Skip to main content
Gut logoLink to Gut
. 2000 Oct;47(4):514–519. doi: 10.1136/gut.47.4.514

Increased incidence of non-Hodgkin's lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low

R Farrell 1, Y Ang 1, P Kileen 1, D O'Briain 1, D Kelleher 1, P Keeling 1, D Weir 1
PMCID: PMC1728075  PMID: 10986211

Abstract

BACKGROUND—There is concern that the incidence of non-Hodgkin's lymphoma (NHL) will rise with increasing use of immunosuppressive therapy.
AIMS—Our aim was to determine the risk of NHL in a large cohort of patients with inflammatory bowel disease (IBD), and to study the association between IBD, NHL, and immunosuppressive therapy.
METHODS—We studied 782 IBD patients (238 of whom received immunosuppressive therapy) who attended our medical centre between 1990 and 1999 (median follow up 8.0 years). Standardised incidence ratios (SIRs) and 95% confidence intervals (CI) were calculated. Expected cases were derived from 1995 age and sex specific incidence rates recorded by the National Cancer Registry of Ireland.
RESULTS—There were four cases of NHL in our IBD cohort (SIR 31.2; 95% CI 2.0-85; p=0.0001), all of whom had received immunosuppressive therapy: azathioprine (n=2), methotrexate (n=1), and methotrexate and cyclosporin (n=1). Our immunosuppressive group had a significantly (59 times) higher risk of NHL compared with that expected in the general population (p=0.0001). Three cases were intestinal NHL and one was mesenteric. Mean age at NHL diagnosis was 49 years, mean duration of IBD at the time of NHL diagnosis was 3.1 years, and mean duration between initiation of immunosuppressive therapy and diagnosis of NHL was 20 months.
CONCLUSIONS—Although underlying IBD may be a causal factor in the development of intestinal NHL, our experience suggests that immunosuppressive drugs can significantly increase the risk of NHL in IBD. This must be weighed against the improved quality of life and clinical benefit immunosuppressive therapy provides for IBD patients.


Keywords: inflammatory bowel disease; non-Hodgkin's lymphoma; immunosuppressive therapy; azathioprine; methotrexate; cyclosporin

