Cancer-associated Retinopathy Research Articles

Cancer-associated Retinopathy with Retinal Periphlebitis in a Patient with Ovarian Cancer

Purpose: To describe a case of cancer-associated retinopathy (CAR) due to ovarian cancer presenting with retinal periphlebitis and a negative-type pattern electroretinogram (ERG).Design: Case report.Methods: Retrospective chart review.Results: A negative-type ERG in the setting of progressive vision loss and retinal periphlebitis led to the discovery of metastatic ovarian cancer and ultimately the diagnosis of CAR.Conclusions: CAR can present with periphlebitis and a negative-type ERG. Greater awareness of these associations may allow for earlier detection of future cases.

Paraneoplastic retinopathy associated with retroperitoneal liposarcoma

We report a case of paraneoplastic retinopathy associated with a retroperitoneal liposarcoma. A 42-year-old man was referred to our hospital with complaints of night blindness and blurred vision in the peripheral field. Electroretinograms showed a progressive amplitude reduction in his both eyes. Abdominal magnetic resonance imaging showed a large retroperitoneal mass, and pathologic examination revealed a dedifferentiated liposarcoma. Western blot analysis showed an antiretinal antibody in the serum of our patient, and his serum reacted with the photoreceptors of a bovine retina. To the best of our knowledge, this is the first case of paraneoplastic retinopathy associated with a liposarcoma.

VEGFR1–mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy

VEGF coordinates complex regulation of cellular regeneration and interactions between endothelial and perivascular cells; dysfunction of the VEGF signaling system leads to retinopathy. Here, we show that systemic delivery of VEGF and placental growth factor (PlGF) by protein implantation, tumors, and adenoviral vectors ablates pericytes from the mature retinal vasculature through the VEGF receptor 1 (VEGFR1)-mediated signaling pathway, leading to increased vascular leakage. In contrast, we demonstrate VEGF receptor 2 (VEGFR2) is primarily expressed in nonvascular photoreceptors and ganglion cells. Moreover, blockade of VEGFR1 but not VEGFR2 significantly restores pericyte saturation in mature retinal vessels. Our findings link VEGF and PlGF to cancer-associated retinopathy, reveal the molecular mechanisms of VEGFR1 ligand-mediated retinopathy, and define VEGFR1 as an important target of antiangiogenic therapy for treatment of retinopathy.

Melanoma-Associated Retinopathy

To study 11 patients with melanoma-associated retinopathy (MAR) to clarify the reliability of various methods of diagnostic testing, to determine the underlying antigenic retinal proteins, and to study the clinical histories and types of associated melanomas. Clinical data were obtained from patients with melanoma who developed marked visual problems. Testing included electroretinography, kinetic visual fields, comparative studies of Western blots, and indirect immunohistologic examination to detect antiretinal antibodies, as well as proteomic studies to identify underlying antigenic retinal proteins. Patients with MAR typically have rapid onset of photopsias, scotomata, and loss of central or paracentral vision. Ophthalmoscopy seldom shows significant changes early, but electroretinograms are abnormal. Results of Western blots and immunohistologic examination can show antiretinal antibodies but not always. Most patients (9 of 11) had a strong family history of autoimmune disorders. Any type of melanoma (cutaneous, choroidal, ciliary body, or choroidal nevi) may be associated with this paraneoplastic autoimmune reactivity. MAR may precede or follow the diagnosis of melanoma. Patients with MAR have the same antigenic retinal proteins that have been associated with cancer-associated retinopathy. In addition, 2 new antigenic retinal proteins, aldolase A and aldolase C, were found. There was a high prevalence of positive family histories of autoimmune disease in patients with MAR. To confirm the disorder, multiple clinical and serum diagnostic techniques (Western blot or indirect immunohistologic examination) are needed. Two newly observed antigenic retinal proteins, aldolase A and aldolase C, are associated with MAR.

