ABSTRACT

Purpose: To discuss the autoimmune basis of melanoma-associated retinopathy (MAR) and its implications formanagement and prognosis.

Methods: An unusual history of a woman with melanoma-associated retinopathy is presented in detail. A review ofpublished reports and a summary of 19 reported cases ofMAR provide a basis for discussion.

Results: This case report and other published reports high-light a number of points regarding MAR including the malepredominance, prolonged survival in several patients andlack of response to immunosuppression.

Conclusions: Melanoma-associated retinopathy may prolongthe survival of patients with metastatic melanoma throughthe autoimmune response. Therefore, treatment of visualsymptoms with immunosuppression needs to be consid-ered carefully.

Key words: autoimmune, immunosuppression, melanoma-associated retinopathy, survival.

INTRODUCTION

Melanoma-associated retinopathy (MAR) has become anincreasingly recognized clinical entity over the past decade.At least 19 cases have now been reported, 18 of them weremen.1–19 Melanoma-associated retinopathy has been seenonly in patients with cutaneous melanoma. Electro-physiological, immunological and histopathological datasuggest that the retinopathy is the result of antibodies produced against retinal bipolar cells. These cells share anepitope with melanoma cells. Recently, the antigen responsible for stimulating antibody production has beenidentified.3,4

Patients typically present with sudden onset night blind-ness, shimmering photopsias and electroretinogram (ERG)findings resembling congenital stationary night blindness(CSNB), months to years after discovery and excision of theinitial lesion.5,6 The onset of MAR may herald the presenceof metastatic disease. Visual symptoms and loss of visualacuity are not usually progressive. Colour vision alsoremains intact.7,8

Here we present an unusual case of MAR in a 43-year-oldwoman. This patient has been disease free for 6 years sinceonset of her MAR and removal of a metastatic small bowelmelanoma discovered shortly after. The issue of whether theautoimmune response resulting in MAR prolongs survival isdiscussed.

CASE REPORT

A previously well 43-year-old woman presented to hergeneral practitioner in July 1986 with a pigmented skinlesion at the base of her neck. Excision biopsy revealed aClark Level 5 melanoma. She then underwent radical exci-sion of the melanoma together with adjuvant radiotherapy.In July 1990, she represented with metastatic disease: twocutaneous lesions, one on her back and one in her axilla andtwo adjoining, apical lung lesions. The cutaneous metastaseswere excised and an extensive wedge resection of her lungmetastases was performed. She remained well until Februaryof 1991 when she was diagnosed with iron deficiencyanaemia. Despite extensive investigations, a cause for theanaemia could not be found and she was commenced oniron supplements. During August of the same year, she dis-covered two further melanomas in her groin and one in herscalp. Her oncologist decided that she should be treatedwith several courses of chemotherapy rather than undergofurther surgery.

Dacarbazine intravenously and lomustine (CCNU)120 mg orally were given 6 weeks apart. About 4.5 weeksafter the lomustine had been given, she awoke from her

Clinical and Experimental Ophthalmology (2001) 29, 235–238

Original Article

Melanoma-associated retinopathy: does autoimmunity prolongsurvival?Colin Chan MBBS(Hons) and Justin O’Day FRACOThe Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia

� Correspondence: Dr Colin Chan, The Royal Victorian Eye and Ear Hospital, 32 Gisborne Street, East Melbourne, Victoria 3002, Australia.

Email: chunkeng@yahoo.com

sleep to find she had difficulty seeing in the dark, sensitivityto glare and swirling lights in both her central and periph-eral visual fields. These symptoms had not been presentbefore she went to sleep that night. Five days after the onsetof these symptoms, she received her third course ofchemotherapy (lomustine 120 mg orally). After treatment,she noted increased glare. She was on no other medicationsexcept the iron supplements at this time.

She presented to the Emergency department of TheRoyal Victorian Eye and Ear Hospital 1 week after the initialonset of her symptoms on 6 November 1991. Examinationrevealed visual acuities of 6/12 in the right eye which corrected with pinhole to 6/9, and 6/5 in the left eye. Colourvision was normal by Ishihara testing and there was no relative afferent pupillary defect. Fundi were essentiallynormal. Electro-encephalogram (EEG), computed tomogra-phy scan (CT) and magnetic resonance imaging (MRI) ofthe brain, visual evoked responses (VER), and lumbar punc-ture all were normal. At this time, the patient refused toundergo any further chemotherapy. The lumps in her scalpand groin disappeared over a number of months followingthe onset of her visual symptoms.

She was then reviewed several times at the ocular diag-nostic clinic during 1992 and 1993. Visual acuity remainedstable. Colour vision on retesting revealed a deutanomolousdefect in the left eye. Dark adaptometry showed very highscotopic thresholds. Electroretinographic testing yielded alow amplitude B wave and larger than expected A wave underscotopic conditions; photopic responses were normal as wasresponse to 30Hz flicker. The retinal vessels in the left eyewere attenuated. Her ophthalmologist made provisional diag-noses of late onset retinitis pigmentosa or lomustine toxicity.

At the beginning of 1994, she became profoundlyanaemic with a haemoglobin of 50. Despite an iron infusion,she remained anaemic and it was decided to undertake anexploratory laparotomy. This revealed metastatic melanomain her small bowel which was subsequently resected.

A different ophthalmologist saw her at the end of 1997 atwhich time the diagnosis of MAR was first suggested. Serumwas sent to Professor A Milam in Seattle and was found tocontain autoantibodies to retinal bipolar cells. This corre-lated with previously documented cases of MAR.4–6,9–11 Herserum was also borderline positive to the melanoma antigenNY-ESO-1.

Since the patient’s initial presentation, her visual acuity inher left eye has gradually declined to 6/12 associated withthe emergence of a left central scotoma and generalizedconstriction of both fields, and a left relative afferent pupil-lary defect. Colour vision in the left eye has also declined to0/14 on Ishihara testing. A repeat of her oculodiagnostics atthe end of 1999 showed delayed VER and reduced photopicB-wave amplitudes in the left eye. Both discs also nowappeared pale. She has, however, remained free of recurrentmelanoma since her bowel resection in 1994, a disease freeperiod of over six years.

DISCUSSION

At least 19 cases of melanoma-associated retinopathy(MAR) have now been reported.1–19 Typical symptoms ofthis paraneoplastic syndrome are sudden onset night blind-ness and shimmering photopsias.5,6 As illustrated in Table 1,onset of MAR occurs months to years after the initial

236 Chan and O’Day

Table 1. Summary of 19 available case reports of melanoma-associated retinopathy (MAR)1–19

Case Age Sex Time between Time between Antibody Survival after Treatmentno. (years) initial lesion and initial lesion and positive diagnosis of

MAR (months) metastases (months) initial lesion (years)

1* 48 F 60 48 Yes > 14 No2 50 M 1 0 Yes Unknown Plasmapheresis3 44 M 24 12 Yes > 4 Prednisolone4 61 M 24 No metastases Unknown > 3 No5 58 M 24 12 Unknown > 3 No6 78 M 2 0 Unknown 5 No7 46 F 16 9 Yes Unknown No8 46 M 3 3 Yes Unknown No9 58 M 180 180 Unknown > 15 No10 60 M 12 14 Unknown Unknown No11 69 M 36 43 Unknown Unknown No12 61 M 36 55 Yes > 1 No13 66 M 0 0 Yes > 1 No14 51 M 0 Unknown Yes Unknown No15 51 M 48 0 Yes > 6 Prednisolone16 64 M 0 No metastases Yes Unknown No17 52 M 17 0 Yes > 4 Prednisolone18 48 M 24 0 Unknown 5 No19 59 M 60 48 Unknown 5 No

*Present case.

diagnosis of melanoma. So far, MAR has been reported onlyin cases of cutaneous melanoma and all but one case havebeen male. However, MAR is still a relatively rare syndromeand may not be diagnosed even by experienced clinicians.This has potentially serious implications as the onset ofMAR may herald the presence of metastatic disease.7,8

The history of this patient is unusual for a number ofreasons. First the patient is a woman. So far, only one otherfemale case of MAR has been reported. This is a far greatermale predominance than for the incidence of cutaneousmelanoma itself, for which the male:female ratio is 1.4 : 1.20 Second, this patient had scalp and groin metas-tases, which regressed after an incomplete course of chemo-therapy. Finally and most importantly, she has remaineddisease free now for more than 6 years. Most authors predicta median survival of 4–6 months once melanoma has metas-tasized.3,20–22 This woman’s first metastatic lesion was firstdiscovered in 1990. Furthermore, she presumably had asmall bowel metastasis in 1991 when she was first diagnosedwith iron deficiency anaemia. This lesion was not resecteduntil 3 years later. Her survival to the present time is clearlybeyond that predicted.

The issues raised by this case history are therefore three-fold.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 andother paraneoplastic syndromes.