Full Text

The Full Text of this article is available as a PDF (123.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bailin P. L., Tindall J. P., Roenigk H. H., Jr, Hogan M. D. Is methotrexate therapy for psoriasis carcinogenic? A modified retrospective-prospective analysis. JAMA. 1975 Apr 28;232(4):359–362. [PubMed] [Google Scholar]
  2. Bickston S. J., Lichtenstein G. R., Arseneau K. O., Cohen R. B., Cominelli F. The relationship between infliximab treatment and lymphoma in Crohn's disease. Gastroenterology. 1999 Dec;117(6):1433–1437. doi: 10.1016/s0016-5085(99)70294-5. [DOI] [PubMed] [Google Scholar]
  3. Bouhnik Y., Lémann M., Mary J. Y., Scemama G., Taï R., Matuchansky C., Modigliani R., Rambaud J. C. Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Lancet. 1996 Jan 27;347(8996):215–219. doi: 10.1016/s0140-6736(96)90402-x. [DOI] [PubMed] [Google Scholar]
  4. CORNES J. S., SMITH J. C., SOUTHWOOD W. F. Lymphosarcoma in chronic ulcerative colitis with report of two cases. Br J Surg. 1961 Jul;49:50–53. doi: 10.1002/bjs.18004921311. [DOI] [PubMed] [Google Scholar]
  5. Caspi O., Polliack A., Klar R., Ben-Yehuda D. The association of inflammatory bowel disease and leukemia--coincidence or not? Leuk Lymphoma. 1995 Apr;17(3-4):255–262. doi: 10.3109/10428199509056830. [DOI] [PubMed] [Google Scholar]
  6. Cleary M. L., Warnke R., Sklar J. Monoclonality of lymphoproliferative lesions in cardiac-transplant recipients. Clonal analysis based on immunoglobulin-gene rearrangements. N Engl J Med. 1984 Feb 23;310(8):477–482. doi: 10.1056/NEJM198402233100801. [DOI] [PubMed] [Google Scholar]
  7. Cockburn I. T., Krupp P. The risk of neoplasms in patients treated with cyclosporine A. J Autoimmun. 1989 Oct;2(5):723–731. doi: 10.1016/s0896-8411(89)80010-1. [DOI] [PubMed] [Google Scholar]
  8. Connell W. R., Kamm M. A., Dickson M., Balkwill A. M., Ritchie J. K., Lennard-Jones J. E. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet. 1994 May 21;343(8908):1249–1252. doi: 10.1016/s0140-6736(94)92150-4. [DOI] [PubMed] [Google Scholar]
  9. Das K. M., Valenzuela I., Morecki R. Crohn disease lymph node homogenates produce murine lymphoma in athymic mice. Proc Natl Acad Sci U S A. 1980 Jan;77(1):588–592. doi: 10.1073/pnas.77.1.588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dragosics B., Bauer P., Radaszkiewicz T. Primary gastrointestinal non-Hodgkin's lymphomas. A retrospective clinicopathologic study of 150 cases. Cancer. 1985 Mar 1;55(5):1060–1073. doi: 10.1002/1097-0142(19850301)55:5<1060::aid-cncr2820550523>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  11. EDWARDS F. C., TRUELOVE S. C. THE COURSE AND PROGNOSIS OF ULCERATIVE COLITIS. III. COMPLICATIONS. Gut. 1964 Feb;5:1–22. doi: 10.1136/gut.5.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ekbom A., Helmick C., Zack M., Adami H. O. Extracolonic malignancies in inflammatory bowel disease. Cancer. 1991 Apr 1;67(7):2015–2019. doi: 10.1002/1097-0142(19910401)67:7<2015::aid-cncr2820670731>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  13. Ekbom A., Helmick C., Zack M., Adami H. O. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med. 1990 Nov 1;323(18):1228–1233. doi: 10.1056/NEJM199011013231802. [DOI] [PubMed] [Google Scholar]
  14. Ellman M. H., Hurwitz H., Thomas C., Kozloff M. Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate. J Rheumatol. 1991 Nov;18(11):1741–1743. [PubMed] [Google Scholar]
  15. Freeman C., Berg J. W., Cutler S. J. Occurrence and prognosis of extranodal lymphomas. Cancer. 1972 Jan;29(1):252–260. doi: 10.1002/1097-0142(197201)29:1<252::aid-cncr2820290138>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  16. Friedman H. B., Silver G. M., Brown C. H. Lymphoma of the colon simulating ulcerative colitis. Report of four cases. Am J Dig Dis. 1968 Oct;13(10):910–917. doi: 10.1007/BF02237577. [DOI] [PubMed] [Google Scholar]
  17. Gelb A., Zalusky R. The use of azathiaprine and 6-mercaptopurine (6-MP) as immunosuppressive therapy in inflammatory bowel disease and its role in the etiology of lymphocytic lymphoma. Am J Gastroenterol. 1983 May;78(5):316–316. [PubMed] [Google Scholar]
  18. Greenstein A. J., Gennuso R., Sachar D. B., Heimann T., Smith H., Janowitz H. D., Aufses A. H., Jr Extraintestinal cancers in inflammatory bowel disease. Cancer. 1985 Dec 15;56(12):2914–2921. doi: 10.1002/1097-0142(19851215)56:12<2914::aid-cncr2820561232>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  19. Greenstein A. J., Mullin G. E., Strauchen J. A., Heimann T., Janowitz H. D., Aufses A. H., Jr, Sachar D. B. Lymphoma in inflammatory bowel disease. Cancer. 1992 Mar 1;69(5):1119–1123. doi: 10.1002/cncr.2820690510. [DOI] [PubMed] [Google Scholar]
  20. Gridley G., McLaughlin J. K., Ekbom A., Klareskog L., Adami H. O., Hacker D. G., Hoover R., Fraumeni J. F., Jr Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst. 1993 Feb 17;85(4):307–311. doi: 10.1093/jnci/85.4.307. [DOI] [PubMed] [Google Scholar]
  21. Hussell T., Isaacson P. G., Crabtree J. E., Spencer J. The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet. 1993 Sep 4;342(8871):571–574. doi: 10.1016/0140-6736(93)91408-e. [DOI] [PubMed] [Google Scholar]
  22. Isomäki H. A., Hakulinen T., Joutsenlahti U. Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritis. J Chronic Dis. 1978;31(11):691–696. doi: 10.1016/0021-9681(78)90071-1. [DOI] [PubMed] [Google Scholar]