Clinicopathological Roles of Aberrantly Expressed Recoverin in Malignant Tumor Cells

Purpose: Cancer-associated retinopathy (CAR) is an ocular manifestation of a paraneoplastic syndrome whereby immunological reactions toward recoverin, a retina-specific calcium binding protein, and other retinal antigens aberrantly expressed in tumor cells are elicited. As a consequence, photoreceptor cell degeneration is induced. To elucidate the pathological role of the aberrantly expressed recoverin, we studied the recoverin expression levels in various malignant tumors and the effects of the expressed recoverin on the sensitivity to anti-cancer drugs. Methods: Recoverin expression levels were determined by immunohistochemistry with anti-human recoverin monoclonal antibody on multiple tissue arrays obtained from several lung, stomach, colon and other cancers. In the presence of several anti-cancer drugs, including anti-tumor antibiotics, plant alkaloids and anti-metabolites, cytotoxicity assay was performed using recoverin-positive or recoverin-negative A549 cells originating from human lung adenocarcinoma. Results: Immunofluorescence labeling revealed that recoverin immunoreactivities were detected at approximately 10–40% of malignant tumor tissues. Cytotoxic effects by anti-cancer drugs were higher in recoverin-positive A549 cells as compared to recoverin-negative cells. Conclusion: The present data may correlate with the previous observation that recoverin-expressing cancer cells induced tumor immunity and a favorable prognosis for primary cancer in CAR patients.

Autoimmunity in retinal degeneration: Autoimmune retinopathy and age-related macular degeneration

Autoantibody production is associated with a variety of ocular disorders, including autoimmune retinopathy (AIR) and age-related macular degeneration (AMD). A breakdown of immunologic tolerance (ocular immune privilege), including the blood–retinal barrier, anti-immune and anti-inflammatory proteins, and anterior chamber-associated immune deviation may play important roles in these disorders. Although the exact triggers for ocular autoimmunity are unknown, autoimmune targeting of retinal tissue is clearly associated with and may contribute to the pathogenesis of both AIR and AMD. Autoantibody production has long been associated with AIR, a collection of disorders that includes cancer-associated retinopathy, melanoma-associated retinopathy and non-paraneoplastic autoimmune retinopathy. A growing body of evidence indicates that AMD pathogenesis, too, involves ocular inflammation and autoimmunity. Identification and quantification of autoantibodies produced in patients with AIR and AMD may assist with diagnosis, prognosis, and choice of treatments. Animal models that allow investigation of ocular autoimmunity will also be needed to better understand the disease processes and to develop novel therapies. In this review we discuss ocular immune privilege and potential mechanisms of autoimmunity in the eye. We describe how autoimmunity relates to the pathogenesis of AIR and AMD. We explain how the antigen microarray technique is used to detect autoantibodies in patient serum samples, and discuss how current animal models for AMD can be used to investigate autoimmune pathogenesis. Finally, we outline unanswered questions and exciting areas of future study related to autoimmune retinal degeneration.

Management of Autoimmune Retinopathies With Immunosuppression

To report the results of treating autoimmune retinopathy (AIR) with immunosuppression therapy. Retrospective review of 30 consecutive patients with AIR followed for 3 to 89 months (median, 17 months) who were treated with immunosuppression (systemic or local). Subgroups were cancer-associated retinopathy (CAR), nonparaneoplastic AIR (npAIR), and npAIR with cystoid macular edema (npAIR/CME). Outcome measures were improvement of Snellen visual acuity by at least 2 lines, expansion of the visual field area by more than 25%, and resolution of CME. Overall, 21 of 30 patients (70%) showed improvement. All 6 CAR patients, 7 of 13 (54%) with npAIR, and 8 of 11 (73%) with npAIR/CME showed improvement. Five of 21 patients (24%) had improvement in visual acuity, 15 of 21 (71%) had expansion of visual field area, and 6 of 11 (55%) had resolution of CME. Twenty-six of 30 patients exhibited diffuse retinal atrophy without pigment deposits. An autoimmune family history was common in all the groups: npAIR, 69% (9 of 13); npAIR/CME, 64% (7 of 11); and CAR, 50% (3 of 6). Long-term treatment with immunosuppression resulted in clinical improvement in all subgroups of AIR. The most responsive subgroup was CAR; the least was npAIR. These results challenge the commonly held belief that AIR is untreatable.

