Letters to the Editor Renal Cell Carcinoma Metastatic to the Orbit in a Patient With Wegener Granulomatosis
W
e read with great interest the editorial “Tigers and Snakes in Neuro-Ophthalmology,” which discussed, among other things, Occam razor and Hickam dictum (1). We evaluated a patient with long-standing Wegener granulomatosis, untreated during the preceding 6 months, who presented with proptosis, diplopia, and compressive optic neuropathy from a renal cell carcinoma (RCC) metastasis to the orbit, supporting Hickam dictum that “Patients can have as many diseases as they damn well please.” A 71-year-old man reported vision loss in both eyes and horizontal binocular diplopia for several weeks. In addition, he noted mild left eye pain and occasional epistaxis. He had been diagnosed with Wegener granulomatosis 13 years before on the basis of a renal biopsy. The disease was limited to his kidneys and had been well controlled with various combinations of cyclophosphamide, azathioprine, and prednisone. His recent treatment had included oral prednisone (7.5 mg daily) and azathioprine (150 mg daily). However, against medical advice, he had stopped taking his immunosuppressants for 6 months before presentation. His history was remarkable for Graves' disease with lid retraction (but no other symptoms or signs to suggest thyroid eye disease), atrial fibrillation, hypertension, diabetes mellitus, and a subdural hematoma requiring surgical evacuation. On examination, vision was 20/50, right eye and 20/200, left eye. Pupils were isocoric, but there was left relative afferent pupillary defect of 1.5 log units. There was 3 mm of proptosis of the left eye with a moderate left abduction deficit. Anterior segment examination revealed bilateral cataracts, and intraocular pressures were normal. Dilated funduscopic examination
showed trace temporal optic disc pallor in the left eye. Kinetic visual fields revealed central depression in the right eye and a dense cecocentral scotoma in the left eye. Magnetic resonance imaging (MRI) showed a wellcircumscribed extraconal mass in the lateral portion of the left orbit (Fig. 1A, B). On computed tomography (CT), the mass was noncalcified, extending into the superior orbital fissure, and eroding the greater wing of the sphenoid base (Fig. 1C). There was no sinus disease on MRI or CT. Laboratory investigations revealed positive P-ANCA (titer, 1:2560) and myeloperoxidase antibodies (titer .8.0). Proteinase 3 antibodies were not detected. The elevated P-ANCA titer suggested a possible Wegener granulomatosis relapse. Because there was a compressive left optic neuropathy and the imaging findings were atypical for orbital involvement from Wegener granulomatosis, a lateral orbitotomy was performed. Histologically, the lesion consisted of lobules of cells separated by a fine capillary network (Fig. 2). The cells had round-to oval-shaped nuclei and abundant clear cytoplasm, some with foamy cytoplasmic vacuoles. The nuclei ranged from bland to moderately pleomorphic with nuclear vacuoles and prominent nucleoli. Immunohistochemistry (IHC) demonstrated positivity with pancytokeratin, AE1/AE3, PAX8, and vimentin with focal positivity with the RCC marker. IHC for cytokeratins 7 and 20 were negative. These findings were consistent with the clear cell variant of RCC. CT of the chest, abdomen, and pelvis showed an 11 · 15 · 11 cm right renal mass, compatible with RCC, with multiple pulmonary nodules and a lytic lesion in the right femur suspicious for metastases. The patient was treated with radiation therapy to the femoral lesion and pazopanib (selective tyrosine kinase inhibitor) chemotherapy. Although a metastatic lesion to the left orbit was considered in the differential diagnosis of our patient, the finding of a RCC metastasis was unexpected. This neoplasm accounts for approximately 5% of orbital metastases (2).
FIG. 1. Magnetic resonance imaging shows a well-circumscribed left orbital mass with homogenous signal on sagittal T1 imaging (A) and heterogeneous high signal on axial fluid-attenuated inversion recovery imaging (B). On axial computed tomography (C), the mass is noncalcified, extending into the superior orbital fissure, and eroding the greater wing of the sphenoid bone.
94
Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 94-105
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Letters to the Editor
FIG. 2. Histopathology of orbital mass. A. There are lobules of cells with clear cytoplasm and round nuclei separated by a fine vascular network (hematoxylin & eosin, ·100). B. Positive cytoplasmic staining for pancytokeratin is present (diaminobenzide [DAB] with hematoxylin counterstain, ·100). C. Nuclear staining is seen for PAX 8 (DAB with hematoxylin counterstain, ·100). D. There is focal cytoplasmic positivity for the RCC marker (DAB with hematoxylin counterstain, ·100).
