ORIGINAL ARTICLE

Clinical and Histologic Findings in Patients WithUveal Melanomas After Taking Tumor NecrosisFactor-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 tumornecrosis factor-a (TNF-a) inhibitors.Patients and Methods: We report 3 cases of uveal melanoma occurring after treatment with TNF-ainhibitors, 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 sub-sequent development of uveal melanomas. The 2 women had inflammatory bowel disease and had beenfollowed up for melanocytic tumors that grewmarkedly within 1 year after beginning treatment with TNF-ainhibitors to the point of requiring treatment. One had histologic confirmation of the melanoma. The malepatient had rheumatoid arthritis that was being treated with TNF-a inhibitors. Serial ultrasonography wasperformed to monitor bilateral diffuse scleritis, and within 16 months of initiation of TNF-a inhibitortherapy, a choroidal mass was detected that continued to grow over the next 3months. The patient elected tohave 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 tothe growing literature suggesting a correlation between TNF-a inhibitors and the development of ma-lignant neoplasms. Considering the association between cutaneous melanoma and TNF-a inhibitors, werecommend that patients have an eye examination before initiation of TNF-a inhibitors, and those withpreexisting nevi should be followed up at regular intervals.

ª 2014 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2014;89(11):1481-1486

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From the Department ofOphthalmology (G.D.,D.R.S., S.B., J.S.P.), Divisionof Anatomic Pathology(D.R.S.), and Departmentof Molecular Medicine(J.S.P.), Mayo Clinic,Rochester, MN;Department of Ophthal-mology, Yale University,New Haven, CT (S.C.K.,M.A.M.); and VitreoRetinalSurgery, PA, Edina, MN(P.A.Q.).

A lthough effective in the treatment ofmany inflammatory conditions, tumornecrosis factor-a (TNF-a) inhibitors

suppress the immune system, increasing a pa-tient’s risk of infection or reactivation of latenttuberculosis and the development of demyelin-ating disease or lymphoma.1-3 In recent years,the literature regarding the association of TNF-ainhibitors and malignant neoplasms other thanlymphoma has expanded to include solid organtumors. Immunosuppression and malignanttumors have been discussed in multiple studies,and the results strongly suggest an increased riskof skin carcinomas in immunosuppressed trans-plant recipients.4,5 Evidence also shows that thecorrelation is dependent on both the durationand the intensity of the immunosuppression,confirming causality.6

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Because of the inflammatory nature of thediseases treated by TNF-a inhibitors, it hasbeen difficult to confirm a causality of thedevelopment of malignant disease. One attemptto better determine the cause was a large studyof the risk of malignant neoplasms in patientswith rheumatoid arthritis (RA) in which the in-vestigators were able to control for the therapiesgiven. They found that among patients withRA, those treated with TNF-a inhibitors had agreater risk of development of nonmelanomaskin cancer.7 A similar study in patients withgranulomatosis with polyangiitis found anincreased incidence of solid organ malignantneoplasms in patients treated with etanerceptcompared with placebo.8

A potential mechanism of the increased riskof malignant disease with TNF-a inhibitors was

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FIGURE 1. Progressionwoman with inflammaAppearance of choroidaon April 23, 2013, shoposterior edge from 2arrowhead).

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discussed by van Horssen et al,9 who suggestedthat TNF-a receptors on tumor endothelialcells contribute to cytotoxicity and necrosis ofsolid tumors. Blockage of TNF-a in the pres-ence of solid tumors would prevent the host’simmunologic responses from combating thetumor or preventing its growth. Penn6 pro-posed a similar concept, that there is a decreasein cancer surveillance with immunosuppres-sant therapy.6 Tumor necrosis factor-a hasalso been used with peripheral limb infusionsto prevent in-transit metastases of peripheralmelanomas, with good outcomes.10,11 In vitrostudies have demonstrated paradoxical activityof TNF-a on cancers; these data suggest thatTNF-a increases melanocyte invasion.12,13

To our knowledge, we report the first casesof patients presenting with intraocular tumorsafter being treated with TNF-a inhibitors.

PATIENTS AND METHODSAfter institutional review board approval, westudied 3 cases of uveal melanoma occurringafter treatment with TNF-a inhibitors, 2from Mayo Clinic in Rochester, Minnesota,and 1 from Yale University in New Haven,Connecticut. The study period was February27, 2009, through July 15, 2013.

