ORIGINAL ARTICLE
Clinical and Histologic Findings in Patients With Uveal Melanomas After Taking Tumor Necrosis Factor-a Inhibitors Gena Damento, BSHS; Shaheen C. Kavoussi, MD; Miguel A. Materin, MD; Diva R. Salomão, MD; Polly A. Quiram, MD, PhD; Soranya Balasubramaniam, MD; and Jose S. Pulido, MD, MS, MPH Abstract Objective: To describe the progression of uveal melanocytic lesions to melanomas after initiation of tumor necrosis factor-a (TNF-a) inhibitors. Patients and Methods: We report 3 cases of uveal melanoma occurring after treatment with TNF-a inhibitors, 2 from Mayo Clinic and 1 from Yale University. The study took place from February 27, 2009, through July 15, 2013. Results: Two women and one man with inflammatory disease who received TNF-a inhibitors had subsequent development of uveal melanomas. The 2 women had inflammatory bowel disease and had been followed up for melanocytic tumors that grew markedly within 1 year after beginning treatment with TNF-a inhibitors to the point of requiring treatment. One had histologic confirmation of the melanoma. The male patient had rheumatoid arthritis that was being treated with TNF-a inhibitors. Serial ultrasonography was performed to monitor bilateral diffuse scleritis, and within 16 months of initiation of TNF-a inhibitor therapy, a choroidal mass was detected that continued to grow over the next 3 months. The patient elected to have enucleation, which revealed uveal melanoma and thinning of the sclera from the previous scleritis. Conclusion: Our 3 cases of uveal melanocytic tumors occurring after the use of TNF-a inhibitors add to the growing literature suggesting a correlation between TNF-a inhibitors and the development of malignant neoplasms. Considering the association between cutaneous melanoma and TNF-a inhibitors, we recommend that patients have an eye examination before initiation of TNF-a inhibitors, and those with preexisting nevi should be followed up at regular intervals. ª 2014 Mayo Foundation for Medical Education and Research
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lthough effective in the treatment of many inflammatory conditions, tumor necrosis factor-a (TNF-a) inhibitors suppress the immune system, increasing a patient’s risk of infection or reactivation of latent tuberculosis and the development of demyelinating disease or lymphoma.1-3 In recent years, the literature regarding the association of TNF-a inhibitors and malignant neoplasms other than lymphoma has expanded to include solid organ tumors. Immunosuppression and malignant tumors have been discussed in multiple studies, and the results strongly suggest an increased risk of skin carcinomas in immunosuppressed transplant recipients.4,5 Evidence also shows that the correlation is dependent on both the duration and the intensity of the immunosuppression, confirming causality.6
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Because of the inflammatory nature of the diseases treated by TNF-a inhibitors, it has been difficult to confirm a causality of the development of malignant disease. One attempt to better determine the cause was a large study of the risk of malignant neoplasms in patients with rheumatoid arthritis (RA) in which the investigators were able to control for the therapies given. They found that among patients with RA, those treated with TNF-a inhibitors had a greater risk of development of nonmelanoma skin cancer.7 A similar study in patients with granulomatosis with polyangiitis found an increased incidence of solid organ malignant neoplasms in patients treated with etanercept compared with placebo.8 A potential mechanism of the increased risk of malignant disease with TNF-a inhibitors was
Mayo Clin Proc. n November 2014;89(11):1481-1486 n http://dx.doi.org/10.1016/j.mayocp.2014.08.012 www.mayoclinicproceedings.org n ª 2014 Mayo Foundation for Medical Education and Research
For editorial comment, see page 1467 From the Department of Ophthalmology (G.D., D.R.S., S.B., J.S.P.), Division of Anatomic Pathology (D.R.S.), and Department of Molecular Medicine (J.S.P.), Mayo Clinic, Rochester, MN; Department of Ophthalmology, Yale University, New Haven, CT (S.C.K., M.A.M.); and VitreoRetinal Surgery, PA, Edina, MN (P.A.Q.).