Although rare, there are reports of Wegener granulomatosis associated with RCC. The 2 entities may present simultaneously (3), or RCC may develop years after diagnosis of Wegener granulomatosis (4–6). Simultaneous presentation of these conditions has led some to speculate that the 2 diseases share a collective pathogenetic pathway and that the malignancy may even contribute to the development of autoimmunity and vasculitis (3). In contrast, the delayed presentation of RCC suggests that immunosuppressive treatment, especially cyclophosphamide, may be responsible for the increased risk of RCC (4–6). Cyclophosphamide has been implicated in the development of other malignancies, including bladder cancer and acute myeloid leukemia, especially if the cumulative dose exceeds 36 g (7). Because our patient presented with RCC 13 years after the diagnosis of Wegener granulomatosis, we believe that immunosuppressive therapy likely contributed to the development of the malignancy.
John J. Chen Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa Namrata Singh Department of Rheumatology, University of Iowa, Iowa City, Iowa Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 94-105
John J. Brinkley Amanda C. Maltry Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa Bruno A. Policeni Department of Radiology, University of Iowa, Iowa City, Iowa Nasreen A. Syed Department of Ophthalmology and Visual Sciences, University of Iowa; Department of Pathology, University of Iowa; and Ophthalmology Service, Iowa City VA Medical Center, Iowa City, Iowa Richard C. Allen Department of Ophthalmology and Visual Sciences, University of Iowa; Department of Otolaryngology—Head and Neck Surgery, University of Iowa, Iowa City, Iowa Reid A. Longmuir Department of Ophthalmology and Visual Sciences, University of Iowa; Ophthalmology Service, Iowa City VA Medical Center, Iowa City, Iowa 95
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Letters to the Editor Matthew J. Thurtell Department of Ophthalmology and Visual Sciences, University of Iowa; Department of Neurology, University of Iowa; Neurology Service, Iowa City VA Medical Center, Iowa City, Iowa
3.
4.
5.
The authors report no conflicts of interest. J. J. Chen and N. Singh are co-first authors.
6.
REFERENCES
7.
1. Shaw HE Jr. Tigers and snakes in neuro-ophthalmology. J Neuroophthalmol. 2014;34:214–217. 2. Shields JA, Shields CL, Brotman HK, Carvalho C, Perez N, Eagle RC Jr. Cancer metastatic to the orbit: the 2000 Robert
Progressive MRI Findings in Creutzfeldt–Jakob Disease
P
arker et al (1) recently reported characteristic magnetic resonance imaging (MRI) findings in 2 confirmed cases of the Heidenhain variant of Creutzfeldt–Jakob disease. The following is a similar case that demonstrates progressive neuroimaging abnormalities.
M. Curts Lecture. Ophthal Plast Reconstr Surg. 2001;17:346–354. Tatsis E, Reinhold-Keller E, Steindorf K, Feller AC, Gross WL. Wegener granulomatosis associated with renal cell carcinoma. Arthritis Rheum. 1999;42:751–756. Bumbasirevic U, Dragicevic D, Janicec A, CemerikicMartinovic V, Cekeravac M, Aleksic V, Tulic C. Renal cancer and Wegener granulomatosis: a case report. World J Surg Oncol. 2011;9:165. Deger SM, Mutluay R, Ebinc FA, Arinsoy T, Sindel S. Renal cell carcinoma associated immunosuppressive therapy: a case report with Wegener granulomatosis. Rheumatol Intl. 2009;30:119–121. Odeh M. Renal cell carcinoma associated with cyclophosphamide therapy for Wegener granulomatosis. Scand J Rheumatol. 1996;25:391–393. Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, Baslund B. Malignancies in Wegener granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol. 2008;35:100–105.
An 89-year-old woman complained of dizziness, unsteadiness, disruption of her sleep pattern, forgetfulness, and gradually worsening vision for several months. She had fallen many times and recently stopped driving. She denied fever, headaches, or other focal neurologic symptoms. She underwent a neurologic examination, which was reported as unremarkable, and MRI was reported to be normal except for agerelated atrophy. Her symptoms were attributed to Alzheimer disease. Her dizziness was treated with meclizine with no relief.
FIG. 1. A. Diffusion-weighted imaging shows subtle ribbon-like areas of restricted diffusion along the gyri of the right cerebral hemisphere. B. Repeat imaging 1 month later demonstrates progression of the disease and involvement of the left occipital cortex.