  23. Jones M., Symmons D., Finn J., Wolfe F. Does exposure to immunosuppressive therapy increase the 10 year malignancy and mortality risks in rheumatoid arthritis? A matched cohort study. Br J Rheumatol. 1996 Aug;35(8):738–745. doi: 10.1093/rheumatology/35.8.738. [DOI] [PubMed] [Google Scholar]
  24. Kamel O. W., van de Rijn M., Weiss L. M., Del Zoppo G. J., Hench P. K., Robbins B. A., Montgomery P. G., Warnke R. A., Dorfman R. F. Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med. 1993 May 6;328(18):1317–1321. doi: 10.1056/NEJM199305063281806. [DOI] [PubMed] [Google Scholar]
  25. Kingsmore S. F., Hall B. D., Allen N. B., Rice J. R., Caldwell D. S. Association of methotrexate, rheumatoid arthritis and lymphoma: report of 2 cases and literature review. J Rheumatol. 1992 Sep;19(9):1462–1465. [PubMed] [Google Scholar]
  26. Kinlen L. J. Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am J Med. 1985 Jan 21;78(1A):44–49. doi: 10.1016/0002-9343(85)90245-1. [DOI] [PubMed] [Google Scholar]
  27. Kinlen L. J., Sheil A. G., Peto J., Doll R. Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs. Br Med J. 1979 Dec 8;2(6203):1461–1466. doi: 10.1136/bmj.2.6203.1461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lenzen R., Borchard F., Lübke H., Strohmeyer G. Colitis ulcerosa complicated by malignant lymphoma: case report and analysis of published works. Gut. 1995 Feb;36(2):306–310. doi: 10.1136/gut.36.2.306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Loehr W. J., Mujahed Z., Zahn F. D., Gray G. F., Thorbjarnarson B. Primary lymphoma of the gastrointestinal tract: a review of 100 cases. Ann Surg. 1969 Aug;170(2):232–238. doi: 10.1097/00000658-196908000-00011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lémann M., Bonhomme P., Bitoun A., Messing B., Modigliani R., Rambaud J. C. Traitement de la maladie de Crohn par l'azathioprine ou la 6-mercaptopurine. Etude rétrospective chez 126 malades. Gastroenterol Clin Biol. 1990;14(6-7):548–554. [PubMed] [Google Scholar]
  31. Persson P. G., Karlén P., Bernell O., Leijonmarck C. E., Broström O., Ahlbom A., Hellers G. Crohn's disease and cancer: a population-based cohort study. Gastroenterology. 1994 Dec;107(6):1675–1679. doi: 10.1016/0016-5085(94)90807-9. [DOI] [PubMed] [Google Scholar]
  32. Present D. H., Meltzer S. J., Krumholz M. P., Wolke A., Korelitz B. I. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989 Oct 15;111(8):641–649. doi: 10.7326/0003-4819-111-8-641. [DOI] [PubMed] [Google Scholar]
  33. Renton P., Blackshaw A. J. Colonic lymphoma complicating ulcerative colitis. Br J Surg. 1976 Jul;63(7):542–545. doi: 10.1002/bjs.1800630712. [DOI] [PubMed] [Google Scholar]
  34. Robert M. E., Kuo F. C., Longtine J. A., Sklar J. L., Schrock T., Weidner N. Diffuse colonic mantle cell lymphoma in a patient with presumed ulcerative colitis: detection of a precursor monoclonal lymphoid population using polymerase chain reaction and immunohistochemistry. Am J Surg Pathol. 1996 Aug;20(8):1024–1031. doi: 10.1097/00000478-199608000-00011. [DOI] [PubMed] [Google Scholar]
  35. SATALINE L. R., MOBLEY E. M., KIRKHAM W. Ulcerative colitis complicated by colonic lymphoma. Gastroenterology. 1963 Mar;44:342–347. [PubMed] [Google Scholar]
  36. Sandborn W. J. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol. 1996 Mar;91(3):423–433. [PubMed] [Google Scholar]
  37. Schattner A., Kozak N., Lassry Y., Sokolovskaya N. Primary intestinal T-cell lymphoma and sclerosing cholangitis: a cytokine-mediated association? J Intern Med. 1998 Dec;244(6):537–541. [PubMed] [Google Scholar]
  38. Shepherd N. A., Hall P. A., Williams G. T., Codling B. W., Jones E. L., Levison D. A., Morson B. C. Primary malignant lymphoma of the large intestine complicating chronic inflammatory bowel disease. Histopathology. 1989 Oct;15(4):325–337. doi: 10.1111/j.1365-2559.1989.tb01585.x. [DOI] [PubMed] [Google Scholar]
  39. Shetty K., Rybicki L., Brzezinski A., Carey W. D., Lashner B. A. The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol. 1999 Jun;94(6):1643–1649. doi: 10.1111/j.1572-0241.1999.01156.x. [DOI] [PubMed] [Google Scholar]
  40. Son H. J., Rhee P. L., Kim J. J., Koh K. C., Paik S. W., Rhee J. C., Koh Y. H. Primary T-cell lymphoma of the colon. Korean J Intern Med. 1997 Jun;12(2):238–241. doi: 10.3904/kjim.1997.12.2.238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Stein C. M., Pincus T., Yocum D., Tugwell P., Wells G., Gluck O., Kraag G., Torley H., Tesser J., McKendry R. Combination treatment of severe rheumatoid arthritis with cyclosporine and methotrexate for forty-eight weeks: an open-label extension study. The Methotrexate-Cyclosporine Combination Study Group. Arthritis Rheum. 1997 Oct;40(10):1843–1851. doi: 10.1002/art.1780401018. [DOI] [PubMed] [Google Scholar]
  42. Wychulis A. R., Beahrs O. H., Woolner L. B. Malignant lymphoma of the colon. A study of 69 cases. Arch Surg. 1966 Aug;93(2):215–225. doi: 10.1001/archsurg.1966.01330020007002. [DOI] [PubMed] [Google Scholar]
  43. Ziegler J. L., Beckstead J. A., Volberding P. A., Abrams D. I., Levine A. M., Lukes R. J., Gill P. S., Burkes R. L., Meyer P. R., Metroka C. E. Non-Hodgkin's lymphoma in 90 homosexual men. Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med. 1984 Aug 30;311(9):565–570. doi: 10.1056/NEJM198408303110904. [DOI] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES