Clinical and Experimental Ophthalmology (2001) 29, 235–238
Original Article Melanoma-associated retinopathy: does autoimmunity prolong survival? Colin Chan MBBS(Hons) and Justin O’Day FRACO The Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
ABSTRACT Purpose: To discuss the autoimmune basis of melanomaassociated retinopathy (MAR) and its implications for management and prognosis. Methods: An unusual history of a woman with melanomaassociated retinopathy is presented in detail. A review of published reports and a summary of 19 reported cases of MAR provide a basis for discussion. Results: This case report and other published reports highlight a number of points regarding MAR including the male predominance, prolonged survival in several patients and lack of response to immunosuppression. Conclusions: Melanoma-associated retinopathy may prolong the survival of patients with metastatic melanoma through the autoimmune response. Therefore, treatment of visual symptoms with immunosuppression needs to be considered carefully. Key words: autoimmune, immunosuppression, melanomaassociated retinopathy, survival.
INTRODUCTION Melanoma-associated retinopathy (MAR) has become an increasingly recognized clinical entity over the past decade. At least 19 cases have now been reported, 18 of them were men.1–19 Melanoma-associated retinopathy has been seen only in patients with cutaneous melanoma. Electrophysiological, immunological and histopathological data suggest that the retinopathy is the result of antibodies produced against retinal bipolar cells. These cells share an epitope with melanoma cells. Recently, the antigen responsible for stimulating antibody production has been identified.3,4
Patients typically present with sudden onset night blindness, shimmering photopsias and electroretinogram (ERG) findings resembling congenital stationary night blindness (CSNB), months to years after discovery and excision of the initial lesion.5,6 The onset of MAR may herald the presence of metastatic disease. Visual symptoms and loss of visual acuity are not usually progressive. Colour vision also remains intact.7,8 Here we present an unusual case of MAR in a 43-year-old woman. This patient has been disease free for 6 years since onset of her MAR and removal of a metastatic small bowel melanoma discovered shortly after. The issue of whether the autoimmune response resulting in MAR prolongs survival is discussed.
CASE REPORT A previously well 43-year-old woman presented to her general practitioner in July 1986 with a pigmented skin lesion at the base of her neck. Excision biopsy revealed a Clark Level 5 melanoma. She then underwent radical excision of the melanoma together with adjuvant radiotherapy. In July 1990, she represented with metastatic disease: two cutaneous lesions, one on her back and one in her axilla and two adjoining, apical lung lesions. The cutaneous metastases were excised and an extensive wedge resection of her lung metastases was performed. She remained well until February of 1991 when she was diagnosed with iron deficiency anaemia. Despite extensive investigations, a cause for the anaemia could not be found and she was commenced on iron supplements. During August of the same year, she discovered two further melanomas in her groin and one in her scalp. Her oncologist decided that she should be treated with several courses of chemotherapy rather than undergo further surgery. Dacarbazine intravenously and lomustine (CCNU) 120 mg orally were given 6 weeks apart. About 4.5 weeks after the lomustine had been given, she awoke from her
■ Correspondence: Dr Colin Chan, The Royal Victorian Eye and Ear Hospital, 32 Gisborne Street, East Melbourne, Victoria 3002, Australia. Email:
[email protected]
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Chan and O’Day
Table 1. Summary of 19 available case reports of melanoma-associated retinopathy (MAR)1–19 Case no. 1* 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Age (years)
Sex
48 50 44 61 58 78 46 46 58 60 69 61 66 51 51 64 52 48 59
F M M M M M F M M M M M M M M M M M M
Time between initial lesion and MAR (months) 60 1 24 24 24 2 16 3 180 12 36 36 0 0 48 0 17 24 60
Time between initial lesion and metastases (months) 48 0 12 No metastases 12 0 9 3 180 14 43 55 0 Unknown 0 No metastases 0 0 48
Antibody positive Yes Yes Yes Unknown Unknown Unknown Yes Yes Unknown Unknown Unknown Yes Yes Yes Yes Yes Yes Unknown Unknown
Survival after diagnosis of initial lesion (years) > 14 Unknown >4 >3 >3 5 Unknown Unknown > 15 Unknown Unknown >1 >1 Unknown >6 Unknown >4 5 5
Treatment
No Plasmapheresis Prednisolone No No No No No No No No No No No Prednisolone No Prednisolone No No
*Present case.
