Paraneoplastic retinopathies are characterized by retinal dysfunction owing to the remote effects of systemic malignancy.1 The mechanism of retinal degeneration in these syndromes is believed to be related to the presence of autoantibodies against tumor-related antigens that cross-react with molecularly similar retinal antigens. The two most frequently described paraneoplastic retinopathies are cancer-associated retinopathy and melanoma-associated retinopathy (MAR), each of which has well-described clinical and electrophysiologic features. Cancer-associated retinopathy is most commonly associated with small-cell lung carcinoma but has also been associated with breast, cervical, and uterine cancer. Recoverin, one of the antigens implicated in cancer-associated retinopathy, has been detected in a patient with autoimmune retinopathy in the absence of demonstrable malignancy.2 We report a case of presumed paraneoplastic retinopathy associated clinicopathologically with a mature teratoma.
A 39-year-old Gambian woman was referred for evaluation of bilateral vitritis. Three months before her initial visit, she noted the sudden onset of blurred vision, nyctalopia, shimmering photopsias, and a migrainous head ache. Her ocular symptoms gradually worsened during the following 3 months, despite resolution of headache symptoms. Her medical history was remarkable only for childhood malaria treated with quinine. Her ophthalmic history was unremarkable.
Ophthalmic evaluation documented visual acuity of 20/16 OD and 20/25 OS with intraocular pressures of 15 mmHg OD and 13 mmHg OS. Results of anterior segment biomicroscopy were normal in both eyes. Funduscopic examination revealed 1+ vitreous cells in the right eye and 2+ vitreous cells in the left eye, with no vitreous haze in either eye. The optic nerve cup-disc ratio was 0.9 OU without pallor or edema (Figure 1A and B). The maculae were normal. Mild arteriolar attenuation and peripheral vascular sheathing were present in both eyes. Distinct areas of peripheral retinal pigment epithelial depigmentation were present bilaterally (Figure 1C). Results of a comprehensive laboratory evaluation, including serum chemistry, liver functions, complete blood cell count, syphilis serologic testing, and angiotensin-converting enzyme levels, were unremarkable. Humphrey visual fields were profoundly constricted bilaterally(Figure 2). In electroretinograms(ERGs) recorded according to the international standard technique, 3 combined (rod-and-cone–mediated) maximal responses had an "electronegative" configuration (Figure 3A). Cone-mediated ERGs elicited by 100-millisecond stimuli showed absence of the "on" response with relative preservation of the "off" response (Figure 3B).
Photographs illustrate optic nerve cupping and retinovascular attenuation in the right eye (A) and left eye (B). C, The demarcation line is between normal-appearing retinal pigment epithelium in the posterior pole of the right eye and hypopigmented retinal pigment epithelium in the periphery.
Full-threshold Humphrey 30-2 visual fields, stimulus size V in the right (A) and left (B) eyes, demonstrate profoundly constricted visual fields recorded at the initial visit. There were no fixation losses or false-positive errors in either study (false-negative errors, 5/19 in the right eye and 4/11 in the left eye).
Patient electroretinograms (ERGs) and ERGs from representative healthy controls. A, An ERG elicited by brief(10-millisecond), bright (1.64-candela/m2) full-field flashes after dark adaptation. The vertical line denotes flash onset. Note that the b-wave amplitude (OD, 131 µV; OS, 42 µV; lower limit of normal, 373 µV) is considerably more reduced than the a-wave amplitude (OD, 253 µV; OS, 107 µV; lower limit of normal, 188 µV). B, An ERG elicited by prolonged (100-millisecond), bright (1.64-candela/m2) full-field flashes after light adaptation. The vertical lines denote flash onset (0 milliseconds) and offset (100 milliseconds). Note that the amplitude of "on" responses is considerably more reduced than that of "off" responses.
The characteristic ERG and clinical history raised the possibility of MAR. Results of comprehensive dermatologic and systemic metastatic evaluations were negative, except for a computed tomographic scan of the chest, which revealed a cystic anterior mediastinal mass consistent with teratoma (Figure 4). Two fine-needle aspirations of the mass were performed and were nondiagnostic. Serum analyses for α-fetoprotein and β–human chorionic gonadotropin, tumor markers for teratoma, were negative. During the following 6 months, the patient received 3 periocular injections of 40 mg of triamcinolone acetonide (Kenalog; Bristol-Myers Squibb, New York, NY) in both eyes. There was a subsequent decrease in the vitreous cell count and documented improvement in the visual fields bilaterally (Figure 5). During this time, serial computed tomographic scans demonstrated progressive growth of the mediastinal lesion, threatening the great vessels of the chest. Median sternotomy and excisional resection of the tumor was subsequently performed.
Computed tomographic scan demonstrates multicystic anterior mediastinal teratoma in the retrosternal position, anterior to the cardiac structures.
Full-threshold Humphrey 30-2 visual fields, stimulus size V in both eyes after 3 rounds of periocular steroids. A, Right eye (no fixation losses or false-positive errors; false-negative errors, 2/18); B, left eye (fixation losses, 2/28; no false-positive errors; false-negative errors, 2/17).