96
Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 94-105
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
W
e read with great interest the editorial “Tigers and Snakes in Neuro-Ophthalmology,” which discussed, among other things, Occam razor and Hickam dictum (1). We evaluated a patient with long-standing Wegener granulomatosis, untreated during the preceding 6 months, who presented with proptosis, diplopia, and compressive optic neuropathy from a renal cell carcinoma (RCC) metastasis to the orbit, supporting Hickam dictum that “Patients can have as many diseases as they damn well please.” A 71-year-old man reported vision loss in both eyes and horizontal binocular diplopia for several weeks. In addition, he noted mild left eye pain and occasional epistaxis. He had been diagnosed with Wegener granulomatosis 13 years before on the basis of a renal biopsy. The disease was limited to his kidneys and had been well controlled with various combinations of cyclophosphamide, azathioprine, and prednisone. His recent treatment had included oral prednisone (7.5 mg daily) and azathioprine (150 mg daily). However, against medical advice, he had stopped taking his immunosuppressants for 6 months before presentation. His history was remarkable for Graves' disease with lid retraction (but no other symptoms or signs to suggest thyroid eye disease), atrial fibrillation, hypertension, diabetes mellitus, and a subdural hematoma requiring surgical evacuation. On examination, vision was 20/50, right eye and 20/200, left eye. Pupils were isocoric, but there was left relative afferent pupillary defect of 1.5 log units. There was 3 mm of proptosis of the left eye with a moderate left abduction deficit. Anterior segment examination revealed bilateral cataracts, and intraocular pressures were normal. Dilated funduscopic examination
showed trace temporal optic disc pallor in the left eye. Kinetic visual fields revealed central depression in the right eye and a dense cecocentral scotoma in the left eye. Magnetic resonance imaging (MRI) showed a wellcircumscribed extraconal mass in the lateral portion of the left orbit (Fig. 1A, B). On computed tomography (CT), the mass was noncalcified, extending into the superior orbital fissure, and eroding the greater wing of the sphenoid base (Fig. 1C). There was no sinus disease on MRI or CT. Laboratory investigations revealed positive P-ANCA (titer, 1:2560) and myeloperoxidase antibodies (titer .8.0). Proteinase 3 antibodies were not detected. The elevated P-ANCA titer suggested a possible Wegener granulomatosis relapse. Because there was a compressive left optic neuropathy and the imaging findings were atypical for orbital involvement from Wegener granulomatosis, a lateral orbitotomy was performed. Histologically, the lesion consisted of lobules of cells separated by a fine capillary network (Fig. 2). The cells had round-to oval-shaped nuclei and abundant clear cytoplasm, some with foamy cytoplasmic vacuoles. The nuclei ranged from bland to moderately pleomorphic with nuclear vacuoles and prominent nucleoli. Immunohistochemistry (IHC) demonstrated positivity with pancytokeratin, AE1/AE3, PAX8, and vimentin with focal positivity with the RCC marker. IHC for cytokeratins 7 and 20 were negative. These findings were consistent with the clear cell variant of RCC. CT of the chest, abdomen, and pelvis showed an 11 · 15 · 11 cm right renal mass, compatible with RCC, with multiple pulmonary nodules and a lytic lesion in the right femur suspicious for metastases. The patient was treated with radiation therapy to the femoral lesion and pazopanib (selective tyrosine kinase inhibitor) chemotherapy. Although a metastatic lesion to the left orbit was considered in the differential diagnosis of our patient, the finding of a RCC metastasis was unexpected. This neoplasm accounts for approximately 5% of orbital metastases (2).
FIG. 1. Magnetic resonance imaging shows a well-circumscribed left orbital mass with homogenous signal on sagittal T1 imaging (A) and heterogeneous high signal on axial fluid-attenuated inversion recovery imaging (B). On axial computed tomography (C), the mass is noncalcified, extending into the superior orbital fissure, and eroding the greater wing of the sphenoid bone.
94
Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 94-105
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Letters to the Editor
FIG. 2. Histopathology of orbital mass. A. There are lobules of cells with clear cytoplasm and round nuclei separated by a fine vascular network (hematoxylin & eosin, ·100). B. Positive cytoplasmic staining for pancytokeratin is present (diaminobenzide [DAB] with hematoxylin counterstain, ·100). C. Nuclear staining is seen for PAX 8 (DAB with hematoxylin counterstain, ·100). D. There is focal cytoplasmic positivity for the RCC marker (DAB with hematoxylin counterstain, ·100).