sleep to find she had difficulty seeing in the dark, sensitivity to glare and swirling lights in both her central and peripheral visual fields. These symptoms had not been present before she went to sleep that night. Five days after the onset of these symptoms, she received her third course of chemotherapy (lomustine 120 mg orally). After treatment, she noted increased glare. She was on no other medications except the iron supplements at this time. She presented to the Emergency department of The Royal Victorian Eye and Ear Hospital 1 week after the initial onset of her symptoms on 6 November 1991. Examination revealed visual acuities of 6/12 in the right eye which corrected with pinhole to 6/9, and 6/5 in the left eye. Colour vision was normal by Ishihara testing and there was no relative afferent pupillary defect. Fundi were essentially normal. Electro-encephalogram (EEG), computed tomography scan (CT) and magnetic resonance imaging (MRI) of the brain, visual evoked responses (VER), and lumbar puncture all were normal. At this time, the patient refused to undergo any further chemotherapy. The lumps in her scalp and groin disappeared over a number of months following the onset of her visual symptoms. She was then reviewed several times at the ocular diagnostic clinic during 1992 and 1993. Visual acuity remained stable. Colour vision on retesting revealed a deutanomolous defect in the left eye. Dark adaptometry showed very high scotopic thresholds. Electroretinographic testing yielded a low amplitude B wave and larger than expected A wave under scotopic conditions; photopic responses were normal as was response to 30Hz flicker. The retinal vessels in the left eye were attenuated. Her ophthalmologist made provisional diagnoses of late onset retinitis pigmentosa or lomustine toxicity.
At the beginning of 1994, she became profoundly anaemic with a haemoglobin of 50. Despite an iron infusion, she remained anaemic and it was decided to undertake an exploratory laparotomy. This revealed metastatic melanoma in her small bowel which was subsequently resected. A different ophthalmologist saw her at the end of 1997 at which time the diagnosis of MAR was first suggested. Serum was sent to Professor A Milam in Seattle and was found to contain autoantibodies to retinal bipolar cells. This correlated with previously documented cases of MAR.4–6,9–11 Her serum was also borderline positive to the melanoma antigen NY-ESO-1. Since the patient’s initial presentation, her visual acuity in her left eye has gradually declined to 6/12 associated with the emergence of a left central scotoma and generalized constriction of both fields, and a left relative afferent pupillary defect. Colour vision in the left eye has also declined to 0/14 on Ishihara testing. A repeat of her oculodiagnostics at the end of 1999 showed delayed VER and reduced photopic B-wave amplitudes in the left eye. Both discs also now appeared pale. She has, however, remained free of recurrent melanoma since her bowel resection in 1994, a disease free period of over six years.
DISCUSSION At least 19 cases of melanoma-associated retinopathy (MAR) have now been reported.1–19 Typical symptoms of this paraneoplastic syndrome are sudden onset night blindness and shimmering photopsias.5,6 As illustrated in Table 1, onset of MAR occurs months to years after the initial
Autoimmunity and MAR diagnosis of melanoma. So far, MAR has been reported only in cases of cutaneous melanoma and all but one case have been male. However, MAR is still a relatively rare syndrome and may not be diagnosed even by experienced clinicians. This has potentially serious implications as the onset of MAR may herald the presence of metastatic disease.7,8 The history of this patient is unusual for a number of reasons. First the patient is a woman. So far, only one other female case of MAR has been reported. This is a far greater male predominance than for the incidence of cutaneous melanoma itself, for which the male:female ratio is 1.4 : 1.20 Second, this patient had scalp and groin metastases, which regressed after an incomplete course of chemotherapy. Finally and most importantly, she has remained disease free now for more than 6 years. Most authors predict a median survival of 4–6 months once melanoma has metastasized.3,20–22 This woman’s first metastatic lesion was first discovered in 1990. Furthermore, she presumably had a small bowel metastasis in 1991 when she was first diagnosed with iron deficiency anaemia. This lesion was not resected until 3 years later. Her survival to the present time is clearly beyond that predicted. The issues raised by this case history are therefore threefold. 1 Does the autoimmune response, which is thought to result in MAR, improve survival? 2 If the visual deterioration is progressive, what treatment options should be considered? 