984; 97: 173-83. 6. Macfarlane AW, Verbov JL. Necrobiotic xanthogranuloma with paraproteinemia. Br J Dermatol1985; 113:339-43. 7. Holden CA, Winkelmann RK, Wilson Jones E. Necrobiotic xanthogranuloma: a report of four cases. Br J Dermatol 1986; 114:241-50. 8. Bullock JD, Bartley GB, Campbell RJ, et al. Necrobiotic xanthogranuloma with proteinemia. Case report and a pathogenetic theory. Ophthalmology 1986; 93:1233-6. 9. Finan MC, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia. A review of22 cases. Medicine 1986; 65:376-88. 10. Finelli LG, Ratz JL. Plasmapheresis, a treatment modality for necrobiotic xanthogranuloma. J Am Acad Dermatol 1987; 17:351-4. 11. Venencie PY, Puissant A, Verola 0, et al. Necrobiotic xanthogranuloma with myeloma. A case report. Cancer 1987; 59:588-92. 12. Scupham RK, Fretzin DF. Necrobiotic xanthogranuloma with paraproteinemia. Arch Pathol Lab Med 1989; 113: 1389-91. 13. Jakobiec FA, Font RL. Orbit. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook; 3rd ed. Vol. 3. Philadelphia: WB Saunders, 1986; 2729-30. 14. Haynes BF, Kaiser-Kupfer MI, Mason P, Fauci AS. Cogan syndrome: studies in thirteen patients, long-term follow-up, and a review of the literature. Medicine 1980; 59:426-41. 15. Vollertsen RS, McDonald TJ, Younge BR, et al. Cogan's syndrome: 18 cases and a review of the literature. Mayo Clin Proc 1986; 61 :344-61. 16. Kyle RA, Lust JA. Monoclonal gammopathies of undetermined significance. Sem Hematol 1989; 26: 176-200.
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F
our cases are presented that illustrate a wide spectrum of ophthalmologic and systemic features of necrobiotic xanthogranuloma (NXG). Case 1 initially had signs of Cogan syndrome, and then developed chronic lymphocytic leukemia. Case 2, the first case of NXG to undergo autopsy, had progressive cicatricial lid retraction and corneal perforation. Case 3 had a more typical presentation of diplopia and blepharoptosis caused by orbital and periorbital infiltrative masses. Case 4 had non deforming periocular skin lesions over a 6-year period. In all four cases, the diagnosis was made on the basis of characteristic histopathologic and laboratory findings. Although the cause of NXG is still obscure, in many cases it appears to be a forerunner of Iymphoproliferative diseases. Ophthalmology 1992; 99:103-107
The term "necrobiotic xanthogranuloma with paraproteinemia" (NXG) was first used in 1980 to describe an inflammatory subset of normolipemic xanthomas. I Since then, approximately 34 cases have been reported in the medical literature. I- 12 Patients with NXG develop multiple xanthomatous plaques with prominent telangiectasia and bulky subcutaneous nodules that most commonly are found in the periorbital area, trunk, and extremities. The lesions tend to ulcerate and progress. The ophthalmic findings include firm lid nodules and, less frequently, conjunctival hyperemia, episcleral plaques, uveitis, and infiltrative orbital masses. The accompanying paraproteinemia tends to be an IgG monoclonal gammopathy, either kappa or lambda. Neutropenia, hypocomplemen-
Originally received: July 15, 1991. Revision accepted: September 13, 1991. I W. K. Kellogg Eye Center, Department of Ophthalmology, University of Michigan, Ann Arbor. 2 Department of Neurology, University of Michigan, Ann Arbor. 3 Departments of Dermatology and Pathology, University of Michigan, Ann Arbor. Dr. Dotan is currently affiliated with the Department of Ophthalmology, Kaplan Hospital, Rehovot, and the Hebrew University-Hadassah Medical School, Jerusalem, Israel. Presented in part at the Frank B. Walsh Society Meeting, February 1990. Dr. Dotan was supported in part by a grant from the American Physicians Fellowship. Reprint requests to Wayne T. Cornblath, MD, W. K. Kellogg Eye Center, University of Michigan, 1000 Wall St, Ann Arbor, MI 48105.
temia, cryoglobulinemia, hyperlipidemia, and associated malignancies are additional variable features. We report four patients with a spectrum of ocular and systemic manifestations of NXG examined at the University of Michigan (Table 1). In the first patient, signs overlapped with Cogan syndrome, interstitial keratitis with vestibuloauditory dysfunction, an association not previously described. The second patient represents the first reported case of NXG to undergo autopsy. The remaining cases share features of previously reported cases but help to illustrate the wide range of the disease.