Case 1In November 2011, a 28-year-old woman wasdiagnosed as having inflammatory bowel diseaseand required multiple courses of corticosteroidsfor symptom control. Because of the difficulty inmanaging the disease, 6 months after diagnosis

of choroidal nevus to melanoma in a 28-year-oldtory bowel disease treated with infliximab. A,l nevus (arrow) on April 11, 2012. B, Image takenws the growth of the lesion by comparing the012 (black arrowhead) to that of 2013 (white

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the patient began treatment with infliximab,100-mg infusions every 8 weeks, and azathio-prine, 125 mg daily. With these medications,she was able to achieve and maintain clinicalremission. In April 2012, an asymptomaticchoroidal nevus had been detected in her righteye. The nevus, approximately 9�15 mm atthe base with no elevation, was more than 3mm from the fovea, and somemelanolipofuscin,but no subretinal fluid or drusen, was noted(Figure 1, A). Ten months after initiation ofinfliximab, the patient began to notice intermit-tent light flashes in her right eye, followed a fewweeks later by a persistent decrease in vision. Ex-amination revealed a choroidal melanoma,15.7�12.6�4.9 mm, and both fluid and mela-nolipofuscin (Figure 1, B).

Case 2A 67-year-old man was diagnosed as havingRA in 1985. He was treated with etanerceptuntil T-cell leukemia developed in 2007, forwhich he underwent chemotherapy and hadsince been symptom free. In 2009, diffusescleritis with choroidal thickening secondaryto his RA, which was being treated with leflu-nomide and prednisone, was detected in botheyes (Figure 2, A, B, and D).

Over the next 2 years, the patient was fol-lowed up in ophthalmology for the scleritis inboth eyes. Serial ultrasonography was per-formed to monitor the choroidal effusions. InJune 2010, leflunomide was switched to adali-mumab for treatment of his RA. The scleritisimproved in both eyes, but 16 months later,ultrasonography detected a pigmented choroidalmass measuring 8.1�9.7�3.0 mm in the pa-tient’s left eye without ciliary body involve-ment. His vision at that time was 20/50þ1 inthe right eye and 20/150þ1 in the left withintraocular pressure of 18 mm Hg in the righteye and 14 mm Hg in the left. The tumorcontinued to grow, and the patient elected tohave enucleation in January 2012, whichrevealed a 9.7�10.7�4.3-mm ciliochoroidalmelanoma (Figure 2, C).

Case 3Since 1996, a 64-year-old woman had under-gone ophthalmologic examination every 6months for observation of a choroidal nevusin her right eye. The patient was asymptomaticduring 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 manwith rheumatoid arthritis treated with etanercept, leflunomide, and adalimumab. Slit-lamp examination inFebruary 2009 revealed areas of diffuse scleritis (arrows) in the right (A) and left (B) eyes. C, Ultraso-nography of the left eye 16 months after beginning adalimumab detected melanoma (arrow). D, His-tologic examination revealed scleral thinning (arrows) with focal chronic inflammation due to chronicscleritis (hematoxylin-eosin, original magnification �40).

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associated subretinal fluid and was not locatedin the posterior pole. An examination in 1998recorded the lesion as 4.5�4.5 mm at the basewith a thickness of 1 mm and noted the pres-ence of extensive drusen.

In 2010, the patient began taking subcu-taneous adalimumab, 40 mg every otherweek, for treatment of recently diagnosedCrohn disease. She had not taken any immu-nomodulators before this time. The followingyear, the nevus appeared to have progressed,and the patient was referred to a retinaspecialist because of concern about mela-noma. At her examination in March 2011,the lesion measured 13 mm in diameter andwas 4.9 mm thick (Figure 3). The patient re-ported no symptoms at the time, and herbest corrected visual acuity was 20/20 in theright eye and 20/25 in the left with intraocularpressure of 14 mm Hg bilaterally. A trans-scleral biopsy was performed for confirmationof the choroidal melanoma, and the patientwas treated with a brachytherapy device.

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DISCUSSIONThe literature supports that immunosuppres-sion increases a patient’s risk of overall malig-nancy. Evidence also suggests that this is trueof melanomasdimmunosuppression increasesa patient’s risk of development of cutaneousmelanoma to 3.2 times that of the generalpopulation.14 Alaibac et al15 also proposedthat the immune system acts to suppress mel-anocytic growth.

Numerous cases concerning developmentof malignant neoplasms after beginning treat-ment with a TNF-a inhibitor have also beenreported. Esser et al16 and Wong et al17

described cases in which rapid tumor develop-ment followed the administration of inflixi-mab. Etanercept and adalimumab reportedlycaused a recurrence of latent metastatic mela-noma 1 month after initiation of etanerceptin one patient and 6 months after initiationof adalimumab treatment in another.18

Meta-analyses focusing on the relationshipof TNF-a inhibition and melanoma risk have

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FIGURE 3. Progression of a choroidal nevus that had been monitored for 15 years to melanoma in a64-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).

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yielded conflicting results. For example, Nar-done et al19 reported a significant association be-tween antieTNF-a agents and the developmentof melanoma. With these results, they suggestedthat the US Food and Drug Administrationstrengthen their labeling for antieTNF-a medi-cations. However, studies by Askling et al20 andothers21,22 were unable to verify this increasedrisk. Some investigators have suggested thatthe conflicting data might be due to potentialpublication biases and sponsorship of studiesby drug manufacturers.23 Research independentof the pharmaceutical industry is needed, as wellas the use of larger populations, longer follow-up, and better reporting of adverse effects withinthe studies.

A population cohort study in Sweden foundthat patients with RA treated with TNF-a inhib-itors had a 1.5-fold increased risk of invasivecutaneous melanoma compared with the gen-eral population.24 This increased risk was notseen in patients whose RA was treated withnonbiological medications. Of further interest,a dramatically increased risk was found inmen taking TNF-a inhibitors compared withwomen, with hazard ratios of 2.7 and 1.2,respectively.24

Although cutaneous and uveal melanomasshare a melanocytic origin, important differ-ences in genetic sequence variations havebeen identified. Van Raamsdonk et al25 notedthat sequence variations of BRAF, NRAS, andKIT are found in cutaneous melanoma butnot in uveal melanoma. The converse is alsodiscussed in the literature. Sequence variations

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in GNAQ and GNA11 are found in most uvealmelanomas but in only 6% of cutaneous mela-nomas.26 This evidence suggests an evolu-tionary process that differs in the 2 forms ofmelanoma, raising concern about reliance solelyon studies focused on cutaneous melanomas.

Our cases add to the growing literature sug-gesting a correlation between TNF-a inhibitorsand the development of malignant neoplasms.Our patients had a history of eye abnormalitiesbefore the development of the melanoma, 2with choroidal nevi and 1 with chronic diffusescleritis. A preexisting choroidal nevus is aknown risk factor for the development of mel-anoma. In addition, our findings support theproposal by Smith and Skelton27 that TNF-areceptor therapy may lessen the immune sys-tem’s control over subclinical tumors. Patientswith chronically inflamed organs are also athigher risk of development of solid malignanttumors.28,29 This increased risk in patientswith chronic inflammation could explain thedevelopment of the melanoma in our patientwith diffuse scleritis.

Because our case series is small, there arelimitations in the application of our findingsto larger populations. Currently, TNF-a inhib-itors are used so commonly that the cases couldhave occurred even in the absence of their use.However, our cases add to the growing litera-ture suggesting a correlation between TNF-ainhibitors and the development of malignantneoplasms. The variability of the results oflarger studies on this topic suggests that furthernonbiased research should be undertaken to

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determine which patients are at risk for tumordevelopment with TNF-a antagonist treat-ment. Knowledge of which risk factors arepertinent would allow physicians to determinethe safest treatment for their patients. Determi-nation of long-term safety is especially impor-tant because recent evidence supports the useof TNF-a inhibition to treat ocular disease.30

Physicians should be mindful of the recommen-dations from the risk factor analysis by Shieldset al31 in patients that have a choroidal nevusbut those who are using TNF-a inhibitorsshould have more frequent evaluations thancomparable non-immunosuppressed patients.

CONCLUSIONOur 3 cases of uveal melanocytic tumorsoccurring after the use of TNF-a inhibitorsadd to the growing literature suggesting a cor-relation between TNF-a inhibitors and thedevelopment of malignant neoplasms. Consid-ering the association between cutaneous mela-noma and TNF-a inhibitors, we recommendthat patients have an eye examination beforeinitiation of TNF-a inhibitors, and thosewith preexisting nevi should be followed upat regular intervals.

Abbreviations and Acronyms: TNF-a = tumor necrosisfactor-a; RA = rheumatoid arthritis

Grant Support: This work was supported in part by agenerous grant from Terrance and Judi Paul and an unre-stricted grant from Research to Prevent Blindness, Inc.

Correspondence: Address to Jose S. Pulido, MD, MS, MPH,Department of Ophthalmology and Department of Molec-ular Medicine, Mayo Clinic, 200 First St SW, Rochester, MN55905 (pulido.jose@mayo.edu).

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