Autoimmunity against carbonic anhydrase II affects retinal cell functions in autoimmune retinopathy

Autoantibodies against various retinal proteins, including anti-carbonic anhydrase II (CAII) autoantibodies, have been found in patients with cancer-associated retinopathy and autoimmune retinopathy without diagnosed cancer. We studied sera from retinopathy patients that showed reactivity with a 30-kDa retinal protein, which was identified as carbonic anhydrase II (CAII), and immunolabeled cells in human retina. The goal of the study was to examine whether patients' autoantibodies induce pathogenic effects on the catalytic function of CAII, which may have metabolic consequences on cell survival. Our findings revealed that anti-CAII autoantibodies have the capacity to induce cellular damage by impairing CAII cellular function through inhibiting the catalytic activity of CAII in a dose dependent manner, decreasing intracellular pH, increasing intracellular calcium, which in effect decreases retinal cell viability. The destabilized catalytic function of CAII and alterations in cytosolic pH were found very early, suggesting that autoantibodies are the inducers of apoptosis. In summary, our study showed that anti-CAII autoantibodies provoke pathogenic effects on retinal cells by decreasing cell survival by blocking the CAII cellular functions. The current experiments may facilitate better understanding the role of the immune system in retinal degeneration and help to develop better strategies for therapy of autoimmune retinopathy.

Optical coherence tomography findings in paraneoplastic pseudovitelliform lesions in melanoma-associated retinopathy

To report an unusual case of paraneoplastic pseudovitelliform lesions associated with melanoma-associated retinopathy (MAR). Observational case report. Retrospective review of the ophthalmic examination, fundus photography, fluorescein angiography, electroretinogram (ERG), and optical coherence tomography (OCT) of a patient with MAR. A 65-year-old Caucasian man with a two-year history of metastatic melanoma was referred for evaluation of a six-month history of nyctalopia. Funduscopic examination in both eyes revealed multiple, creamy, yellow, pseudovitelliform lesions in the posterior pole, varying in size from 100-500 mum, at the level of the outer retinal/retinal pigment epithelium (RPE) junction, coalescing along the inferior portion, with overlying macular neurosensory detachments. OCT showed bilateral macular neurosensory detachments with multiple small areas of high reflectivity at the level of the outer retinal/RPE junction. ERG demonstrated a selective loss of the b-wave and a normal a-wave under dark adapted, scotopic conditions. Clinicians should be aware of this atypical presentation of MAR that may include pseudovitelliform retinal findings.

Autoimmune retinopathy: A review and summary

Three main forms of autoimmune retinopathy (AIR) have been identified over the last 15 years: cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), and nonneoplastic autoimmune retinopathy (npAIR). In this chapter, the term AIR will be used to encompass all three disorders where there is commonality to their features. Complicating the issue is that AIR can be a secondary complication of other conditions such as retinitis pigmentosa, ocular trauma, birdshot retinopathy, acute zonal occult outer retinopathy (AZOOR), or multiple evanescent white dot syndrome (MEWDS). The many forms of AIR tend to have common clinical features despite the fact that there has been no uniform set of anti-retinal antibodies circulating in these patients. Patients tend to have a wide variance of anti-retinal antibody activity often with three to six different antibodies found on immunoblots. Patients typically present with a sudden onset of photopsia, rapid visual loss, and abnormal electroretinograms (ERGs). Most patients have a panretinal degeneration without pigment deposits.

