Pathophysiology
Dr. Kudchadkar: Dr. Gonzalez, can you discuss how the phenomenon of MAR develops?
Dr. Rene Gonzalez: MAR is essentially an autoimmune disease. Autoimmune disease involves molecular mimicry in which tumor antigens share similar epitopes to patient self-epitopes leading to a cross-reaction. Activated T and B cells respond to the foreign antigen, but they also react to the self-proteins because they share similar peptide sequences. This is what leads to the damage of self-tissue.[2] Although this general concept is likely true, there are many hypotheses as to the exact pathophysiology of MAR. Cancer-associated retinopathy may sometimes be related to the p53 gene mutation that is documented in many cancer cells. Mutated p53 produces the recoverin protein that is highly immunogenic and thus leads to antirecoverin antibody production.[3,4]
Differential Diagnosis of Loss of B-Wave on ERG
This IgG antibody can penetrate the blood-retina barrier and bind to recoverin in the photoreceptor cells. This leads to increased phosphorylation of the molecule rhodopsin, which is involved in the phototransduction pathway, thus causing activation of the caspase-dependent apoptotic pathways and leading to photoreceptor cell death.[4]
Western blots have been used to analyze patients’ serum against normal donor retinal proteins.[5] They essentially show antiretinal IgG bands of activity. The antibodies are active against a number of proteins, not just recoverin. The antibodies have also been found against alpha-enolase, arrestin, carbonic anhydrase, TULP-1, photoreceptor cell–specific nuclear proteins, and heat shock protein 70.[5] The exact mechanism of photoreceptor death from these other antibodies is not clearly understood.
Some cases of MAR have no detectable antibodies by Western blot. However, many of these reports have been shown to have positive bipolar staining on normal human histologic slides and counterstaining for human immunoglobulin.[1,6,7] These findings have not been documented in all patients with no detectable antibodies by Western blot.
Histologically one can see a marked reduction in the density of bipolar cells and secondary trans-synaptic atrophy of ganglion cells.[8] This correlates well with the ERG findings and pathophysiology in MAR patients that were discussed earlier.
Overall, MAR is secondary to an antibody triggering death of bipolar cells. These antibodies can be variable, but treatment should be aimed at suppressing antibody production, removing the antibody from circulation, and/or blocking antibody action.
Melanoma and MAR
Dr. Kudchadkar: Dr. Lewis, does MAR develop in patients with a specific stage of melanoma?
Dr. Karl Lewis: There is no direct correlation between melanoma stage and the development of autoimmune retinopathy. However, in the largest series of patients reported, 28 of 62 had metastatic disease.[1] This suggests that more patients with advanced disease develop MAR. Given that it is thought that the antibodies develop secondarily to a cross-reaction between melanoma and self, one could theorize that the greater the amount of disease, the more likely one is to develop antibodies. However, this is yet to be proven.
Dr. Kudchadkar: Dr. Lewis, is the development of MAR related to prognosis?
Dr. Lewis: Given the rarity of MAR, it is very difficult to prove a relationship between the syndrome and prognosis. However, many have hypothesized that patients who develop autoimmune disease have a better prognosis compared to those who do not. This hypothesis is prevalent throughout many different cancer types, not just melanoma.
Authors of case reports involving spontaneous tumor regression have theorized that the patient’s immune system produced antibodies to destroy the cancer cells.[9-11] In lung cancer, antineural and antinuclear antibodies have been shown to be positive stage-independent prognostic factors.[12] This has been seen in gynecologic cancer patients as well, with autoantibodies to heat shock protein associated with improved survival.[13]
Approved therapies for melanoma include immune therapies such as interleukin-2 (Proleukin) and interferon. The fact that melanoma responds to immune therapy is further evidence that autoimmunity may be a favorable prognostic factor. Gogas et al evaluated melanoma patients treated with interferon alfa-2b(Drug information on interferon alfa-2b) (Intron A) and found that the appearance of autoantibodies or clinical manifestations of autoimmunity were associated with a statistically significant improvement in survival.[14] Overall, though, there is not enough evidence to prove MAR as a favorable prognostic factor in melanoma patients.
Dr. Gonzalez: If autoimmunity is hypothesized to be a good prognostic indicator, is there any indication that treatment of the retinopathy will decrease survival?
Dr. Lewis: Given the rarity of the disease, this is another question for which it is difficult to have a conclusive answer. If our patient has a clinical indication, the answer to your question is that the treatment of the retinopathy does not alter prognosis. Theoretically, immnunosuppression in melanoma would be harmful because of the role of immunity in this disease. There is no conclusive evidence that this is true in the treatment of MAR. However, if the visual symptoms are minimal and nonprogressive, one may want to avoid immunosuppression in light of the theoretical risks.
Maude Becker: What other cancers are associated with retinopathy?
Dr. Kudchadkar: In the mid-1970s, Hoyt first documented paraneoplastic-associated blindness as a remote complication of cancer.[15] Besides melanoma, other cancers associated with cases of retinopathy are those of the lung, ovaries, and colon. Though the presence of this phenomenon in cancer patients is rare, the diagnosis of autoimmune retinopathy should trigger a cancer workup in individual patients. Colonoscopy and chest-x-ray are indicated in patients diagnosed with autoimmune retinopathy but no prior history of cancer, especially in smokers or those greater than 50 years of age.
Treatment
Dr. Lewis: What are the treatment options for MAR?
Dr. Gonzalez: Treatment should be aimed at either blocking antibody function or decreasing antibody production. Most commonly, steroids are used initially, but alternatives like IVIg and plasmapheresis have also been used. There is no standard of care in the treatment of MAR.
Although steroids are commonly tried initially, most case reports do not document success with this treatment.[16] Six of seven patients in one case-series failed to respond to steroids alone.[1] Steroid doses are commonly about 1 mg/kg, with most case reports documenting the use of 60 to 80 mg of prednisone(Drug information on prednisone) daily. One case report demonstrated an improvement with prednisone, but in this case steroids were combined with azathioprine(Drug information on azathioprine), gabapentin(Drug information on gabapentin), and plasmapheresis.
IVIg was used in our patient with great clinical success. However, now that we are years from his last documented evidence of disease, the patient still requires a monthly IVIg infusion. The reduction or even elimination of melanoma does not preclude progression of MAR, and this has been documented in other case reports as well.[17] If the infusion of IVIg is delayed, the patient’s visual symptoms return.
Plamsapheresis has been used on rare occasion for the treatment of MAR. However, one must also continue to suppress antibody production with another method, because pheresis will not stop production.
There is no definitive treatment for MAR, although steroids, IVIg, and plasmapheresis are the most common treatments documented in the literature. In theory, an anti–B-cell monoclonal antibody like rituximab(Drug information on rituximab) (Rituxan) might be used; however, there are no reports of its use in MAR or any cancer-associated retinopathy.
Conclusions
Dr. Kudchadkar: Melanoma-associated retinopathy is a rare but distinct clinical entity that must be considered in any melanoma patient with visual symptoms, especially a flashing lights phenomenon. Visual fields are often affected and ERG can be diagnostic for this disease. If recurrent disease is not documented at the time of MAR diagnosis, one should consider repeat imaging in order to look for recurrent melanoma. The relationship of MAR to melanoma disease status and prognosis remains unclear. Treatment options include prednisone, plasmapheresis, and IVIg. Prednisone and plasmapheresis has had minimal success alone; however, case-reports of IVIg therapy, including this one, have shown some success.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