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discussed by van Horssen et al,9 who suggested that TNF-a receptors on tumor endothelial cells contribute to cytotoxicity and necrosis of solid tumors. Blockage of TNF-a in the presence of solid tumors would prevent the host’s immunologic responses from combating the tumor or preventing its growth. Penn6 proposed a similar concept, that there is a decrease in cancer surveillance with immunosuppressant therapy.6 Tumor necrosis factor-a has also been used with peripheral limb infusions to prevent in-transit metastases of peripheral melanomas, with good outcomes.10,11 In vitro studies have demonstrated paradoxical activity of TNF-a on cancers; these data suggest that TNF-a increases melanocyte invasion.12,13 To our knowledge, we report the first cases of patients presenting with intraocular tumors after being treated with TNF-a inhibitors. PATIENTS AND METHODS After institutional review board approval, we studied 3 cases of uveal melanoma occurring after treatment with TNF-a inhibitors, 2 from Mayo Clinic in Rochester, Minnesota, and 1 from Yale University in New Haven, Connecticut. The study period was February 27, 2009, through July 15, 2013. Case 1 In November 2011, a 28-year-old woman was diagnosed as having inflammatory bowel disease and required multiple courses of corticosteroids for symptom control. Because of the difficulty in managing the disease, 6 months after diagnosis
FIGURE 1. Progression of choroidal nevus to melanoma in a 28-year-old woman with inflammatory bowel disease treated with infliximab. A, Appearance of choroidal nevus (arrow) on April 11, 2012. B, Image taken on April 23, 2013, shows the growth of the lesion by comparing the posterior edge from 2012 (black arrowhead) to that of 2013 (white arrowhead).
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the patient began treatment with infliximab, 100-mg infusions every 8 weeks, and azathioprine, 125 mg daily. With these medications, she was able to achieve and maintain clinical remission. In April 2012, an asymptomatic choroidal nevus had been detected in her right eye. The nevus, approximately 915 mm at the base with no elevation, was more than 3 mm from the fovea, and some melanolipofuscin, but no subretinal fluid or drusen, was noted (Figure 1, A). Ten months after initiation of infliximab, the patient began to notice intermittent light flashes in her right eye, followed a few weeks later by a persistent decrease in vision. Examination revealed a choroidal melanoma, 15.712.64.9 mm, and both fluid and melanolipofuscin (Figure 1, B). Case 2 A 67-year-old man was diagnosed as having RA in 1985. He was treated with etanercept until T-cell leukemia developed in 2007, for which he underwent chemotherapy and had since been symptom free. In 2009, diffuse scleritis with choroidal thickening secondary to his RA, which was being treated with leflunomide and prednisone, was detected in both eyes (Figure 2, A, B, and D). Over the next 2 years, the patient was followed up in ophthalmology for the scleritis in both eyes. Serial ultrasonography was performed to monitor the choroidal effusions. In June 2010, leflunomide was switched to adalimumab for treatment of his RA. The scleritis improved in both eyes, but 16 months later, ultrasonography detected a pigmented choroidal mass measuring 8.19.73.0 mm in the patient’s left eye without ciliary body involvement. His vision at that time was 20/50þ1 in the right eye and 20/150þ1 in the left with intraocular pressure of 18 mm Hg in the right eye and 14 mm Hg in the left. The tumor continued to grow, and the patient elected to have enucleation in January 2012, which revealed a 9.710.74.3-mm ciliochoroidal melanoma (Figure 2, C). Case 3 Since 1996, a 64-year-old woman had undergone ophthalmologic examination every 6 months for observation of a choroidal nevus in her right eye. The patient was asymptomatic during this time. The tumor did not have
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FIGURE 2. Progression of diffuse scleritis with choroidal thickening to melanoma in a 67-year-old man with rheumatoid arthritis treated with etanercept, leflunomide, and adalimumab. Slit-lamp examination in February 2009 revealed areas of diffuse scleritis (arrows) in the right (A) and left (B) eyes. C, Ultrasonography of the left eye 16 months after beginning adalimumab detected melanoma (arrow). D, Histologic examination revealed scleral thinning (arrows) with focal chronic inflammation due to chronic scleritis (hematoxylin-eosin, original magnification 40).