Paraneoplastic syndromes in neuro-ophthalmology

The aim of this review is to discuss and highlight the recent advances in our understanding of paraneoplastic syndromes in neuro-ophthalmology and their significance. The pathophysiologic mechanism in neuro-ophthalmic paraneoplastic syndromes involves an immune response triggered by aberrant expression of onconeuronal antigens that cross-react with antigens in the visual system. Recently, 18-fluoro-deoxy-glucose/positron emission tomography with computed tomography scanning has emerged as a useful modality in diagnosing occult tumors responsible for paraneoplastic syndromes. Paraneoplastic optic neuropathy has been recently associated with the anti-CV2/CRMP-5 antibody. The use of serologic analysis of recombinantly expressed clones (SEREX) has led to the identification of new antigens associated with melanoma-associated retinopathy, such as visual arrestin, rhodopsin, titin, and mitofilin. Calcium-channel blockers and alemtuzumab have been found to improve visual function in cancer-associated retinopathy. Rituximab has been found to be effective in childhood opsoclonus-myoclonus syndrome. A high index of suspicion is needed to diagnose neuro-ophthalmic paraneoplastic syndromes. There have been recent advances in our understanding of the pathophysiology and treatment of these disorders. This will facilitate early treatment of causative occult tumors and improves the prognosis.

Slowly Progressive Cancer-Associated Retinopathy

Slowly Progressive Cancer-Associated Retinopathy

Antibodies to 46-kDa retinal antigen in a patient with breast carcinoma and cancer-associated retinopathy

Cancer-associated retinopathy (CAR) is a rare paraneoplastic syndrome usually associated with small-cell lung carcinoma and serum autoantibodies against recovering. We report the breast cancer woman with visual impairments and electrophysiological abnormalities characteristic of CAR. Her serum contained high-titer antibodies against alpha-enolase but not against other retinal proteins. This suggests that anti-enolase antibodies could be responsible for the development of CAR symptoms.

Cancer-Associated Retinopathy in a Child with Langerhans Cell Histiocytosis

Cancer-Associated Retinopathy in a Child with Langerhans Cell Histiocytosis

Cancer-associated retinopathy (CAR) with electronegative ERG: a case report

Cancer-associated retinopathy (CAR) should be suspected in patients who present with visual symptoms such as rapid unexplained visual loss and seeing shimmering lights, with an abnormal ERG. Electronegative ERG responses are not exclusive to melanoma-associated retinopathy (MAR) but may be seen in CAR as well. We describe a patient with CAR who presented with an electronegative ERG. A 67-year old woman, who presented with complaints of seeing shimmering lights, underwent an extensive ophthalmological and electrophysiological examination. Best-corrected visual acuity was 7/10 in the right and 9/10 in the left eye. Goldmann visual fields showed relative central scotomata and concentric narrowing. Slit-lamp and fundus examination were normal as was fluorescein angiography. Rod-specific ERG responses were severely reduced, with electronegative maximal combined rod-cone responses and delayed cone-responses with normal amplitudes. Melanoma-associated retinopathy was suspected. Extensive dermatological and internal evaluation eventually revealed an oat-cell carcinoma in the right lung. The patient died of pneumonia 2 years after presentation.

Ophthalmic Images

Comment. Cancer-associated retinopathy is most commonly associated with small cell carcinoma of the lung. Cases have also been reported in patients with breast, cervical, uterine, and endometrial carcinoma. An autoimmune mechanism against retinal antigens, including recoverin and enolase, has been proposed. Antibodies against recoverin (a calcium-binding protein found in retinal photoreceptor cells) may activate cell apoptotis via a calcium-dependent pathway leading to retinal degeneration with loss of photoreceptor outer segments and outer nuclear layers seen on histopathology. Cancer-associated retinopathy with antirecoverin antibodies is associated with severe, progressive visual loss and profound abnormalities seen on electroretinography. Various treatments, including systemic steroids, plasmapheresis, and calcium channel blockers, have been tried with little success. Visual symptoms often precede diagnosis of malignancy, and prompt recognition can help identification and treatment at an earlier stage. In our case, OCT showed dramatic thinning of the retina with loss of the inner, highly reflective layer corresponding to the histopathologic changes described. Reduced macular thickness on OCT can be demonstrated acutely in CAR prior to severe visual loss. Optical coherence tomography is a useful noninvasive test in patients with unexplained visual loss and may provide an objective measure of retinal damage in these patients.