3 If autoimmunity does result in improved survival, is immunosuppression the best treatment choice? To explore these issues further, it is necessary first to review current theories on the immunology of MAR and other paraneoplastic syndromes. Anti-retinal bipolar cell antibodies are thought to be responsible for the development of MAR. Antigenic mimicry is suggested as the origin of the autoimmune response. Melanoma cells in these patients have epitopes which are similar to those found on normal bipolar cell proteins.3,4 Professor H Ohguro has recently isolated the antigen responsible for eliciting MAR antibodies (AH Milam, 2000, personal communication). The immune system produces antibodies that cross-react with both the melanoma and bipolar cells. Patients develop night blindness suddenly once there is autoimmune destruction of a critical number of bipolar cells, beyond which transmission through the rod or scotopic pathway is no longer possible.8 This model is supported by immunological, histological and electrophysiological findings. The antibodies are detected in serum from patients by indirect immunofluorescence on cryosections of unfixed retina where antibodies label retinal bipolar cells.1 At present, there is no test to measure the titre of antibodies (AH Milam, 2000, personal communication). Histopathology reveals normal photoreceptor cells but a marked reduction in the density of bipolar cells and secondary transynaptic atrophy of the ganglion cells.2 This correlates with ERG changes. Depolarizing bipolar cells are responsible for generating the B wave of the
237 ERG by creating potassium currents channelled through the Müller cells. The ERG of MAR patients have diminished scotopic B-wave amplitude and relatively normal photopic responses. There is also preservation of the OFF response (response of bipolar cells when the light is switched off) with a diminished ON response.4,9 The concept of a patient’s immune system producing antibodies to destroy neoplastic cells is not new. There are numerous case reports of spontaneous tumour regression that propose this as a mechanism.21–23 There are also specific examples of auto-antibodies produced in response to a neoplasm that result in prolonged survival. The presence of antineural and antinuclear antibodies have been shown to be positive stage-independent prognostic factors in small cell and non-small cell lung cancer.24 In addition, breast cancer patients with auto-antibodies to the 27-kd heat shock protein have improved survival.25 Based on the concept of autoimmunity, numerous tumour vaccines are currently being trialled. Most work has been done so far on melanoma antigens such as tyrosinase, MelanA/Mart-1 and gp100. One polyvalent melanoma vaccine has been shown to increase median and 5-year survival of stage 3 and 4 melanoma patients.21,22 With this in mind, if the immune system is able to help combat tumour progression, are immunosuppressive therapies such as corticosteroids and plasmapheresis the best options for the treatment of paraneoplastic visual loss? Certainly, they have been tried on a number of occasions with limited or no success in patients with MAR. Oral prednisolone has been used in four cases.10,12,13 The only patient in whom an improvement in vision was reported had concurrent uveitis. Oral prednisolone has also been used in patients with cancer-associated retinopathy (CAR) with better results. Guy and Aptsiauri summarize the reports of prednisolone use and state that 10 of 16 patients with CAR had an improvement in their vision.14 The degree of improvement varied widely between patients. This suggests that the results from corticosteroid treatment of CAR cannot be extrapolated to MAR. Plasmapheresis has also been used in the treatment of MAR, without apparent beneficial effects.3 Guy and Aptsiauri report three cases of paraneoplastic visual loss (none of them MAR) treated with intravenous immunoglobulin. Only one of these three patients had an improvement in their vision.14 We would suggest that in patients with no progression of their visual symptoms and prolonged survival, immunosuppression should probably be avoided. Management of patients with progressive visual symptoms is a more difficult issue. At present there is no evidence to support immunosuppression as a viable treatment. Also due to the rarity of MAR, any data on treatments will be qualitative and retrospective. Further elucidation of the pathophysiology of MAR may provide a direction for future treatment options. Melanoma-associated retinopathy often arises at the same time as the discovery of metastases and it can be difficult to exclude chemotoxicity as a cause for the visual symptoms. Lomustine toxicity was the initial diagnosis
238 given to our patient. Although ocular side-effects are known to occur with use of lomustine, they are usually transient and not of major significance. There is only one reference in the literature which reports visual loss associated with lomustine. However, these patients also had low-dose radiation and it was proposed that synergism between the chemotherapy and radiation resulted in visual loss.26,27 Nathanson et al. report that blurred vision can also occur with high dose dacarbazine.28 However, it is unlikely that chemotoxicity was the cause of our patient’s visual symptoms. Her symptoms were typical of MAR and she was also positive for antiretinal bipolar cell antibodies. Melanoma-associated retinopathy, although rare, must be considered as a possible cause for visual symptoms in patients with a known past history of cutaneous melanoma. The management of MAR is a difficult problem as no therapies have yet to be shown to be effective. The use of immunosuppresive agents in the treatment of MAR certainly must be queried in view of a number of case reports demonstrating prolonged survival, presumably due to autoimmunity.
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