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Long-term Persistence of Antirecoverin Antibodies in Endometrial Cancer-Associated Retinopathy
Arch Ophthalmol. 1998;116:251-253.
Autoantibodies to recoverin are found in the serum of patients with cancer-associated retinopathy syndrome (CAR), in which retinal degeneration occurs in the presence of systemic tumor growth without metastasis to the eye. The presence of antirecoverin antibodies has, so far, been associated with small cell carcinoma of the lung. We describe a patient with an endometrial carcinoma who possesses T cells and antibodies that react with recoverin. The demonstration of autoantibodies in a patient's serum is important to the diagnosis of CAR and cancer and monitoring treatment of diseases. Although several studies have reported the presence of antibodies specific to CAR antigens even before the diagnosis of cancer, to date, no long-term follow-up studies have examined the prevalence of antirecoverin antibodies in those patients' recoverin.
Report of a Case
A 61-year-old white woman had endometrial cancer in 1991 and had had a hysterectomy for undifferentiated carcinoma with neuroendocrine features in September 1991. In July 1992, metastatic disease of the lumbar spine was detected. The tumor was surgically removed; she was treated with a combination of radiation and 5-fluorouracil. In October 1992, she noticed floaters, "dark" vision with a loss of color vision in the left eye, and "blurring vision" in the right eye. Visual acuity was 20/70 OD and counting fingers OS. A fundus examination showed vitreous cells (possible vitreitis) and optic nerve pallor. In December 1992, her vision worsened. Her blood serum tested positive for the presence of antirecoverin antibodies, which led to the diagnosis of CAR. She was given methylprednisolone (Medrol), and her vision improved to 20/25+ with full color vision and full fields in the right eye, and 20/400 with poor, but improved, color vision and damaged fields in the left eye with eccentric gaze. She had osteoporosis and posterior subcapsular cataracts; treatment with steroids was tapered. Her vision decreased again, and she tested positive for recoverin antibodies in March 1993. Her dose of methylprednisolone was increased, which led to improvement in her visual acuity to 20/25 OD and 20/400 OS, but by May 1993, her vision deteriorated again. She received no positive effect from increasing her dose of methylprednisolone even to very high doses; therefore, treatment with methylprednisolone was stopped. Results of multiple metastatic workups, including magnetic resonance imaging, computed tomographic scans, bone scans, blood tests, x-ray films, and clinical examinations, were negative. Cancer-associated retinopathy antigens tested negative. The patient was given a combination of megestrol acetate (Megace) and 714X (an experimental drug to prevent cancer recurrence). In December 1993, her electroretinogram showed no cone response, despite computer averaging, and a highly abnormal rod response, about 1% of normal. Dark adaptation was elevated. In February 1994, she underwent left hip replacement for a hip fracture that was due to the heavy steroid treatment. In January and April 1994, plasmapheresis was performed and her color vision improved immediately; however, in May, her vision worsened again. Her electroretinogram showed a barely detected response, about half of the response 6 months previously. In August 1994, the antibody titer started to gradually increase and reached a very high level (1:12800). There were no signs of metastasis. She was prescribed To pa Torf Preparation, a natural immunomodulator drug. The antirecoverin antibody level dropped dramatically and reached almost normal levels in July 1995; at this point her visual acuity stabilized at hand motions OU.
Antirecoverin activities of serum antibodies and lymphocytes were measured over 3 years (Figure 1). The specificity of antibodies was confirmed by immunostaining of purified recoverin (Figure 2). Isotyping showed that antirecoverin antibodies were mostly IgG1. Because we recently have demonstrated that recoverin was expressed in lung carcinoma of a patient with CAR,1 we tested the patient's tumor for recoverin expression. A reverse transcription–polymerase chain reaction yielded the predicted size of products corresponding to the recoverin sequence from the endometrial carcinoma and a normal donor retina used as a control source of recoverin, Figure 2.