Case Reports Case 1. A 45-year-old man with a history of splenomegaly, abdominal lymphadenopathy, and lymphocytosis on bone marrow biopsy noted conjunctival injection without discharge in January 1977. This was followed by two episodes of acute vertigo, bilateral tinnitus, and hearing loss that initially responded to oral prednisone and later to intravenous corticosteroids. A monoclonal IgG kappa spike of 1190 mg/dl was present (normal IgG, 590 to 1581 mg/dl). By 1980, his hearing loss was unresponsive to corticosteroids. Cyclophosphamide was started but later stopped because of side effects. In 1983, visual function was normal in the presence of bilateral annular sclerokeratitis and optic disc edema (Figs lA, I B). Computed tomographic (CT) scans ofthe head and lumbar puncture, including opening pressure, were normal. Xanthomatous lesions on the face, trunk, and extremities were clinically believed to be "dermatofibroma" (Fig 2). Three years later, biopsy of his facial lesions yielded a diagnosis of "necrobiotic xanthogranuloma." The lesions were initially controlled with local injection of triamcinolone acetonide but eventually required cyclophosphamide (750 mg), vincristine (2 mg), and prednisone
103
Ophthalmology
Volume 99, Number 1, January 1992
Table 1. Clinical Features of Four Patients with Necrobiotic Xanthogranuloma and Paraproteinemia Patient
(yrs)
Sex
Length of Follow-up
1
45
M
13 yrs
2
64
F
2 yrs
Skin lesions, cicatricial retraction, corneal perforation
3
59 70
F F
1 yr 2 mos
Diplopia, blepharoptosis, skin lesions Skin lesions of eyelids, shoulders, scalp and leg lesions
No.
4
Age
Features
Treatment and Course
Cogan syndrome, optic disc edema, skin lesions, myocardial infarct, chronic lymphocytic leukemia
Initial control with local injection, then systemic chemotherapy; lesions recurred requiring local injection and excision for control Lesions progressed despite multiple chemotherapies and plasmapheresis; eventual death from pneumonia Resolution of lesions with chemotherapy Control with intralesional therapy for 6 years
(100 mg) in monthly cycles. Most recently, excision oflesions has been necessary. During this interval, the patient had a subendocardial infarction and a cardiac arrest. Coronary angiography was normal. A cochlear implant was inserted for severe hearing loss. In March 1990, the patient was diagnosed with chronic lymphocytic leukemia. Case 2. A 64-year-old woman with a history of periorbital xanthomas, hypercholesterolemia and carcinoma of the cervix presented in 1971 with granulomatous uveitis, peripheral neuropathy, and nodular lung lesions. The diagnosis of sarcoidosis was confirmed with liver, skin, and bone marrow biopsies. Additional findings included leukopenia, cryofibrinogenemia, hypersplenism, and IgG kappa monoclonal gammopathy. In 1976, the patient developed severe ulceration of her facial xanthomas followed by cellulitis, which progressed despite skin grafts. Skin biopsy was diagnosed as "xanthohistiolytic granulorna." (This part of her history has been previously reported. I) Ophthalmologic examination disclosed visual acuities of counting fingers in the right eye and 20/100 in the left, bilateral lid retraction, and exposure keratitis with corneal ulceration in the right eye. Treatment consisted of bilateral tarsorrhaphies and topical lubricants. Repeat skin biopsies showed "necrotizing xanthogranulomas." Her xanthomas became more confluent and ulcerated (Fig 3). Bilateral conjunctiVal flaps were done for corneal ulcers. One month later she had a permanent tarsorrhaphy of the left eyelids for persisting keratitis, but, despite this, a corneal perforation developed. Visual acuity was light perception in both eyes with extensive corneal scarring. Dapsone (300 mg per day), cyclophosphamide (100 mg per day), clofazimine, and plasmapheresis failed to improve her skin lesions. She died of pneumonia in May 1978. Autopsy showed