associated subretinal fluid and was not located in the posterior pole. An examination in 1998 recorded the lesion as 4.54.5 mm at the base with a thickness of 1 mm and noted the presence of extensive drusen. In 2010, the patient began taking subcutaneous adalimumab, 40 mg every other week, for treatment of recently diagnosed Crohn disease. She had not taken any immunomodulators before this time. The following year, the nevus appeared to have progressed, and the patient was referred to a retina specialist because of concern about melanoma. At her examination in March 2011, the lesion measured 13 mm in diameter and was 4.9 mm thick (Figure 3). The patient reported no symptoms at the time, and her best corrected visual acuity was 20/20 in the right eye and 20/25 in the left with intraocular pressure of 14 mm Hg bilaterally. A transscleral biopsy was performed for confirmation of the choroidal melanoma, and the patient was treated with a brachytherapy device. Mayo Clin Proc. n November 2014;89(11):1481-1486 www.mayoclinicproceedings.org
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DISCUSSION The literature supports that immunosuppression increases a patient’s risk of overall malignancy. Evidence also suggests that this is true of melanomasdimmunosuppression increases a patient’s risk of development of cutaneous melanoma to 3.2 times that of the general population.14 Alaibac et al15 also proposed that the immune system acts to suppress melanocytic growth. Numerous cases concerning development of malignant neoplasms after beginning treatment with a TNF-a inhibitor have also been reported. Esser et al16 and Wong et al17 described cases in which rapid tumor development followed the administration of infliximab. Etanercept and adalimumab reportedly caused a recurrence of latent metastatic melanoma 1 month after initiation of etanercept in one patient and 6 months after initiation of adalimumab treatment in another.18 Meta-analyses focusing on the relationship of TNF-a inhibition and melanoma risk have
http://dx.doi.org/10.1016/j.mayocp.2014.08.012
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FIGURE 3. Progression of a choroidal nevus that had been monitored for 15 years to melanoma in a 64-year-old woman with Crohn disease. One year after the patient began treatment with adalimumab, ultrasonography (A) and funduscopic examination (B) revealed progression to melanoma (arrows).
yielded conflicting results. For example, Nardone et al19 reported a significant association between antieTNF-a agents and the development of melanoma. With these results, they suggested that the US Food and Drug Administration strengthen their labeling for antieTNF-a medications. However, studies by Askling et al20 and others21,22 were unable to verify this increased risk. Some investigators have suggested that the conflicting data might be due to potential publication biases and sponsorship of studies by drug manufacturers.23 Research independent of the pharmaceutical industry is needed, as well as the use of larger populations, longer followup, and better reporting of adverse effects within the studies. A population cohort study in Sweden found that patients with RA treated with TNF-a inhibitors had a 1.5-fold increased risk of invasive cutaneous melanoma compared with the general population.24 This increased risk was not seen in patients whose RA was treated with nonbiological medications. Of further interest, a dramatically increased risk was found in men taking TNF-a inhibitors compared with women, with hazard ratios of 2.7 and 1.2, respectively.24 Although cutaneous and uveal melanomas share a melanocytic origin, important differences in genetic sequence variations have been identified. Van Raamsdonk et al25 noted that sequence variations of BRAF, NRAS, and KIT are found in cutaneous melanoma but not in uveal melanoma. The converse is also discussed in the literature. Sequence variations 1484
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in GNAQ and GNA11 are found in most uveal melanomas but in only 6% of cutaneous melanomas.26 This evidence suggests an evolutionary process that differs in the 2 forms of melanoma, raising concern about reliance solely on studies focused on cutaneous melanomas. Our cases add to the growing literature suggesting a correlation between TNF-a inhibitors and the development of malignant neoplasms. Our patients had a history of eye abnormalities before the development of the melanoma, 2 with choroidal nevi and 1 with chronic diffuse scleritis. A preexisting choroidal nevus is a known risk factor for the development of melanoma. In addition, our findings support the proposal by Smith and Skelton27 that TNF-a receptor therapy may lessen the immune system’s control over subclinical tumors. Patients with chronically inflamed organs are also at higher risk of development of solid malignant tumors.28,29 This increased risk in patients with chronic inflammation could explain the development of the melanoma in our patient with diffuse scleritis. Because our case series is small, there are limitations in the application of our findings to larger populations. Currently, TNF-a inhibitors are used so commonly that the cases could have occurred even in the absence of their use. However, our cases add to the growing literature suggesting a correlation between TNF-a inhibitors and the development of malignant neoplasms. The variability of the results of larger studies on this topic suggests that further nonbiased research should be undertaken to
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determine which patients are at risk for tumor development with TNF-a antagonist treatment. Knowledge of which risk factors are pertinent would allow physicians to determine the safest treatment for their patients. Determination of long-term safety is especially important because recent evidence supports the use of TNF-a inhibition to treat ocular disease.30 Physicians should be mindful of the recommendations from the risk factor analysis by Shields et al31 in patients that have a choroidal nevus but those who are using TNF-a inhibitors should have more frequent evaluations than comparable non-immunosuppressed patients. CONCLUSION Our 3 cases of uveal melanocytic tumors occurring after the use of TNF-a inhibitors add to the growing literature suggesting a correlation between TNF-a inhibitors and the development of malignant neoplasms. Considering the association between cutaneous melanoma and TNF-a inhibitors, we recommend that patients have an eye examination before initiation of TNF-a inhibitors, and those with preexisting nevi should be followed up at regular intervals. Abbreviations and Acronyms: TNF-a = tumor necrosis factor-a; RA = rheumatoid arthritis Grant Support: This work was supported in part by a generous grant from Terrance and Judi Paul and an unrestricted grant from Research to Prevent Blindness, Inc. Correspondence: Address to Jose S. Pulido, MD, MS, MPH, Department of Ophthalmology and Department of Molecular Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]).
REFERENCES 1. de Silva S, Devlin S, Panaccione R. Optimizing the safety of biologic therapy for IBD. Nat Rev Gastroenterol Hepatol. 2010;7(2): 93-101. 2. Diak P, Siegel J, La Grenade L, Choi L, Lemery S, McMahon A. Tumor necrosis factor alpha blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum. 2010;62(8):2517-2524. 3. Jackson JM. TNF-alpha inhibitors [published correction appears in Dermatol Ther. 2008;21(2):150]. Dermatol Ther. 2007;20(4): 251-264. 4. Gutierrez-Dalmau A, Campistol JM. Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review. Drugs. 2007;67(8):1167-1198. 5. Le Mire L, Hollowood K, Gray D, Bordea C, Wojnarowska F. Melanomas in renal transplant recipients. Br J Dermatol. 2006; 154(3):472-477.
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6. Penn I. Post-transplant malignancy: the role of immunosuppression. Drug Saf. 2000;23(2):101-113. 7. Chakravarty EF, Michaud K, Wolfe F. Skin cancer, rheumatoid arthritis, and tumor necrosis factor inhibitors. J Rheumatol. 2005;32(11):2130-2135. 8. Stone JH, Holbrook JT, Marriott MA, et al; Wegener’s Granulomatosis Etanercept Trial Research Group. Solid malignancies among patients in the Wegener’s Granulomatosis Etanercept Trial. Arthritis Rheum. 2006;54(5):1608-1618. 9. van Horssen R, Ten Hagen TL, Eggermont AM. TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist. 2006;11(4):397-408. 10. Grünhagen DJ, Brunstein F, Graveland WJ, van Geel AN, de Wilt JH, Eggermont AM. One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases. Ann Surg. 2004; 240(6):939-947. 11. Kroon HM, Moncrieff M, Kam PC, Thompson JF. Outcomes following isolated limb infusion for melanoma: a 14-year experience. Ann Surg Oncol. 2008;15(11):3003-3013. 12. Cantón I, Eves PC, Szabo M, et al. Tumor necrosis factor alpha increases and alpha-melanocyte-stimulating hormone reduces uveal melanoma invasion through fibronectin. J Invest Dermatol. 2003;121(3):557-563. 13. Katerinaki E, Evans GS, Lorigan PC, MacNeil S. TNF-alpha increases human melanoma cell invasion and migration in vitro: the role of proteolytic enzymes. Br J Cancer. 2003;89(6): 1123-1129. 14. Jensen P, Hansen S, Møller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40(2, pt 1):177-186. 15. Alaibac M, Piaserico S, Rossi CR, et al. Eruptive melanocytic nevi in patients with renal allografts: report of 10 cases with dermoscopic findings. J Am Acad Dermatol. 2003;49(6):1020-1022. 16. Esser AC, Abril A, Fayne S, Doyle JA. Acute development of multiple keratoacanthomas and squamous cell carcinomas after treatment with infliximab. J Am Acad Dermatol. 2004;50(5, suppl):S75-S77. 17. Wong JC, Bressler B, Salh B, Yoshida EM, Chatur N. Development of testicular germ cell cancer following successful infliximab induction therapy for ulcerative colitis. J Crohns Colitis. 2011;5(2):162-164. 18. Fulchiero GJ Jr, Salvaggio H, Drabick JJ, et al. Eruptive latent metastatic melanomas after initiation of antitumor necrosis factor therapies. J Am Acad Dermatol. 2007;56(5, suppl): S65-S67. 19. Nardone B, Hammel JA, Raisch DW, Weaver LL, Schneider D, West DP. Melanoma associated with tumour necrosis factor-a inhibitors: a Research on Adverse Drug events And Reports (RADAR) project. Br J Dermatol. 2014;170(5):1170-1172. 20. Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, Symmons D. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiol Drug Saf. 2011;20(2):119-130. 21. Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, et al. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA. 2012;308(9):898-908. 22. Thompson AE, Rieder SW, Pope JE. Tumor necrosis factor therapy and the risk of serious infection and malignancy in patients with early rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheum. 2011;63(6): 1479-1485. 23. Ioannidis JP, Karassa FB, Druyts E, Thorlund K, Mills EJ. Biologic agents in rheumatology: unmet issues after 200 trials and $200 billion sales. Nat Rev Rheumatol. 2013;9(11):665-673. 24. Raaschou P, Simard JF, Holmqvist M, Askling J; ARTIS Study Group. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population
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based prospective cohort study from Sweden. BMJ. 2013;346: f1939. 25. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010; 363(23):2191-2199. 26. Feng X, Degese MS, Iglesias-Bartolome R, et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a Trio-regulated Rho GTPase signaling circuitry. Cancer Cell. 2014;25(6):831-845. 27. Smith KJ, Skelton HG. Rapid onset of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis after starting tumor necrosis factor alpha receptor IgG1-Fc fusion complex therapy. J Am Acad Dermatol. 2001;45(6):953-956.
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28. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13(11): 759-771. 29. Ohnishi S, Ma N, Thanan R, et al. DNA damage in inflammation-related carcinogenesis and cancer stem cells. Oxid Med Cell Longev. 2013;2013:387014. 30. Rifkin LM, Birnbaum AD, Goldstein DA. TNF inhibition for ophthalmic indications: current status and outlook. BioDrugs. 2013;27(4):347-357. 31. Shields CL, Furuta M, Berman EL, et al. Choroidal nevus transformation into melanoma: analysis of 2514 consecutive cases. Arch Ophthalmol. 2009;127(8):981-987.
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Clinical and Histologic Findings in Patients With Uveal Melanomas After Taking Tumor Necrosis Factor-a Inhibitors Gena Damento, BSHS; Shaheen C. Kavoussi, MD; Miguel A. Materin, MD; Diva R. Salomão, MD; Polly A. Quiram, MD, PhD; Soranya Balasubramaniam, MD; and Jose S. Pulido, MD, MS, MPH Abstract Objective: To describe the progression of uveal melanocytic lesions to melanomas after initiation of tumor necrosis factor-a (TNF-a) inhibitors. Patients and Methods: We report 3 cases of uveal melanoma occurring after treatment with TNF-a inhibitors, 2 from Mayo Clinic and 1 from Yale University. The study took place from February 27, 2009, through July 15, 2013. Results: Two women and one man with inflammatory disease who received TNF-a inhibitors had subsequent development of uveal melanomas. The 2 women had inflammatory bowel disease and had been followed up for melanocytic tumors that grew markedly within 1 year after beginning treatment with TNF-a inhibitors to the point of requiring treatment. One had histologic confirmation of the melanoma. The male patient had rheumatoid arthritis that was being treated with TNF-a inhibitors. Serial ultrasonography was performed to monitor bilateral diffuse scleritis, and within 16 months of initiation of TNF-a inhibitor therapy, a choroidal mass was detected that continued to grow over the next 3 months. The patient elected to have enucleation, which revealed uveal melanoma and thinning of the sclera from the previous scleritis. Conclusion: Our 3 cases of uveal melanocytic tumors occurring after the use of TNF-a inhibitors add to the growing literature suggesting a correlation between TNF-a inhibitors and the development of malignant neoplasms. Considering the association between cutaneous melanoma and TNF-a inhibitors, we recommend that patients have an eye examination before initiation of TNF-a inhibitors, and those with preexisting nevi should be followed up at regular intervals. ª 2014 Mayo Foundation for Medical Education and Research
A
lthough effective in the treatment of many inflammatory conditions, tumor necrosis factor-a (TNF-a) inhibitors suppress the immune system, increasing a patient’s risk of infection or reactivation of latent tuberculosis and the development of demyelinating disease or lymphoma.1-3 In recent years, the literature regarding the association of TNF-a inhibitors and malignant neoplasms other than lymphoma has expanded to include solid organ tumors. Immunosuppression and malignant tumors have been discussed in multiple studies, and the results strongly suggest an increased risk of skin carcinomas in immunosuppressed transplant recipients.4,5 Evidence also shows that the correlation is dependent on both the duration and the intensity of the immunosuppression, confirming causality.6
n
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Because of the inflammatory nature of the diseases treated by TNF-a inhibitors, it has been difficult to confirm a causality of the development of malignant disease. One attempt to better determine the cause was a large study of the risk of malignant neoplasms in patients with rheumatoid arthritis (RA) in which the investigators were able to control for the therapies given. They found that among patients with RA, those treated with TNF-a inhibitors had a greater risk of development of nonmelanoma skin cancer.7 A similar study in patients with granulomatosis with polyangiitis found an increased incidence of solid organ malignant neoplasms in patients treated with etanercept compared with placebo.8 A potential mechanism of the increased risk of malignant disease with TNF-a inhibitors was
Mayo Clin Proc. n November 2014;89(11):1481-1486 n http://dx.doi.org/10.1016/j.mayocp.2014.08.012 www.mayoclinicproceedings.org n ª 2014 Mayo Foundation for Medical Education and Research
For editorial comment, see page 1467 From the Department of Ophthalmology (G.D., D.R.S., S.B., J.S.P.), Division of Anatomic Pathology (D.R.S.), and Department of Molecular Medicine (J.S.P.), Mayo Clinic, Rochester, MN; Department of Ophthalmology, Yale University, New Haven, CT (S.C.K., M.A.M.); and VitreoRetinal Surgery, PA, Edina, MN (P.A.Q.).
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discussed by van Horssen et al,9 who suggested that TNF-a receptors on tumor endothelial cells contribute to cytotoxicity and necrosis of solid tumors. Blockage of TNF-a in the presence of solid tumors would prevent the host’s immunologic responses from combating the tumor or preventing its growth. Penn6 proposed a similar concept, that there is a decrease in cancer surveillance with immunosuppressant therapy.6 Tumor necrosis factor-a has also been used with peripheral limb infusions to prevent in-transit metastases of peripheral melanomas, with good outcomes.10,11 In vitro studies have demonstrated paradoxical activity of TNF-a on cancers; these data suggest that TNF-a increases melanocyte invasion.12,13 To our knowledge, we report the first cases of patients presenting with intraocular tumors after being treated with TNF-a inhibitors. PATIENTS AND METHODS After institutional review board approval, we studied 3 cases of uveal melanoma occurring after treatment with TNF-a inhibitors, 2 from Mayo Clinic in Rochester, Minnesota, and 1 from Yale University in New Haven, Connecticut. The study period was February 27, 2009, through July 15, 2013. Case 1 In November 2011, a 28-year-old woman was diagnosed as having inflammatory bowel disease and required multiple courses of corticosteroids for symptom control. Because of the difficulty in managing the disease, 6 months after diagnosis
FIGURE 1. Progression of choroidal nevus to melanoma in a 28-year-old woman with inflammatory bowel disease treated with infliximab. A, Appearance of choroidal nevus (arrow) on April 11, 2012. B, Image taken on April 23, 2013, shows the growth of the lesion by comparing the posterior edge from 2012 (black arrowhead) to that of 2013 (white arrowhead).
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the patient began treatment with infliximab, 100-mg infusions every 8 weeks, and azathioprine, 125 mg daily. With these medications, she was able to achieve and maintain clinical remission. In April 2012, an asymptomatic choroidal nevus had been detected in her right eye. The nevus, approximately 915 mm at the base with no elevation, was more than 3 mm from the fovea, and some melanolipofuscin, but no subretinal fluid or drusen, was noted (Figure 1, A). Ten months after initiation of infliximab, the patient began to notice intermittent light flashes in her right eye, followed a few weeks later by a persistent decrease in vision. Examination revealed a choroidal melanoma, 15.712.64.9 mm, and both fluid and melanolipofuscin (Figure 1, B). Case 2 A 67-year-old man was diagnosed as having RA in 1985. He was treated with etanercept until T-cell leukemia developed in 2007, for which he underwent chemotherapy and had since been symptom free. In 2009, diffuse scleritis with choroidal thickening secondary to his RA, which was being treated with leflunomide and prednisone, was detected in both eyes (Figure 2, A, B, and D). Over the next 2 years, the patient was followed up in ophthalmology for the scleritis in both eyes. Serial ultrasonography was performed to monitor the choroidal effusions. In June 2010, leflunomide was switched to adalimumab for treatment of his RA. The scleritis improved in both eyes, but 16 months later, ultrasonography detected a pigmented choroidal mass measuring 8.19.73.0 mm in the patient’s left eye without ciliary body involvement. His vision at that time was 20/50þ1 in the right eye and 20/150þ1 in the left with intraocular pressure of 18 mm Hg in the right eye and 14 mm Hg in the left. The tumor continued to grow, and the patient elected to have enucleation in January 2012, which revealed a 9.710.74.3-mm ciliochoroidal melanoma (Figure 2, C). Case 3 Since 1996, a 64-year-old woman had undergone ophthalmologic examination every 6 months for observation of a choroidal nevus in her right eye. The patient was asymptomatic during this time. The tumor did not have
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FIGURE 2. Progression of diffuse scleritis with choroidal thickening to melanoma in a 67-year-old man with rheumatoid arthritis treated with etanercept, leflunomide, and adalimumab. Slit-lamp examination in February 2009 revealed areas of diffuse scleritis (arrows) in the right (A) and left (B) eyes. C, Ultrasonography of the left eye 16 months after beginning adalimumab detected melanoma (arrow). D, Histologic examination revealed scleral thinning (arrows) with focal chronic inflammation due to chronic scleritis (hematoxylin-eosin, original magnification 40).
associated subretinal fluid and was not located in the posterior pole. An examination in 1998 recorded the lesion as 4.54.5 mm at the base with a thickness of 1 mm and noted the presence of extensive drusen. In 2010, the patient began taking subcutaneous adalimumab, 40 mg every other week, for treatment of recently diagnosed Crohn disease. She had not taken any immunomodulators before this time. The following year, the nevus appeared to have progressed, and the patient was referred to a retina specialist because of concern about melanoma. At her examination in March 2011, the lesion measured 13 mm in diameter and was 4.9 mm thick (Figure 3). The patient reported no symptoms at the time, and her best corrected visual acuity was 20/20 in the right eye and 20/25 in the left with intraocular pressure of 14 mm Hg bilaterally. A transscleral biopsy was performed for confirmation of the choroidal melanoma, and the patient was treated with a brachytherapy device. Mayo Clin Proc. n November 2014;89(11):1481-1486 www.mayoclinicproceedings.org
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DISCUSSION The literature supports that immunosuppression increases a patient’s risk of overall malignancy. Evidence also suggests that this is true of melanomasdimmunosuppression increases a patient’s risk of development of cutaneous melanoma to 3.2 times that of the general population.14 Alaibac et al15 also proposed that the immune system acts to suppress melanocytic growth. Numerous cases concerning development of malignant neoplasms after beginning treatment with a TNF-a inhibitor have also been reported. Esser et al16 and Wong et al17 described cases in which rapid tumor development followed the administration of infliximab. Etanercept and adalimumab reportedly caused a recurrence of latent metastatic melanoma 1 month after initiation of etanercept in one patient and 6 months after initiation of adalimumab treatment in another.18 Meta-analyses focusing on the relationship of TNF-a inhibition and melanoma risk have
http://dx.doi.org/10.1016/j.mayocp.2014.08.012
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FIGURE 3. Progression of a choroidal nevus that had been monitored for 15 years to melanoma in a 64-year-old woman with Crohn disease. One year after the patient began treatment with adalimumab, ultrasonography (A) and funduscopic examination (B) revealed progression to melanoma (arrows).
yielded conflicting results. For example, Nardone et al19 reported a significant association between antieTNF-a agents and the development of melanoma. With these results, they suggested that the US Food and Drug Administration strengthen their labeling for antieTNF-a medications. However, studies by Askling et al20 and others21,22 were unable to verify this increased risk. Some investigators have suggested that the conflicting data might be due to potential publication biases and sponsorship of studies by drug manufacturers.23 Research independent of the pharmaceutical industry is needed, as well as the use of larger populations, longer followup, and better reporting of adverse effects within the studies. A population cohort study in Sweden found that patients with RA treated with TNF-a inhibitors had a 1.5-fold increased risk of invasive cutaneous melanoma compared with the general population.24 This increased risk was not seen in patients whose RA was treated with nonbiological medications. Of further interest, a dramatically increased risk was found in men taking TNF-a inhibitors compared with women, with hazard ratios of 2.7 and 1.2, respectively.24 Although cutaneous and uveal melanomas share a melanocytic origin, important differences in genetic sequence variations have been identified. Van Raamsdonk et al25 noted that sequence variations of BRAF, NRAS, and KIT are found in cutaneous melanoma but not in uveal melanoma. The converse is also discussed in the literature. Sequence variations 1484
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in GNAQ and GNA11 are found in most uveal melanomas but in only 6% of cutaneous melanomas.26 This evidence suggests an evolutionary process that differs in the 2 forms of melanoma, raising concern about reliance solely on studies focused on cutaneous melanomas. Our cases add to the growing literature suggesting a correlation between TNF-a inhibitors and the development of malignant neoplasms. Our patients had a history of eye abnormalities before the development of the melanoma, 2 with choroidal nevi and 1 with chronic diffuse scleritis. A preexisting choroidal nevus is a known risk factor for the development of melanoma. In addition, our findings support the proposal by Smith and Skelton27 that TNF-a receptor therapy may lessen the immune system’s control over subclinical tumors. Patients with chronically inflamed organs are also at higher risk of development of solid malignant tumors.28,29 This increased risk in patients with chronic inflammation could explain the development of the melanoma in our patient with diffuse scleritis. Because our case series is small, there are limitations in the application of our findings to larger populations. Currently, TNF-a inhibitors are used so commonly that the cases could have occurred even in the absence of their use. However, our cases add to the growing literature suggesting a correlation between TNF-a inhibitors and the development of malignant neoplasms. The variability of the results of larger studies on this topic suggests that further nonbiased research should be undertaken to
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UVEAL MELANOMAS AFTER TNF-a INHIBITORS
determine which patients are at risk for tumor development with TNF-a antagonist treatment. Knowledge of which risk factors are pertinent would allow physicians to determine the safest treatment for their patients. Determination of long-term safety is especially important because recent evidence supports the use of TNF-a inhibition to treat ocular disease.30 Physicians should be mindful of the recommendations from the risk factor analysis by Shields et al31 in patients that have a choroidal nevus but those who are using TNF-a inhibitors should have more frequent evaluations than comparable non-immunosuppressed patients. CONCLUSION Our 3 cases of uveal melanocytic tumors occurring after the use of TNF-a inhibitors add to the growing literature suggesting a correlation between TNF-a inhibitors and the development of malignant neoplasms. Considering the association between cutaneous melanoma and TNF-a inhibitors, we recommend that patients have an eye examination before initiation of TNF-a inhibitors, and those with preexisting nevi should be followed up at regular intervals. Abbreviations and Acronyms: TNF-a = tumor necrosis factor-a; RA = rheumatoid arthritis Grant Support: This work was supported in part by a generous grant from Terrance and Judi Paul and an unrestricted grant from Research to Prevent Blindness, Inc. Correspondence: Address to Jose S. Pulido, MD, MS, MPH, Department of Ophthalmology and Department of Molecular Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]).
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