Antitumor necrosis factor alpha (anti-TNFα) agents have substantially altered the management of inflammatory bowel diseases (IBD). Their benefits must however be weighed against increased risks for infections, lymphoma, and possibly other malignancies. We report on a 27-year-old man, with a six-year history of ulcerative colitis maintained on mesalamine suppositories, presenting with clinical, radiographic and biopsy evidence of an acute colitis flare. Due to the refractory nature of his disease, infliximab was started, resulting in induction of remission within six weeks. Three months after the first dose of infliximab, the patient was diagnosed with a testicular mixed germ cell tumor requiring orchiectomy. Four cases of testicular cancer development among patients using anti-TNFα agents have been identified. Given the prevalence of IBD in young men and recent suggestions for “top–down therapy,” testicular cancer as a potential complication of anti-TNFα agents should be further explored on a population basis.
Antitumor necrosis factor alpha agents
Testicular germ cell cancer
Infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha (anti-TNFα), is effective for inducing and maintaining response and remission in moderate to severe ulcerative colitis.1 Its benefits need to be balanced against increased risks for infections, lymphoma, and possibly other malignancies and autoimmune phenomenon.2 We report a man diagnosed with testicular germ cell cancer three months after his first dose of induction infliximab for management of ulcerative colitis.
2 Case report
A 27-year-old man diagnosed six years earlier with ulcerative proctitis, maintained in remission with mesalamine suppositories, was presented to the emergency department with symptoms and signs consistent with a colitis flare. At colonoscopy, circumferential inflammatory changes and ulcerations were present from the rectum to the mid transverse colon; the colonoscope could not be advanced safely beyond this point. Biopsies confirmed intense diffuse chronic inflammation with cryptitis and crypt abscesses consistent with ulcerative colitis. Despite hydrocortisone enemas, ciprofloxacin, metronidazole, oral prednisone and intravenous methylprednisolone, remission was not induced. Standard induction infliximab was started with subsequent infusions two and six weeks later. The last dose was associated with a return to clinical remission.
Three months after the first dose of infliximab, the patient noted acute right-sided testicular swelling and tenderness and a palpable hard mass three times the normal size. An initial clinical diagnosis of epididymitis was made, but a course of antibiotics resulted in no symptomatic relief, prompting investigation with a scrotal ultrasound. A 5 × 3 × 3.7-cm irregular heterogeneous mass occupying the entire right testicle was noted. Abdominal and pelvic computed tomography immediately prior to start of infliximab administration did not show obvious evidence of an aberrant scrotal mass, although the scan was a routine one and not a dedicated testicular image. Following urological assessment, a right inguinal orchiectomy was performed with histology, confirming a mixed seminomatous (70%) and non seminomatous (30%) germ cell tumor. There was no penetration to the tunica albuginea, rete testis or epididymis, nor was there any lymphovascular invasion; the resection margins were clear. Abdominal and pelvic computed tomography postoperatively did not show evidence of nodal or metastatic disease, and he was therefore categorized as clinical stage I disease. Due to the malignancy diagnosis, infliximab was discontinued, and perioperatively he developed clinical signs of recurrent colitis, confirmed on flexible sigmoidoscopy. Oral prednisone, with azathioprine maintenance, was recommended for disease control. Due to their side effect profiles, the patient chose instead to use oral and suppository formulations of mesalamine, agents he previously responded to. On reassessment seven months after the last dose of infliximab, the disease remained clinically quiescent.
Anti-TNFα agents have a role in the management of not only severe IBD but also rheumatoid arthritis and seronegative spondyloarthropathies such as ankylosing spondylitis and psoriatic arthritis. Their significant clinical benefits must however be weighed against the adverse effects of increased risks for infections, non-Hodgkin's lymphoma, and possibly other malignancies.2
Testicular cancer temporally developing after administration of anti-TNFα agents has not been previously independently described. However, it has been reported as part of registry review and clinical trials. A case of testicular seminoma necessitating orchiectomy diagnosed five years after a patient's last infliximab infusion was identified in a Spanish registry of IBD patients treated with this agent and followed for nine years.3 In Keystone et al.'s double-blinded placebo-controlled study evaluating adalimumab use in rheumatoid arthritis patients receiving concomitant methotrexate, a case of testicular seminoma was diagnosed in the adalimumab group eight weeks into the study.4 In the double-blinded placebo control ASSERT trial, ankylosing spondylitis patients were randomized to either 96 weeks of infliximab therapy or a second group initially on placebo with crossover to infliximab. One patient in the crossover group developed non seminomatous testicular cancer approximately one year after the last dose of infliximab.5 More recently, Diak et al. conducted a review of the United States Food and Drug Administration's Adverse Event Reporting System, identifying 48 postmarketing cases of malignancy in children using anti-TNFα agents, one of which was a 16-year-old boy who developed yolk sac tumor one month after commencement of etanercept for juvenile idiopathic arthritis.6
Although it is unclear if these cases would have developed in the absence of anti-TNFα agents, a biologic association is plausible considering TNFα's role in the physiological mechanisms governing germ cell apoptosis. In a model of autoimmune orchitis, a form of chronic inflammation, binding of TNFα to TNF receptor 1 (a death domain containing transmembrane protein within the family of death receptors) on germ cells induced their apoptosis, likely via activation of caspase and/or mitochondrial pathways like Bid and Bax. Employing Etanercept neutralized TNFα's apoptotic effect.7 Since aberrant immune responses are thought to contribute to IBD as well as certain co-existing conditions like primary sclerosing cholangitis, autoimmune orchitis may yet represent another site of dysregulation. Indeed, circulating antibodies to human spermatozoa have been documented in IBD patients.8 Use of anti-TNFα agents in these susceptible individuals with inflammatory conditions, where high concentrations of TNFα have a pro-apoptotic effect, may contribute to uninhibited germ cell proliferation.
TNF's antitumor effects on testicular cancer itself have been more directly demonstrated by Miki et al., who administered recombinant human TNF within two histological types of human testicular cancers heterotransplanted in mice, resulting in clinical and histological tumor regression.9
Considering TNFα's pro-apoptotic role in inflammatory states, and antitumor effects against testicular germ cell tumors, administration of anti-TNFα agents may contribute to de novo or accelerated testicular germ cell tumor development.
Despite the lack of evidence for malignancy prior to infliximab commencement, considering the large size of the testicular mass, it is possible clinically occult disease existed before treatment. Infliximab, as a catalyst, may have exacerbated this predisposition, although it directly contributing to de novo neoplastic development remains a possibility. Since IBD frequently targets young adult men, the population group with the highest incidence of testicular germ cell tumors, studies using population based registries to compare the incidence of this type of malignancy between IBD and rheumatology patients using anti-TNFα agents and baseline groups are warranted. Confirmation of this clinical observation is particularly important given the recent idea of “top–down therapy” in both IBD and certain rheumatological conditions, whereby intensive therapies like biologics would be introduced early in patients, in hopes of interrupting disease progression, and avoiding both disease and medication related complications.10,11 Clinically, it may be prudent for scrotal examinations to be conducted by clinicians prior to initiating and during treatment of anti-TNFα, and by patients after completion of therapy.
Conflict of interest
J. W. was involved in the acquisition and interpretation of data and the drafting of the article. B. B., B. S. and E. Y. took clinical care of the patient and revised the article critically for important intellectual content. N. C. took clinical care of the patient, conceived and designed the study, and revised it critically. No funding supported this manuscript.
Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial Arthritis Rheum 5020041400–1411