Although rare, there are reports of Wegener granulomatosis associated with RCC. The 2 entities may present simultaneously (3), or RCC may develop years after diagnosis of Wegener granulomatosis (4–6). Simultaneous presentation of these conditions has led some to speculate that the 2 diseases share a collective pathogenetic pathway and that the malignancy may even contribute to the development of autoimmunity and vasculitis (3). In contrast, the delayed presentation of RCC suggests that immunosuppressive treatment, especially cyclophosphamide, may be responsible for the increased risk of RCC (4–6). Cyclophosphamide has been implicated in the development of other malignancies, including bladder cancer and acute myeloid leukemia, especially if the cumulative dose exceeds 36 g (7). Because our patient presented with RCC 13 years after the diagnosis of Wegener granulomatosis, we believe that immunosuppressive therapy likely contributed to the development of the malignancy.
John J. Chen Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa Namrata Singh Department of Rheumatology, University of Iowa, Iowa City, Iowa Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 94-105
John J. Brinkley Amanda C. Maltry Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa Bruno A. Policeni Department of Radiology, University of Iowa, Iowa City, Iowa Nasreen A. Syed Department of Ophthalmology and Visual Sciences, University of Iowa; Department of Pathology, University of Iowa; and Ophthalmology Service, Iowa City VA Medical Center, Iowa City, Iowa Richard C. Allen Department of Ophthalmology and Visual Sciences, University of Iowa; Department of Otolaryngology—Head and Neck Surgery, University of Iowa, Iowa City, Iowa Reid A. Longmuir Department of Ophthalmology and Visual Sciences, University of Iowa; Ophthalmology Service, Iowa City VA Medical Center, Iowa City, Iowa 95
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Letters to the Editor Matthew J. Thurtell Department of Ophthalmology and Visual Sciences, University of Iowa; Department of Neurology, University of Iowa; Neurology Service, Iowa City VA Medical Center, Iowa City, Iowa
3.
4.
5.
The authors report no conflicts of interest. J. J. Chen and N. Singh are co-first authors.
6.
REFERENCES
7.
1. Shaw HE Jr. Tigers and snakes in neuro-ophthalmology. J Neuroophthalmol. 2014;34:214–217. 2. Shields JA, Shields CL, Brotman HK, Carvalho C, Perez N, Eagle RC Jr. Cancer metastatic to the orbit: the 2000 Robert
Progressive MRI Findings in Creutzfeldt–Jakob Disease
P
arker et al (1) recently reported characteristic magnetic resonance imaging (MRI) findings in 2 confirmed cases of the Heidenhain variant of Creutzfeldt–Jakob disease. The following is a similar case that demonstrates progressive neuroimaging abnormalities.
M. Curts Lecture. Ophthal Plast Reconstr Surg. 2001;17:346–354. Tatsis E, Reinhold-Keller E, Steindorf K, Feller AC, Gross WL. Wegener granulomatosis associated with renal cell carcinoma. Arthritis Rheum. 1999;42:751–756. Bumbasirevic U, Dragicevic D, Janicec A, CemerikicMartinovic V, Cekeravac M, Aleksic V, Tulic C. Renal cancer and Wegener granulomatosis: a case report. World J Surg Oncol. 2011;9:165. Deger SM, Mutluay R, Ebinc FA, Arinsoy T, Sindel S. Renal cell carcinoma associated immunosuppressive therapy: a case report with Wegener granulomatosis. Rheumatol Intl. 2009;30:119–121. Odeh M. Renal cell carcinoma associated with cyclophosphamide therapy for Wegener granulomatosis. Scand J Rheumatol. 1996;25:391–393. Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, Baslund B. Malignancies in Wegener granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol. 2008;35:100–105.
An 89-year-old woman complained of dizziness, unsteadiness, disruption of her sleep pattern, forgetfulness, and gradually worsening vision for several months. She had fallen many times and recently stopped driving. She denied fever, headaches, or other focal neurologic symptoms. She underwent a neurologic examination, which was reported as unremarkable, and MRI was reported to be normal except for agerelated atrophy. Her symptoms were attributed to Alzheimer disease. Her dizziness was treated with meclizine with no relief.
FIG. 1. A. Diffusion-weighted imaging shows subtle ribbon-like areas of restricted diffusion along the gyri of the right cerebral hemisphere. B. Repeat imaging 1 month later demonstrates progression of the disease and involvement of the left occipital cortex.
96
Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 94-105
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
