Case Report: Lymphoma Arising in an Ileal Pouch Anal Anastomosis After Immunomodulatory Therapy for Inflammatory Bowel Disease
2006; Elsevier BV; Volume: 4; Issue: 8 Linguagem: Inglês
10.1016/j.cgh.2006.05.024
ISSN1542-7714
AutoresLauren K. Schwartz, Michelle Kang Kim, Morton Coleman, Simon Lichtiger, Amy Chadburn, Ellen Scherl,
Tópico(s)Immunodeficiency and Autoimmune Disorders
ResumoThe risk of lymphoma in inflammatory bowel disease (IBD) has raised concerns regarding the lymphogenic potential of immunomodulatory therapy. The link between immunosuppressive therapy and lymphoma risk is well established in patients with solid organ transplantations. In this population, it is postulated that lymphocytes infected with the Epstein-Barr virus (EBV) proliferate unchecked due to impaired cell-mediated immunity. A similar phenomenon may occur in IBD patients treated with multiple immunomodulators and biological agents. In this report, we describe a case of EBV-positive non-Hodgkin's lymphoma arising in the ileal pouch of a patient with ulcerative colitis. This patient was maintained on prednisone (>20 mg/day) for 8 months, cyclosporine for 7 months, and 6-mercaptopurine for nearly 2 years prior to a single infusion of infliximab (5 mg/kg). The cumulative effects of more than three agents, simultaneously and/or sequentially, may simulate posttransplantation immunosuppression and pose a significant threat of malignancy. Such patients may warrant more aggressive diagnostic surveillance and evaluation. The risk of lymphoma in inflammatory bowel disease (IBD) has raised concerns regarding the lymphogenic potential of immunomodulatory therapy. The link between immunosuppressive therapy and lymphoma risk is well established in patients with solid organ transplantations. In this population, it is postulated that lymphocytes infected with the Epstein-Barr virus (EBV) proliferate unchecked due to impaired cell-mediated immunity. A similar phenomenon may occur in IBD patients treated with multiple immunomodulators and biological agents. In this report, we describe a case of EBV-positive non-Hodgkin's lymphoma arising in the ileal pouch of a patient with ulcerative colitis. This patient was maintained on prednisone (>20 mg/day) for 8 months, cyclosporine for 7 months, and 6-mercaptopurine for nearly 2 years prior to a single infusion of infliximab (5 mg/kg). The cumulative effects of more than three agents, simultaneously and/or sequentially, may simulate posttransplantation immunosuppression and pose a significant threat of malignancy. Such patients may warrant more aggressive diagnostic surveillance and evaluation. See editorial on page 976. See editorial on page 976. The risk of lymphoma in inflammatory bowel disease (IBD) has raised concerns regarding the lymphogenic potential of immunomodulatory therapy. Azathioprine (AZA), 6-mercaptopurine (6-MP), and cyclosporine (CSA) are immunomodulators used to treat IBD. Infliximab, a chimeric monoclonal antibody against human tumor necrosis factor alpha (TNF-α), is a targeted immunomodulator used for medically refractory and fistulizing Crohn's disease. Infliximab was also recently approved by the US Food and Drug Administration (FDA) for the treatment of moderate ulcerative colitis (UC).1Rutgeerts P. Sandborn W.J. Feagan B.G. et al.Infliximab for induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2005; 353: 2462-2476Crossref PubMed Scopus (3184) Google Scholar The link between immunosuppressive therapy and lymphoma risk is well established in patients who have undergone solid organ transplantation2Opelz G. Dohler B. Lymphomas after solid organ transplantation a collaborative transplant study report.Am J Transplant. 2004; 4: 222-230Crossref PubMed Scopus (875) Google Scholar, 3Opelz G. Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients.Lancet. 1993; 342: 1514-1516Abstract PubMed Scopus (614) Google Scholar and, to a lesser extent, in those with rheumatoid arthritis (RA).4Beauparlant P. Papp K. Haraoui B. The incidence of cancer associated with the treatment of rheumatoid arthritis.Semin Arthritis Rheum. 1999; 29: 148-158Abstract Full Text PDF PubMed Scopus (82) Google Scholar In the solid organ transplant population, over 80% of non-Hodgkin's lymphomas contain the genome of the Epstein-Barr virus (EBV).5Reijasse D. Le Pendeven C. Cosnes J. et al.Epstein-Barr virus viral load in Crohn's disease effect of immunosuppressive therapy.Inflamm Bowel Dis. 2004; 10: 85-90Crossref PubMed Scopus (64) Google Scholar It is postulated that EBV-infected lymphocytes proliferate unchecked in the setting of impaired cell-mediated immunity, giving rise to lymphoma. The development of EBV-positive lymphomas in patients with IBD treated with immunomodulators has been reported.6Calaminici M.R. Sheaff M.T. Norton A.J. et al.Ileocaecal Epstein-Barr virus–positive lymphoproliferative disorder complicating Crohn's disease.Histopathology. 1999; 35: 388-390Crossref PubMed Scopus (21) Google Scholar, 7Dayharsh G.A. Loftus Jr, E.V. Sandborn W.J. et al.Epstein-Barr virus–positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine.Gastroenterology. 2002; 122: 72-77Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar, 8Kumar S. Fend F. Quintanilla-Martinez L. et al.Epstein-Barr virus–positive primary gastrointestinal Hodgkin's disease association with inflammatory bowel disease and immunosuppression.Am J Surg Pathol. 2000; 24: 66-73Crossref PubMed Scopus (112) Google Scholar, 9Li S. Borowitz M.J. Primary Epstein-Barr virus–associated Hodgkin disease of the ileum complicating Crohn disease.Arch Pathol Lab Med. 2001; 125: 424-427PubMed Google Scholar, 10Losco A. Gianelli U. Cassani B. et al.Epstein-Barr virus–associated lymphoma in Crohn's disease.Inflamm Bowel Dis. 2004; 10: 425-429Crossref PubMed Scopus (43) Google Scholar, 11Wong N.A. Herbst H. Herrmann K. et al.Epstein-Barr virus infection in colorectal neoplasms associated with inflammatory bowel disease detection of the virus in lymphomas but not in adenocarcinomas.J Pathol. 2003; 201: 312-318Crossref PubMed Scopus (58) Google Scholar Most IBD-related lymphomas develop at sites of active intestinal inflammation in patients with long-standing disease. Less common are lymphomas arising from the pouch after proctocolectomy with ileal pouch anal anastomosis (IPAA). To date, only 2 cases of pouch-related lymphomas (the EBV status of which was not reported) have been documented in the literature.12Frizzi J.D. Rivera D.E. Harris J.A. et al.Lymphoma arising in an S-pouch after total proctocolectomy for ulcerative colitis report of a case.Dis Colon Rectum. 2000; 43: 540-543Crossref PubMed Scopus (12) Google Scholar, 13Nyam D.C. Pemberton J.H. Sandborn W.J. et al.Lymphoma of the pouch after ileal pouch-anal anastomosis report of a case.Dis Colon Rectum. 1997; 40: 971-972Crossref PubMed Scopus (36) Google Scholar In this report, we describe a case of EBV-positive non-Hodgkin's lymphoma (NHL) arising in the ileal pouch of a patient with UC. Notably, this patient had UC of relatively short duration and was treated with a combination of 4 immunomodulators before the lymphoma developed. Four years before being diagnosed with lymphoma, a 29-year-old man developed hematochezia and was diagnosed with ulcerative proctitis. A year later, his disease progressed to involve the entire colon. Treatment with oral steroids was started but proved unsuccessful. Parenteral steroids also yielded little benefit. Intravenous CSA (4 mg/kg) was ultimately added, and the patient's symptoms improved. One month into the course of oral CSA therapy (8 mg/kg), 6-MP therapy was started. After 1 year of maintenance therapy with 6-MP, the patient self-discontinued the medication and was taking aminosalicylate (ASA) compounds alone. A significant flare-up led to the reinstitution of 6-MP as well as oral steroids. He remained on 6-MP and ASA derivatives for the next 2 years. Over this period, the patient continued to experience flare-ups. Oral steroids and CSA were frequently added to his medical regimen. The aggregate time on prednisone (>20 mg/day) was 8 months, that for CSA was 7 months, and that for 6-MP was nearly 2 years. A single infusion of infliximab (5 mg/kg) was also administered, but this proved ineffective. The patient then underwent a 2-stage subtotal colectomy with IPAA. The pathology was consistent with UC. Postoperatively, the patient developed severe diarrhea with leakage of stool. Pouchography and manometric studies were normal. He was diagnosed with irritable pouch syndrome and treated with antidiarrheal, bulking, and antispasmodic agents, as well as a low-dose tricyclic antidepressant. He also received a course of ciprofloxacin for presumed pouchitis. Despite these measures, his diarrhea persisted. Four months after the IPAA, pouchoscopy was performed and revealed normal findings. No biopsy specimens were obtained at that time. Over the next several months, the patient's condition continued to deteriorate; severe diarrhea, urgency, and weight loss became debilitating. Eleven months after the IPAA, repeat pouchoscopy revealed a polypoid friable mass in the distal pouch (Figure 1A, B). Pathology showed an EBV-positive, CD20-negative, PAX5-positive, and Oct-2 positive diffuse large B-cell lymphoma with immunoblastic features (Figure 2A, B). Polymerase chain reaction analysis revealed a clonal B-cell population. A positron emission tomography scan revealed lymphoma in the cervical lymph nodes, mediastinum, and pelvis. The patient had no family history of lymphoma or other malignancy.Figure 2(A) Routine histological sections showing the presence of large atypical lymphoid cells with prominent nucleoli (black arrows). Mitotic figures are easily identified (white arrows). Hematoxylin-eosin; original magnification 20×. (B) In situ hybridization for EBV using an EBER probe shows many EBV-infected cells as identified by the dark-brown intranuclear positivity. In situ hybridization; original magnification 40×.View Large Image Figure ViewerDownload (PPT) The patient was treated with 2 cycles of CODBLAM IV, consisting of cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine. He subsequently underwent excision of the pouch, which was free of disease. He then completed 4 more cycles of chemotherapy. Three years later, he continues to show no evidence of recurrent lymphoma or gastrointestinal symptoms. Lymphoma occurring in the setting of IBD has been well documented in the medical literature. As early as 1928, Bargen reported 2 cases of NHL in patients with UC.14Bargen J.A. Chronic ulcerative colitis associated with malignant disease, 1928.Dis Colon Rectum. 1994; 37: 727-730Crossref PubMed Scopus (19) Google Scholar Since that time, there have been approximately 70 case reports describing intestinal and extraintestinal lymphoma in patients with IBD. Despite these findings, however, the relationship between IBD and lymphoma risk remains controversial. Six large population-based studies have not shown a significant association between IBD and lymphoma.15Bebb J.R. Logan R.P. Review article does the use of immunosuppressive therapy in inflammatory bowel disease increase the risk of developing lymphoma?.Aliment Pharmacol Ther. 2001; 15: 1843-1849Crossref PubMed Scopus (30) Google Scholar, 16Ekbom A. Helmick C. Zack M. et al.Extracolonic malignancies in inflammatory bowel disease.Cancer. 1991; 67: 2015-2019Crossref PubMed Scopus (205) Google Scholar, 17Karlen P. Lofberg R. Brostrom O. et al.Increased risk of cancer in ulcerative colitis a population-based cohort study.Am J Gastroenterol. 1999; 94: 1047-1052Crossref PubMed Google Scholar, 18Lewis J.D. Bilker W.B. Brensinger C. et al.Inflammatory bowel disease is not associated with an increased risk of lymphoma.Gastroenterology. 2001; 121: 1080-1087Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 19Loftus Jr, E.V. Tremaine W.J. Habermann T.M. et al.Risk of lymphoma in inflammatory bowel disease.Am J Gastroenterol. 2000; 95: 2308-2312Crossref PubMed Google Scholar, 20Palli D. Trallori G. Bagnoli S. et al.Hodgkin's disease risk is increased in patients with ulcerative colitis.Gastroenterology. 2000; 119: 647-653Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 21Persson P.G. Karlen P. Bernell O. et al.Crohn's disease and cancer a population-based cohort study.Gastroenterology. 1994; 107: 1675-1679PubMed Google Scholar Only 1 population-based study has detected an increased risk of lymphoma among men with Crohn's disease.22Bernstein C.N. Blanchard J.F. Kliewer E. et al.Cancer risk in patients with inflammatory bowel disease a population-based study.Cancer. 2001; 91: 854-862Crossref PubMed Scopus (1025) Google Scholar In contrast, most cohort studies based at tertiary referral centers support an increased relative risk of lymphoma in patients with IBD.23Aithal G.P. Mansfield J.C. Review article the risk of lymphoma associated with inflammatory bowel disease and immunosuppressive treatment.Aliment Pharmacol Ther. 2001; 15: 1101-1108Crossref PubMed Scopus (78) Google Scholar, 24Greenstein A.J. Gennuso R. Sachar D.B. et al.Extraintestinal cancers in inflammatory bowel disease.Cancer. 1985; 56: 2914-2921Crossref PubMed Scopus (194) Google Scholar This discrepancy may be related to a population bias at referral centers, where patients are more likely to have severe IBD, to receive aggressive immunomodulatory therapy, and to have multiple illnesses. The development of lymphoma in patients with IBD may be related to chronic inflammation or immunomodulatory therapy. Several pathogenic mechanisms for the development of lymphoma have been proposed, including increased carcinogen exposure secondary to a disturbed mucosal barrier and increased cell turnover resulting in accumulation of genetic mutations.23Aithal G.P. Mansfield J.C. Review article the risk of lymphoma associated with inflammatory bowel disease and immunosuppressive treatment.Aliment Pharmacol Ther. 2001; 15: 1101-1108Crossref PubMed Scopus (78) Google Scholar Iatrogenic immunosuppression is also thought to play a role in EBV-positive lymphomas by disrupting the cell-mediated immune system and allowing EBV-infected lymphocytes to proliferate unchecked. EBV-positive lymphomas have been reported in patients with IBD receiving immunomodulatory therapy. In the pathology literature, the presence of the EBV genome has been described in 4 of 7 cases of colorectal NHL in patients with UC and in 2 of 2 cases of colorectal NHL in patients with Crohn's disease.11Wong N.A. Herbst H. Herrmann K. et al.Epstein-Barr virus infection in colorectal neoplasms associated with inflammatory bowel disease detection of the virus in lymphomas but not in adenocarcinomas.J Pathol. 2003; 201: 312-318Crossref PubMed Scopus (58) Google Scholar Case reports have also described 2 patients with EBV-positive NHL and 4 patients with EBV-positive Hodgkin's lymphoma after treatment for Crohn's disease.6Calaminici M.R. Sheaff M.T. Norton A.J. et al.Ileocaecal Epstein-Barr virus–positive lymphoproliferative disorder complicating Crohn's disease.Histopathology. 1999; 35: 388-390Crossref PubMed Scopus (21) Google Scholar, 8Kumar S. Fend F. Quintanilla-Martinez L. et al.Epstein-Barr virus–positive primary gastrointestinal Hodgkin's disease association with inflammatory bowel disease and immunosuppression.Am J Surg Pathol. 2000; 24: 66-73Crossref PubMed Scopus (112) Google Scholar, 9Li S. Borowitz M.J. Primary Epstein-Barr virus–associated Hodgkin disease of the ileum complicating Crohn disease.Arch Pathol Lab Med. 2001; 125: 424-427PubMed Google Scholar, 10Losco A. Gianelli U. Cassani B. et al.Epstein-Barr virus–associated lymphoma in Crohn's disease.Inflamm Bowel Dis. 2004; 10: 425-429Crossref PubMed Scopus (43) Google Scholar Immunomodulatory therapy may be linked to the presence of EBV in the IBD population. A study comparing lymphoma rates before and after the introduction of AZA/6-MP as maintenance medications found that 1 of 6 lymphomas was EBV-positive before these medications were introduced and 6 of 12 lymphomas were EBV-positive afterward. Notably, 5 of the 7 patients with EBV-positive lymphomas had been treated with 6-MP/AZA, whereas only 1 of 11 EBV-negative patients had been exposed to these medications.7Dayharsh G.A. Loftus Jr, E.V. Sandborn W.J. et al.Epstein-Barr virus–positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine.Gastroenterology. 2002; 122: 72-77Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar AZA and its metabolite 6-MP are immunomodulatory agents implicated in the development of lymphoma in patients with IBD. Studies examining the risk of lymphoma associated with AZA/6-MP have yielded variable results. Heterogeneity in the type, dose, and duration of immunomodulatory therapy may be responsible for this discrepancy. Standard weight-based dosages for AZA and 6-MP are 2.5 mg/kg/day and 1.5 mg/kg/day, respectively.25Dubinsky M.C. Azathioprine, 6-mercaptopurine in inflammatory bowel disease pharmacology, efficacy, and safety.Clin Gastroenterol Hepatol. 2004; 2: 731-743Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 26Sandborn W.J. Rational dosing of azathioprine and 6-mercaptopurine.Gut. 2001; 48: 591-592Crossref PubMed Scopus (121) Google Scholar, 27Sandborn W.J. Tremaine W.J. Wolf D.C. et al.North American Azathioprine Study GroupLack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease.Gastroenterology. 1999; 117: 527-535Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar Most studies assessing lymphoma risk in the IBD population include patients who have received suboptimal dosages. Five of these studies with suboptimal dosing failed to demonstrate an increased risk of lymphoma.28Bouhnik Y. Lemann M. Mary J.Y. et al.Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine.Lancet. 1996; 347: 215-219Abstract PubMed Scopus (378) Google Scholar, 29Connell W.R. Kamm M.A. Dickson M. et al.Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease.Lancet. 1994; 343: 1249-1252Abstract PubMed Scopus (467) Google Scholar, 30Fraser A.G. Orchard T.R. Robinson E.M. et al.Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine.Aliment Pharmacol Ther. 2002; 16: 1225-1232Crossref PubMed Scopus (171) Google Scholar, 31Korelitz B.I. Mirsky F.J. Fleisher M.R. et al.Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine.Am J Gastroenterol. 1999; 94: 3248-3253Crossref PubMed Google Scholar, 32Lewis J.D. Schwartz J.S. Lichtenstein G.R. Azathioprine for maintenance of remission in Crohn's disease benefits outweigh the risk of lymphoma.Gastroenterology. 2000; 118: 1018-1024Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar One negative study used optimal dosing, but did so over a shorter time span than studies demonstrating increased lymphoma risk, suggesting that both dose and duration influence the development of lymphoma.33Present D.H. Meltzer S.J. Krumholz M.P. et al.6-Mercaptopurine in the management of inflammatory bowel disease short- and long-term toxicity.Ann Intern Med. 1989; 111: 641-649Crossref PubMed Scopus (710) Google Scholar Interestingly, 3 of the negative studies documented cases of CNS lymphoma, which, although rare in the general population, occurs at high frequency in immunosuppressed solid organ transplant recipients.28Bouhnik Y. Lemann M. Mary J.Y. et al.Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine.Lancet. 1996; 347: 215-219Abstract PubMed Scopus (378) Google Scholar, 31Korelitz B.I. Mirsky F.J. Fleisher M.R. et al.Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine.Am J Gastroenterol. 1999; 94: 3248-3253Crossref PubMed Google Scholar, 33Present D.H. Meltzer S.J. Krumholz M.P. et al.6-Mercaptopurine in the management of inflammatory bowel disease short- and long-term toxicity.Ann Intern Med. 1989; 111: 641-649Crossref PubMed Scopus (710) Google Scholar In contrast to these reports, other studies have demonstrated an increased risk of lymphoma after purine analog therapy. In a study in which standard dosages were approximated (AZA, 2–2.5 mg/kg/day), a significantly high incidence of NHL was observed among IBD patients (standardized incidence ratio, 31.2; 95% confidence interval, 2.0–85; P = .0001). Of the 4 patients who developed lymphoma, 2 received AZA, 1 received methotrexate, and 1 received a combination of methotrexate plus CSA.34Farrell R.J. Ang Y. Kileen P. et al.Increased incidence of non-Hodgkin's lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low.Gut. 2000; 47: 514-519Crossref PubMed Scopus (200) Google Scholar Another study found an increased risk of EBV-positive lymphomas in the setting of low-dose AZA (50–125 mg/day).7Dayharsh G.A. Loftus Jr, E.V. Sandborn W.J. et al.Epstein-Barr virus–positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine.Gastroenterology. 2002; 122: 72-77Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar Although lower dosages were used, the longer duration of treatment (3–6 years) in this population might have resulted in increased lymphoma risk over time. Notably, none of these studies evaluated patient variation in active metabolite (thioguanine nucleotide) concentration or white blood cell count; these factors reflect the level of AZA/6-MP activity and may correlate with the associated risk of lymphoma. Most recently, a meta-analysis demonstrated a 4-fold-higher risk of lymphoma in patients treated with AZA or 6-MP compared with the general population.35Kandiel A. Fraser A.G. Korelitz B.I. et al.Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.Gut. 2005; 54: 1121-1125Crossref PubMed Scopus (678) Google Scholar Whether this risk warrants a change in treatment strategy is uncertain. According to a decision analysis model, AZA must result in a >9.8-fold increased risk of lymphoma for therapy with alternative medications to be preferred.32Lewis J.D. Schwartz J.S. Lichtenstein G.R. Azathioprine for maintenance of remission in Crohn's disease benefits outweigh the risk of lymphoma.Gastroenterology. 2000; 118: 1018-1024Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar Using this model, a relative risk of 4 does not preclude the use of AZA or 6-MP. That said, the relative risk estimated by the meta-analysis may be artificially low, because most of the included studies used suboptimal dosing. If the risk is in fact higher, then continuing these medications might not be a safe strategy. Infliximab is a powerful biologic agent that, like the purine analogs, carries a risk for lymphoma. Available safety data are derived largely from clinical trials, case reports, and postmarketing surveillance. In 2 blinded, placebo-controlled trials of maintenance infliximab therapy for Crohn's disease, 2 cases of NHL were identified.36Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn's disease the ACCENT I randomised trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3657) Google Scholar, 37Rutgeerts P. D'Haens G. Targan S. et al.Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease.Gastroenterology. 1999; 117: 761-769Abstract Full Text Full Text PDF PubMed Scopus (1071) Google Scholar Another study evaluating the safety profile of infliximab among 500 patients at the Mayo Clinic identified only 1 case of NHL.38Colombel J.F. Loftus Jr, E.V. Tremaine W.J. et al.The safety profile of infliximab in patients with Crohn's disease the Mayo Clinic experience in 500 patients.Gastroenterology. 2004; 126: 19-31Abstract Full Text Full Text PDF PubMed Scopus (848) Google Scholar Postmarketing safety reports have identified 95 additional cases of lymphoma among infliximab-treated patients (73% RA; 21% Crohn's disease). Ten cases of lymphoma have also been identified among RA patients treated with adalimumab, a completely humanized TNF-α antagonist scheduled to soon receive FDA approval for treating Crohn's disease.39Hotline ACoR.in: FDA meeting: update on the safety of new drugs for rheumatoid arthritis (RA) and TNF inhibitors. Vol. 2005. American College of Rheumatology, 2003Google Scholar Experience with solid organ transplantations indicates that lymphomas may arise in the setting of intense immunosuppression. In a large retrospective study, .2% of kidney transplant recipients and 1.2% of heart transplant recipients developed NHL during the first posttransplantation year. These rates are about 20 and 120 times higher, respectively, than the rate in the general population.3Opelz G. Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients.Lancet. 1993; 342: 1514-1516Abstract PubMed Scopus (614) Google Scholar It is speculated that the intensity of immunosuppression among heart transplant recipients is responsible for the higher incidence of lymphoma. Supporting this theory is the fact that dosage reductions in immunosuppressive therapy in this subgroup have led to reduced rates of lymphoma in recent years.2Opelz G. Dohler B. Lymphomas after solid organ transplantation a collaborative transplant study report.Am J Transplant. 2004; 4: 222-230Crossref PubMed Scopus (875) Google Scholar Cases of posttransplantation lymphoma are typically EBV-positive B-cell proliferations.40Chadburn A. Cesarman E. Knowles D.M. Molecular pathology of posttransplantation lymphoproliferative disorders.Semin Diagn Pathol. 1997; 14: 15-26PubMed Google Scholar, 41Knowles D.M. Cesarman E. Chadburn A. et al.Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders.Blood. 1995; 85: 552-565PubMed Google Scholar In this case report, we have described the development of an EBV-positive B-cell lymphoma arising in the ileal pouch of a patient with UC. To date, only 2 other cases of pouch-associated lymphomas have been described. Adenocarcinomas arising from retained rectal mucosa in the anal transition zone and from the ileal mucosa have also been reported.42Stein R.B. Lichtenstein G.R. Complications after ileal pouch anal anastomosis.Semin Gastrointest Dis. 2000; 11: 2-9PubMed Google Scholar One case documents a low-grade B-cell lymphoma arising in an S-pouch 8 years after total proctocolectomy and pouch construction.12Frizzi J.D. Rivera D.E. Harris J.A. et al.Lymphoma arising in an S-pouch after total proctocolectomy for ulcerative colitis report of a case.Dis Colon Rectum. 2000; 43: 540-543Crossref PubMed Scopus (12) Google Scholar The other report describes a large-cell lymphoma of the pouch that did not express pan–B-cell markers.13Nyam D.C. Pemberton J.H. Sandborn W.J. et al.Lymphoma of the pouch after ileal pouch-anal anastomosis report of a case.Dis Colon Rectum. 1997; 40: 971-972Crossref PubMed Scopus (36) Google Scholar Neither case report commented on patient exposure to immunomodulatory therapy before the development of lymphoma. The presence of EBV within the clonal population, as observed in our patient, was also not discussed. The finding of an EBV-positive lymphoma is significant, because it suggests a posttransplantation-like phenomenon in which impaired immune surveillance allows EBV-infected lymphocytes to proliferate unchecked. Although patients with IBD typically receive lower doses of immunomodulatory agents on a more intermittent basis than organ transplant recipients, this finding suggests that the cumulative effect of more than 3 agents can mimic transplant-level immunosuppression. The exact dose/duration of therapy that poses such a risk and the time from exposure to the development of lymphoma has not been clearly established. Treatment courses of AZA/6-MP have ranged from 4 to 94 months in patients diagnosed with lymphoma.35Kandiel A. Fraser A.G. Korelitz B.I. et al.Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.Gut. 2005; 54: 1121-1125Crossref PubMed Scopus (678) Google Scholar Most affected patients seem to develop lymphoma while on treatment, although 3 cases were diagnosed 11 months to 3 years after treatment.29Connell W.R. Kamm M.A. Dickson M. et al.Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease.Lancet. 1994; 343: 1249-1252Abstract PubMed Scopus (467) Google Scholar, 31Korelitz B.I. Mirsky F.J. Fleisher M.R. et al.Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine.Am J Gastroenterol. 1999; 94: 3248-3253Crossref PubMed Google Scholar, 33Present D.H. Meltzer S.J. Krumholz M.P. et al.6-Mercaptopurine in the management of inflammatory bowel disease short- and long-term toxicity.Ann Intern Med. 1989; 111: 641-649Crossref PubMed Scopus (710) Google Scholar This patient was maintained on prednisone (>20 mg/day) for 8 months, CSA for 7 months, and 6-MP for nearly 2 years before a single infusion of infliximab (5 mg/kg). Although chronic mucosal inflammation may have contributed to the development of lymphoma, it is important to note that our patient had a relatively short duration of UC, which suggests a greater contribution from combination immunomodulatory therapy. Individual immunomodulators appear to carry a low absolute risk of lymphoma and provide clear benefits in the treatment of IBD. However, the cumulative effects of more than 3 agents, simultaneously and/or sequentially, might simulate a posttransplantation situation and pose a significant threat of malignancy. Before a fourth immunomodulator is added, the risks and benefits of therapy should be cautiously weighed. Patients with IBD who receive more than 3 immunomodulators or biological therapies may behave more like posttransplantation patients at increased risk for developing an EBV-positive lymphoma. Such patients warrant more aggressive diagnostic surveillance and evaluation. The emerging trend toward using simultaneous and sequential combinations of immunomodulators and novel biological agents underscores the need to establish a lymphoma registry for IBD. Exploring Utilities and Outcomes With Infliximab TherapyClinical Gastroenterology and HepatologyVol. 4Issue 8PreviewThe provocative study presented by Siegel et al1 in this issue of Clinical Gastroenterology and Hepatology provides a framework by which we might quantitatively compare the benefit of disease remission with the adverse events potentially associated with infliximab therapy for Crohn's disease. This editorial serves to comment on the methodologic process used to conduct the study in addition to the clinical implications of the results. Full-Text PDF
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