Anti-retinal bipolar cell antibodies are thought to beresponsible for the development of MAR. Antigenicmimicry is suggested as the origin of the autoimmuneresponse. Melanoma cells in these patients have epitopeswhich are similar to those found on normal bipolar cell pro-teins.3,4 Professor H Ohguro has recently isolated theantigen responsible for eliciting MAR antibodies (AHMilam, 2000, personal communication). The immunesystem produces antibodies that cross-react with both themelanoma and bipolar cells. Patients develop night blind-ness suddenly once there is autoimmune destruction of acritical number of bipolar cells, beyond which transmissionthrough the rod or scotopic pathway is no longer possible.8

This model is supported by immunological, histologicaland electrophysiological findings. The antibodies aredetected in serum from patients by indirect immunofluores-cence on cryosections of unfixed retina where antibodieslabel retinal bipolar cells.1 At present, there is no test tomeasure the titre of antibodies (AH Milam, 2000, personalcommunication). Histopathology reveals normal photore-ceptor cells but a marked reduction in the density of bipolarcells and secondary transynaptic atrophy of the ganglioncells.2 This correlates with ERG changes. Depolarizingbipolar cells are responsible for generating the B wave of the

ERG by creating potassium currents channelled through theMüller cells. The ERG of MAR patients have diminishedscotopic B-wave amplitude and relatively normal photopicresponses. 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 producingantibodies to destroy neoplastic cells is not new. There arenumerous case reports of spontaneous tumour regressionthat propose this as a mechanism.21–23 There are also specific examples of auto-antibodies produced in responseto a neoplasm that result in prolonged survival. The pres-ence of antineural and antinuclear antibodies have beenshown to be positive stage-independent prognostic factorsin small cell and non-small cell lung cancer.24 In addition,breast cancer patients with auto-antibodies to the 27-kdheat shock protein have improved survival.25 Based on theconcept of autoimmunity, numerous tumour vaccines arecurrently being trialled. Most work has been done so far onmelanoma antigens such as tyrosinase, MelanA/Mart-1 andgp100. One polyvalent melanoma vaccine has been shownto increase median and 5-year survival of stage 3 and 4melanoma patients.21,22

With this in mind, if the immune system is able to helpcombat tumour progression, are immunosuppressive thera-pies such as corticosteroids and plasmapheresis the bestoptions for the treatment of paraneoplastic visual loss?Certainly, they have been tried on a number of occasionswith limited or no success in patients with MAR. Oral pred-nisolone has been used in four cases.10,12,13 The only patientin whom an improvement in vision was reported had con-current uveitis. Oral prednisolone has also been used inpatients with cancer-associated retinopathy (CAR) withbetter results. Guy and Aptsiauri summarize the reports ofprednisolone use and state that 10 of 16 patients with CARhad an improvement in their vision.14 The degree ofimprovement varied widely between patients. This suggeststhat the results from corticosteroid treatment of CAR cannotbe extrapolated to MAR. Plasmapheresis has also been usedin the treatment of MAR, without apparent beneficialeffects.3 Guy and Aptsiauri report three cases of paraneo-plastic visual loss (none of them MAR) treated with intra-venous immunoglobulin. Only one of these three patientshad an improvement in their vision.14 We would suggestthat in patients with no progression of their visual symptomsand prolonged survival, immunosuppression should proba-bly be avoided. Management of patients with progressivevisual symptoms is a more difficult issue. At present there isno evidence to support immunosuppression as a viable treat-ment. Also due to the rarity of MAR, any data on treatmentswill be qualitative and retrospective. Further elucidation ofthe pathophysiology of MAR may provide a direction forfuture treatment options.

Melanoma-associated retinopathy often arises at thesame time as the discovery of metastases and it can be difficult to exclude chemotoxicity as a cause for the visualsymptoms. Lomustine toxicity was the initial diagnosis

Autoimmunity and MAR 237

given to our patient. Although ocular side-effects are knownto occur with use of lomustine, they are usually transient and not of major significance. There is only one reference inthe literature which reports visual loss associated withlomustine. However, these patients also had low-dose radia-tion and it was proposed that synergism between thechemotherapy and radiation resulted in visual loss.26,27

Nathanson et al. report that blurred vision can also occurwith high dose dacarbazine.28 However, it is unlikely thatchemotoxicity was the cause of our patient’s visual symp-toms. Her symptoms were typical of MAR and she was alsopositive for antiretinal bipolar cell antibodies.

Melanoma-associated retinopathy, although rare, must beconsidered as a possible cause for visual symptoms in patientswith a known past history of cutaneous melanoma. Themanagement of MAR is a difficult problem as no therapieshave yet to be shown to be effective. The use of immuno-suppresive agents in the treatment of MAR certainly must bequeried in view of a number of case reports demonstratingprolonged survival, presumably due to autoimmunity.

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