ulcerated, xanthomatous lesions ofthe face with less than 10% normal skin remaining and associated scalp and neck lesions. Lesions were present on the arms, chest, abdomen, and legs. The anterior right leg was totally ulcerated, to a depth of 0.3 to 0.5 cm, from the patella to the malleoli. The spleen was enlarged and fibrotic with confluent "xanthohistiocytic granulomata." There was no evidence of vasculitis. The cause of death was bilateral bronchopneumonia and pulmonary edema. Case 3. A 59-year-old woman with a history of hypertension, hypercholesterolemia, xanthelasma, and a benign monoclonal IgG lambda spike of 1775 mg/dl of 3 years' duration presented in March 1989, with complaints of double vision, left blepharoptosis, and swelling ofthe left cheek and both temporal fossae. A CT scan and magnetic resonance imaging 1 month later showed thickening of the left lateral rectus muscle and possibly the right medial rectus (Fig 4). Additional images showed
104
enlargement of the left lacrimal gland. A biopsy of the right temporal fossa showed "annular elastolytic giant cell granulorna." Two weeks later, a left orbital biopsy showed nonspecific inflammation. Prednisone 60 mg every day resulted in improvement of the skin masses, diplopia, and blepharoptosis. In May 1989, visual acuity was 20/20 in both eyes with normal pupils. The left cheek and soft tissues around the left eye were thickened. There was no proptosis, but there was marked resistance to retropulsion in both eyes. Yellowish "xanthelasma-like" lesions were present on the medial portions of both lids. There was 3 mm of blepharoptosis on the left side, and 1 mm on the right. An exodeviation greater than 50 prism diopters was present in primary position (Fig 5). In the right eye, adduction was reduced to 80% and other ductions were full. In the left eye, adduction was absent, elevation was 50%, depression was 50%, and abduction was 100%. Forced ductions were positive. On review, the biopsy of the temporal fossa was diagnosed as NXG. Facial nodules recurred as prednisone was tapered but regressed when prednisone was increased to 20 mg per day. Because of concern about the side effects ofIong-term prednisone therapy, the patient was started on cyclophosphamide 200 mg per day and prednisone 60 mg per day in 5-day cycles. She continues to improve on this regimen. Case 4. A 70-year-old woman with a history ofhypercholesterolemia, hypertension and angina noted a flat, firm lesion on her left shoulder in 1984. Biopsy was "suggestive of granuloma annulare." One year later, similar lesions developed on her scalp and around the left eye. These were removed and said to be granulomas. In 1989, biopsy was performed on lesions around the left eye which were said to be "xanthogranulomas." In 1990, biopsy was performed on a lesion at the right medial canthus and read as NXG. At this time, an IgG of2454 mgfdl (normal, 710 to 1540) was noted. During this same period, the patient underwent intralesional injections of triamcinolone with partial resolution of her lesions. She also had a xanthelasma and a spontaneously waxing and waning lesion on her left lower leg. Her ophthalmologic examination remains normal except for the lesions around the eyes (Fig 6).
Discussion Robertson and Winkelmann5 reported the ophthalmic manifestations in 15 patients from a series of 16 cases of NXG. Firm lid nodules or plaques were by far the most
Top, Figure 1. Bilateral disc edema in case 1. Left, A, right eye. Right, B, left eye. Second row left, Figure 2. Case 1 with lesions of NXG prominently on lower lids bilaterally and also on medial upper lids (arrows). Second row right, Figure 3. Case 2 with necrotic skin lesions of NXG.
Third row left, Figure 4. CT of case 2 shows enlarged recti muscles. Third row right, Figure 5. Case 2 with blepharoptosis, skin lesions, and exophoria. Bottom, Figure 6. Right eye of case 4 with skin lesions ofNXG (arrows).