Acute Optical Coherence Tomographic Findings in Cancer-Associated Retinopathy

Acute Optical Coherence Tomographic Findings in Cancer-Associated Retinopathy

Cancer-associated retinopathy in patients with breast carcinoma

Introduction:Cancer-associated retinopathy (CAR) is a paraneoplastic neurological syndrome resulting in progressive loss of vision and clinical signs of retinal degeneration. It is associated with various types of cancer and is also considered to be an autoimmune disorder that involves cross-reaction between autoantibodies and retinal proteins. The aim of this study was to establish whether immunoreactivity to retinal antigens (RAs) observed in patients with breast cancer is accompanied by any visual impairments.Materials and Methods:Sera of 295 patients with diagnosed breast cancer were screened for the presence of anti-RAs antibodies using immunoblotting. Cellular immunoreactivity to RAs present in retinal extracts and to purified recoverin and arrestin was determined by means of a lymphocyte proliferation assay. Six patients with high-titer antibodies to RAs then underwent ophthalmic and neurological examinations.Results:Four serum samples contained high-titer antibodies to a 46-kDa protein, most probably retinal α-enolase, three had antibodies to a 48-kDa protein identified as retinal arrestin, while 56-, 43-, 41-, and 34-kDa antigens were recognized only by one serum sample each. Moreover, weak cellular response to all the RAs tested was observed in one patient and another patient responded only to retinal extract. Two of the examined patients displayed symptoms of CAR.Conclusions:Immunoreactivity to RAs in patients with breast cancer may also be present in cases without clinical signs of CAR.

Paraneoplastic neurological syndromes

Paraneoplastic neurological syndromes (PNS) can be defined as remote effects of cancer that are not caused by the tumor and its metastasis, or by infection, ischemia or metabolic disruptions. PNS are rare, affecting less than 1/10,000 patients with cancer. Only the Lambert-Eaton myasthenic syndrome is relatively frequent, occurring in about 1% of patients with small cell lung cancer. PNS can affect any part of the central and peripheral nervous system, the neuromuscular junction, and muscle. They can be isolated or occur in association. In most patients, the neurological disorder develops before the cancer becomes clinically overt and the patient is referred to the neurologist who has the charge of identifying a neurological disorder as paraneoplastic. PNS are usually severely disabling. The most common PNS are Lambert-Eaton myasthenic syndrome (LEMS), subacute cerebellar ataxia, limbic encephalitis (LE), opsoclonus-myoclonus (OM), retinopathies (cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), Stiff-Person syndrome (SPS), chronic gastrointestinal pseudoobstruction (CGP), sensory neuronopathy (SSN), encephalomyelitis (EM) and dermatomyositis. PNS are caused by autoimmune processes triggered by the cancer and directed against antigens common to both the cancer and the nervous system, designated as onconeural antigens. Due to their high specificity (> 90%), the best way to diagnose a neurological disorder as paraneoplastic is to identify one of the well-characterized anti-onconeural protein antibodies in the patient's serum. In addition, as these antibodies are associated with a restricted range of cancers, they can guide the search for the underlying tumor at a stage when it is frequently not clinically overt. This is a critical point as, to date, the best way to stabilize PNS is to treat the cancer as soon as possible. Unfortunately, about one-third of patients do not have detectable antibodies and 5% to 10% have an atypical antibody that is not well-characterized. As PNS are believed to be immune-mediated, suppression of the immune response represents another treatment approach.

Long-term survival of a patient with small cell lung cancer associated with cancer-associated retinopathy

Cancer-associated retinopathy (CAR) is a rare paraneoplastic disorder that is frequently found in patients with small cell lung cancer (SCLC); it is caused by autoantibody to the 23-kDa photoreceptor protein, recoverin. We report a 9-year survivor of SCLC after concurrent chemoradiotherapy. His anti-recoverin antibody remains positive. Long-term survival without SCLC recurrence might be related to an autoimmunity mechanism that causes CAR due to the presence of anti-recoverin antibody cross-reacting with retinal cells and tumor cells. The current literature review was conducted to evaluate the impact on overall survival according to anti-recoverin antibody status.