Gross inspection of the tumor revealed a multicystic mass with hair projecting into the central cavity. Histopathologic analysis confirmed the diagnosis of a mature teratoma (Figure 6A). Staining of the tumor with HMB45, an immunoreagant specific for melanocytic elements, was negative (Figure 6B). In contrast, immunostaining with antibodies against retinal S antigen produced avid staining of multiple tissues within the teratoma specimen, demonstrating tumor expression of retinal S antigen (Figure 6C). The patient's serum was also autoreactive against normal rhesus monkey retina (Figure 6D). The patient's vision and visual fields remained stable for 3 months after surgery without any further treatment.
Microphotography of the excised mature teratoma illustrates ectodermal structures (A), including pilosebaceous units and epithelial cells (arrow), and mesodermal structures, including collagen(asterisk), lymphoid tissue (dagger), smooth muscle (double dagger), and adipose tissue (section mark) (hematoxylin-eosin, original magnification ×100). Staining for HMB45 (B), an antigen present in all melanocytic cells, was negative, and staining was positive (C) for antiretinal S antigen in teratoma tissue, including pilosebaceous units (arrow) and mesenchymal cells (asterisk), confirming diffuse tumor expression of retinal S antigen (avidin-biotin complex immunoperoxidase, original magnification ×200). Immunostaining of paraffin-fixed normal rhesus monkey retina with patient sera as the primary antibody and rabbit-antihuman Ig G as the secondary antibody (D) demonstrates positive staining of photoreceptors(arrows), as well as the inner (INL) and outer (ONL) nuclear layers and inner plexiform layer (IPL), corroborating the presence of an autoimmune retinopathy(immunofluorescent microscopy; antibody binding visualized using goat anti–human polyvalent immunoglobulin conjugated to fluorescein-isothiocyanate, original magnification ×200). Similar autofluorescence was obtained on immunostaining of the tumor section (not shown). GC indicates ganglion cell layer; OPL, outer plexiform layer; PR, photoreceptor cell layer.
Teratomas are part of the larger family of dysgerminomas or germ cell tumors. Teratomas are composed of primitive cells that represent more than one germ layer and usually all 3. As the teratoma grows, these cells can differentiate along various germ lines, producing skin appendages, cartilage, bone, thyroid tissue, and any other tissue in the body.4 Teratomas usually originate in the hypothalamus or gonad but uncommonly arise in ectopic locations, including the orbit and mediastinum.5
This is the first report of paraneoplastic retinopathy associated with a mature teratoma. A previous report of retinal periphlebitis mimicking sarcoidosis in a child with a pineal germinoma proposed a paraneoplastic mechanism.6 Electronegative ERGs with abnormal on-responses are typically described in MAR and congenital stationary night blindness.7 The shimmering photopsias, nyctalopia, visual field constriction, and clinical appearance of the patient all were typical of MAR; however, metastatic workup failed to reveal evidence of melanoma or other occult malignancy, except for the mediastinal teratoma. Malignant melanomas may arise de novo in teratomas.8,9 However, histopathological and immunochemical analyses did not demonstrate the presence of melanocytic elements. Expression of retinal S antigen in the teratoma and staining of the normal primate photoreceptors with the patient's serum support an association between the teratoma and the patient's vision loss in this case of presumed paraneoplastic retinopathy.
Although similar clinically and electrophysiologically to MAR, this case differs from the typical MAR presentation in a few notable ways. This patient had bilateral vitritis as an initial sign, which has been reported in MAR; however, her objective and subjective visual field improvement with periocular corticosteroids are distinctly unusual for MAR. In addition, in MAR antiretinal antibodies are typically localized to bipolar cells, explaining the typical electronegative ERG.10 The most avid immunostaining in this case was in the photoreceptor layer, consistent with the presumed pathophysiologic mechanism of an immune response directed against retinal S antigen, which is localized to photoreceptor outer segments. However, the electrophysiologic data are contradictory, suggesting that the site of the major functional defect is proximal to the photoreceptor inner segments, as in MAR. Immunostaining was also present in the inner nuclear layer, albeit less conspicuously than in the photoreceptors. The peripheral retinal pigment epithelial depigmentation and visual field changes that occurred bilaterally may represent sequelae of autoimmune phenomena occurring in the overlying retina.
We described a case of presumed paraneoplastic teratoma-associated retinopathy. This case suggests that benign tumors such as teratomas possibly may be associated with paraneoplastic retinopathy, which has previously been reported only as a sequelae of malignant neoplasms. Additional case reports and/or clinicopathologic investigations may assist in determining the mechanisms of visual loss in such cases.
This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, New York, and core grant 1P30 EY12576-01 (Dr Thirkill) from the National Eye Institute, National Institutes of Health, Bethesda.
The authors have no proprietary interest in the products described in this report.
Corresponding author: Eric B. Suhler, MD, Ophthalmology Service, Portland Veterans' Administration Medical Center, 3710 SW US Veterans' Hospital Rd, Portland, OR 97207 (e-mail: email@example.com).
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