Ophthalmology
Volume 99, Number 1, January 1992
frequent symptom, seen in 13 patients. Scleritis or episcleritis and anterior uveitis were each seen in three patients. Extensive destruction of periorbital tissue with loss of vision occurred in two patients. Conjunctival infiltration, cicatricial symblepharon, and keratoconjunctivitis sicca were each seen in one patient. Since this report,5 a number of other patients with varying ophthalmic presentations have been reported. 6- 12 Our case 1 had conjunctival hyperemia and papular skin lesions typical ofNXG and additional symptoms not previously described that overlap with Cogan syndrome. Cogan syndrome is a disease of young adults characterized by episodes of acute interstitial keratitis with vestibuloauditory dysfunction progressing to deafness. 14,15 Aortic insufficiency and aortitis develop in 10% of cases and, in rare cases, are associated with myocardial infarction due to coronary vasculitis or emboli. Variants of Cogan syndrome have been described with optic disc edema, vasculitis, and in association with rheumatologic syndromes such as Wegener's granulomatosis or rheumatoid arthritis.14 The cause of Cogan syndrome is unknown but possibly autoimmune in nature. Our case 1 had progressive sensorineural hearing loss, chronic optic disc edema, and cardiac disease, all consistent with Cogan syndrome. To our knowledge, neither NXG, monoclonal gammopathy, nor chronic lymphocytic leukemia have been described before with Cogan syndrome. Even the association of NXG and chronic lymphocytic leukemia is rare, with only one previous report. 3 This case raises the possibility of an underlying autoimmune disorder causing both Cogan syndrome and NXG. Our case 2 had a clinical course characterized by aggressive periocular ulcerative skin lesions, lid retraction, and corneal exposure, leading to corneal perforation and blindness. Eventually, lesions spread over most of the face and involved the rest ofthe body to varying degrees. Autopsy showed "xanthohistiocytic granulomata" in the spleen, suggesting internal involvement with NXG. No surgical procedure or systemic treatment was of any benefit throughout her course of treatment. Only two patients have been previously reported with orbital soft tissue destruction by NXG, both resulting in blindness. 10 However, the details of their cases were not reported. This patient demonstrates the potential for a devastating visual and systemic outcome in a rare form of NXG. Our case 3 is similar to a number of previous cases, with ophthalmic symptoms and periocular involvement dominating her course. Codere et al 3 described a similar patient, presenting with restricted ocular motility due to thickened extraocular muscles and infiltrative orbital masses. Spontaneous ulceration of the periocular plaques also developed, as in our case. Bullock et al8 reported a case of bilateral orbital infiltration by a yellowish indurated mass, which was found on histopathologic examination to be NXG. Scupham and Fretzin l2 described a 57-yearold woman with NXG who presented with diplopia, mild blepharoptosis, yellow plaques on her eyelids, and firm cutaneous nodules on her face. Three additional cases overlap with our patient, for a total of six similar cases.
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Our case 4 had a very benign course without significant disfigurement or visual dysfunction. Her management over 6 years has required only local therapy. This case is in sharp distinction to case 2 and illustrates the varying intensity of the disease. Histopathologically, the lesion ofNXG is characterized by granuloma formation throughout the layers of dermis, consisting of inflammatory histiocytes, foam cells, and Touton and foreign body giant cells, surrounded by eosinophilic changes in dermal collagen. 13 Case 2 is the only reported case of NXG to have undergone autopsy. Although the brain was excluded, there was involvement of NXG over a large area of skin and in the spleen, with no evidence of vasculitis. In the differential diagnosis of NXG, one should consider necrobiosis lipoidica, juvenile xanthogranuloma, granuloma annulare, foreign body granuloma, subcutaneous rheumatoid nodules, xanthoma disseminatum, plane normolipemic xanthoma, primary and secondary amyloidosis, and Erdheim-Chester disease. 1,5,9 Necrobiosis lipoidica, the principal entity to be considered, is usually confined to the pretibial areas in patients with diabetes mellitus. In two of our cases, the diagnosis was initially granuloma annulare. In the third case, it was xanthohistiocytic granulomata, and, in the fourth case, it was dermatofibroma. Patients with benign monoclonal gammopathy have a 10% risk of later developing multiple myeloma, macroglobulinemia, amyloidosis, or malignant lymphoproliferative diseases. 16 From previously reported cases with NXG, multiple myeloma developed in five patients, a plasmaproliferative disorder developed in eight, and a lymphoproliferative disorder and lymphocytic leukemia each developed in one patient. 