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Figure 1. Kinetics of antirecoverin antibody levels and antirecoverin lymphocyte activities of a patient with cancer-associated retinopathy. Antirecoverin antibodies were first detected in December 1992. The graph represents data collected in our laboratory since May 1994. The antibody level was measured at 1:400 serum dilution by enzyme-linked immunosorbent assay (squares). Normal level of antirecoverin antibodies gives optical density OD405=0.3. Lymphocyte activities were measured by lymphocyte proliferation assay and are presented as stimulation indexes (bars represent mean of triplicate cultures). Stimulation index for normal individuals is less than 1.5.
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Figure 2. Identification of recoverin by immunoblotting and by RT-PCR. Left, Immunoblotting of recoverin with patient's antibodies. 1 indicates protein molecular standards stained with Coomassie brilliant blue; 2, immunostaining of bovine recoverin (26 kd); and 3, immunostaining of human recoverin (23 kd). The arrow indicates the position of recoverin on the blot. Right, Separation of polymerase chain reaction products amplified from the archived patient's tumor tissue and normal donor retina on 2% agarose gel stained with ethidium bromide. 1 indicates molecular standards; 2, polymerase chain reaction product obtained from the patient's endometrial tumor; and 3, PCR product obtained from human retina. The arrow indicates the position of the product of the expected size of 117 base pairs corresponding to the recoverin sequence. Endometrial carcinoma from a patient without visual symptoms did not produce any PCR product (not shown).
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Comment
Although there have been 3 previous case reports of CAR syndrome associated with endometrial cancer,2-4 to our knowledge this is the first such case where antirecoverin antibodies and T-cell responses have been documented. Until now, antirecoverin antibodies have only been demonstrated in patients with small cell carcinoma of the lung. This case is unique in 2 respects. First, to our knowledge this is the first time that an endometrial cancer in a patient with CAR has been shown to express messenger RNA for recoverin, suggesting that the aberrant expression of this protein, normally expressed only in the eye, might have triggered the abnormal immune response. Also novel is the documentation of persistent elevated level of antirecoverin antibodies in the serum after the presumed source of autoantigen (recoverin in endometrial cells) had been removed.
Our recent studies have shown that antirecoverin autoantibodies could penetrate living cells and trigger retinal cell death that occurs through an apoptotic mechanism.5 If antibodies play a causative role in the syndrome, the prolonged presence of serum antibodies in the circulation is detrimental and should be controlled. Steroid treatment, plasmapheresis, and immunomodulation with Topa Peat Preparation were effective in lowering those antibodies in the serum, vision was stabilized, and occasionally improved. In contrast, T-cell activities were moderate to low, and increases were not accompanied by overt disease, probably suggesting a lesser role in the pathogenicity.
AUTHOR INFORMATION
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This study is supported by grant EY10361 from the National Eye Institute, National Institutes of Health, Bethesda, Md (Dr Adamus).
The studies were performed in accordance with our institution's guidelines. Legacy-Institutional Review Board has approved the protocols and informed consent has been obtained.
Grazyna Adamus, PhD;
Drake Amundson
Portland, Ore
Cynthia MacKay, MD;
Peter Gouras, MD
New York, NY
Corresponding author: Grazyna Adamus, PhD, R. S. Dow Neurological Sciences Institute, 1220 NW 20th Ave, Portland, OR 97209 (e-mail: Adamusg{at}nsi-lhs.org).
REFERENCES
1. Polans A, Witkowska D, Haley T, Amundson D, Baizer L, Adamus G. Recoverin, a photoreceptor-specific calcium binding protein, is expressed by the tumor of a patient with cancer-associated retinopathy. Proc Natl Acad Sci U S A. 1995;92:9176-9180.
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2. Campo E, Brunier MN, Merino MJ. Small carcinoma of the endometrium with associated ocular paraneoplastic syndrome. Cancer. 1992;69:2283-2288.
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3. Crofts JW, Bachynski BN, Odel JG. Visual paraneoplastic syndrome associated with undifferentiated endometrial carcinoma. Can J Ophthalmol. 1988;23:128-132.
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4. Ohkawa T, Kawashima H, Makina S, et al. Cancer-associated retinopathy in a patient with endometrial cancer. Am J Ophthalmol. 1996;122:740-742.
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5. Adamus G, Machnicki M, Seigel GM. Apoptotic retinal cell death induced by autoantibodies of cancer associated retinopathy. Invest Ophthal Vis Sci. 1997;38:283-291.
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