1,5,7,8,10 This is equivalent to a 47% risk of later malignancy. With a longer followup period, this incidence might be even greater. On the basis of this observation, patients with NXG with paraproteinemia should be repeatedly investigated for myeloma or other lymphoproliferative disorders. Although two of our patients had normal bone marrow biopsies on several occasions, the third patient was diagnosed with chronic lymphocytic leukemia 13 years after splenectomy revealed a nonspecific lymphocytosis. In our cases, the paraproteinemia preceded the diagnosis ofNXG by 3,5, and 6 years, respectively. In the fourth patient, the paraproteinemia was discovered after the pathologic diagnosis of NXG was made. Interestingly, the multiple myeloma in three ofthe patients with NXG described by Finan and Winkelmann9 was somewhat unusual in being low grade, generally asymptomatic, and having a prolonged course after chemotherapy. Myeloma associated with NXG may be of the "smoldering" variety. Treatment ofNXG has involved a number of different modalities, including excision, local injection, plasmapheresis, and chemotherapy. The chemotherapeutic agents used in NXG have included methotrexate, azathioprine, melphalan, chlorambucil, cyclophosphamide, nitrogen mustard, and prednisone. 1,3,5,6,8,9,11,12 The response to therapy has varied, but low-dose chemotherapy has generally been beneficial. Response to chemotherapy
Cornblath et al . Necrobiotic Xanthogranuloma also varied in our patients: case 3 had a favorable response to cyclophosphamide and prednisone, case 1 had only a partial response to the combination of cyclophosphamide, vincristine, and prednisone, whereas case 2 failed to respond to dapsone, cyclophosphamide, clofazimine, or plasmapheresis. Case 4 has required only excision and intralesional triamcinolone. Because of the small numbers of reported cases, no firm conclusions as to the efficacy of therapy can be made. The cause ofNXG is unknown. Bullock et al8 suggested that serum immunoglobulins complex with lipids and deposit in the skin, eliciting a giant cell foreign reaction. Venencie et alii hypothesized that the paraproteinemia is the primary phenomenon and that NXG represents a secondary proliferation of the macrophages that have receptors for the Fc portion of IgG. Our first patient, with symptoms of Cogan syndrome, provides further evidence for the likelihood of a dysimmune cause for NXG. It seems plausible that the skin lesions of NXG are an additional manifestation, along with the paraproteinemia, of an underlying hematopoietic or lymphoproliferative disorder of an unusually benign nature. We still lack good understanding of the pathophysiology of this rare disease, for which ophthalmologists can contribute to an early diagnosis. Acknowledgments. The authors thank Dr. W. Carter Lowe, Dr. Thimmiah Ramesh, and Dr. David Reifler for their kind referral of patients.
References 1. Kossard S, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia. JAm Acad Dermatol 1980; 3:25770.
2. Kossard S. Xantogranuloma necrobiotico con paraproteinemia. G Ital Dermatol Venereol 1983; 118:219-22. 3. Codere F, Lee RD, Anderson RL. Necrobiotic xanthogranuloma of the eyelid. Arch Ophthalmol 1983; 101:60-3. 4. Smith SA, Alexander RA, Stasko T, et al. Necrobiotic xanthogranuloma. J Assoc Mil Dermatol 1983; 9:78-83. 5. Robertson DM, Winkelmann RK. Ophthalmic features of necrobiotic xanthogranuloma with paraproteinemia. Am J Ophthalmol 1984; 97: 173-83. 6. Macfarlane AW, Verbov JL. Necrobiotic xanthogranuloma with paraproteinemia. Br J Dermatol1985; 113:339-43. 7. Holden CA, Winkelmann RK, Wilson Jones E. Necrobiotic xanthogranuloma: a report of four cases. Br J Dermatol 1986; 114:241-50. 8. Bullock JD, Bartley GB, Campbell RJ, et al. Necrobiotic xanthogranuloma with proteinemia. Case report and a pathogenetic theory. Ophthalmology 1986; 93:1233-6. 9. Finan MC, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia. A review of22 cases. Medicine 1986; 65:376-88. 10. Finelli LG, Ratz JL. Plasmapheresis, a treatment modality for necrobiotic xanthogranuloma. J Am Acad Dermatol 1987; 17:351-4. 11. Venencie PY, Puissant A, Verola 0, et al. Necrobiotic xanthogranuloma with myeloma. A case report. Cancer 1987; 59:588-92. 12. Scupham RK, Fretzin DF. Necrobiotic xanthogranuloma with paraproteinemia. Arch Pathol Lab Med 1989; 113: 1389-91. 13. Jakobiec FA, Font RL. Orbit. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook; 3rd ed. Vol. 3. Philadelphia: WB Saunders, 1986; 2729-30. 14. Haynes BF, Kaiser-Kupfer MI, Mason P, Fauci AS. Cogan syndrome: studies in thirteen patients, long-term follow-up, and a review of the literature. Medicine 1980; 59:426-41. 15. Vollertsen RS, McDonald TJ, Younge BR, et al. Cogan's syndrome: 18 cases and a review of the literature. Mayo Clin Proc 1986; 61 :344-61. 16. Kyle RA, Lust JA. Monoclonal gammopathies of undetermined significance. Sem Hematol 1989; 26: 176-200.
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