IBD-Related Lymphoma
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1 IBD-Related Lymphoma Larry Burgart MD Staff Pathologist, Allina Health and Minnesota Gastroenterology Clinical Professor of Pathology, University of Minnesota College of Medicine
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5 IBD-Related Lymphoma Goals: 1. Show example of clinical observation leading to investigation 2. Clinical update on lymphoma in IBD
6 IBD-Related Lymphoma 34 year old man. 10-year-history of Crohn disease. Receiving medical therapy for active disease with fistula formation. Symptoms of small bowel obstruction develop. Imaging - mass distorting the ileocecal valve. Segmental resection was performed.
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12 CD20
13 Diagnosis Diffuse large B-cell lymphoma.
14 Diagnosis Diffuse large B-cell lymphoma. Extranodal: transplant or MTX?
15 Post-Transplant Lymphoproliferative Disorder PTLD EBV positive lymphoproliferation» Diffuse large B-cell lymphoma» Classical Hodgkin s lympoma Typically extranodal Variable prognosis» Deaths due to lymphoma» Complete recovery with no treatment or surgery only
16 Add l History Medical therapy consisted of 6 mercaptopurine (6-MP), 100 mg/day for 30 months. 6-MP is azathioprine metabolite. Thiopurines = azathioprine and 6-MP
17 Positive Literature A multicenter trial of 6-MP and prednisone in children with newly diagnosed Crohn s disease. Gastroenterology 2000;119: » 55 children randomised.» First line therapy for moderate to severe disease.» no clinically significant adverse events occurred 6-MP in Crohn s disease: an old friend becomes a new hero. Editorial in same issue.
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20 Diagnosis EBV-positive, immunosuppression-associated diffuse large B-cell lymphoma.
21 Soon followed by similar case Is lymphoma increased in incidence in IBD?»? Due to innate immune suppression. Does 6-MP and/or azathioprine have a causal relationship with lymphoma in IBD?
22 Lymphoma in IBD At least 7 reputable studies on the topic of lymphoma incidence in IBD before thiopurines. Population based studies typically have been negative. Referral center based studies have typically found a small increase.
23 6-MP / AZA, IBD, Lymphoma Incited by 2 cases in several week period. Hard work by Jerry Dayharsh. Multidisciplinary input important.» Bill Sandborn, Ed Loftus, Bill Tremaine Gastroenterology 2002;122:72-77.
24 6-MP / AZA, IBD, Lymphoma 6-MP / AZA use started in Looked at all IBD lymphomas from and Approximately 10,000 IBD patients seen at Mayo in each 8 year period. Approximately 1200 patients treated (thiopurine methyltransferase).
25 Time period n=6 n=12 Age (mean ± SE) 55±3 52±7 Male gender, n (%) 5 (83) 9 (75) Treatment with AZA/6MP, n (%) 0 ( ) 6 (50) EBV-positive lymphoma, n (%) 1 (17) 6 (50) Chronic ulcerative cholitis, n (%) 2 (33) 4 (33) Crohn s disease, n (%) 4 (67) 8 (67)
26 AZA/6MP Exposure and Lymphoma Occurrence in IBD The overall number of IBD patients seen was similar between these two time frames AZA/6MP treated Untreated Number of lymphoma cases EBV-positive lymphoma EBV-positive lymphomas 2 CP
27 Pt Age/ AZA/6MP Lymphoma Lymphoma Years no. Year gender dose EBV site type (IBD) Outcome /M No Lymph node, Small lymphocytic 4 colon mesentery /F No Lymph node, Follicular grade 1 45 para-aortic /M Yes Lymph node, Classical 20 axillary Hodgkin s /M No Lymph node, Mantle cell 0.25 cervical /M No Soft tissue, Multiple myeloma 1 chest wall /M No Ileum Diffuse large B /F No Lymph node, Mantle cell 0 small bowel mesentery /M Yes Cecum Diffuse large B /M No Lymph node, Diffuse large B 64 inguinal /F 6 MP No Liver Diffuse large B 18 Died 1997 of 50 mg/day lymphoma 4 years
28 Pt Age/ AZA/6MP Lymphoma Lymphoma Years no. Year gender dose EBV site type (IBD) Outcome /M No Lymph node, Small 4 colon mesentery lymphocytic /F No Lymph node, Follicular grade 1 45 para-aortic /M Yes Lymph node, Classical 20 axillary Hodgkin s /M No Lymph node, Mantle cell 0.25 cervical /M No Soft tissue, Multiple myeloma 1 chest wall /M No Ileum Diffuse large B /F No Lymph node, Mantle cell 0 small bowel mesentery /M Yes Cecum Diffuse large B /M No Lymph node, Diffuse large B 64 inguinal /F 6 MP No Liver Diffuse large B 18 Died 1997 of 50 mg/day lymphoma 4 years
29 Pt Age/ AZA/6MP Lymphoma Lymphoma Years no. Year gender dose EBV site type (IBD) Outcome /M No Duodenum Marginal zone, 0 MALT /M 6MP Yes Ileum Diffuse large B 15 Surgery and 75 mg/day 6MP stopped; 6 years no recurrence /M No Stomach Plasmacytoma /M 6MP Yes Cecum Diffuse large B 6 Died of 125 mg/day hemophagocytic 1.7 years syndrome /M 6MP Yes Rectum Diffuse large B 8 Surgery and 6MP 125 mg/day stopped; no 3 years recurrence /M No Rectum Diffuse large B /F AZA Yes Lung Classical 40 6MP stopped and 100 mg/day Hodgkin s lymphoma 1.2 years resolved /M 6MP Yes Lymph node, Diffuse large B 6 Died of 50 mg/day axillary hemophagocytic 5 years syndrome
30 Pt Age/ AZA/6MP Lymphoma Lymphoma Years no. Year gender dose EBV site type (IBD) Outcome /M No Duodenum Marginal zone, 0 MALT /M 6MP Yes Ileum Diffuse large B 15 Surgery and 75 mg/day 6MP stopped; 6 years no recurrence /M No Stomach Plasmacytoma /M 6MP Yes Cecum Diffuse large B 6 Died of 125 mg/day hemophagocytic 1.7 years syndrome /M 6MP Yes Rectum Diffuse large B 8 Surgery and 6MP 125 mg/day stopped; no 3 years recurrence /M No Rectum Diffuse large B /F AZA Yes Lung Classical 40 6MP stopped and 100 mg/day Hodgkin s lymphoma 1.2 years resolved /M 6MP Yes Lymph node, Diffuse large B 6 Died of 50 mg/day axillary hemophagocytic 5 years syndrome
31 Pt Age/ AZA/6MP Lymphoma Lymphoma Years no. Year gender dose EBV site type (IBD) Outcome /M No Duodenum Marginal zone, 0 MALT /M 6MP Yes Ileum Diffuse large B 15 Surgery and 75 mg/day 6MP stopped; 6 years no recurrence /M No Stomach Plasmacytoma /M 6MP Yes Cecum Diffuse large B 6 Died of 125 mg/day hemophagocytic 1.7 years syndrome /M 6MP Yes Rectum Diffuse large B 8 Surgery and 6MP 125 mg/day stopped; no 3 years recurrence /M No Rectum Diffuse large B /F AZA Yes Lung Classical 40 6MP stopped and 100 mg/day Hodgkin s lymphoma 1.2 years resolved /M 6MP Yes Lymph node, Diffuse large B 6 Died of 50 mg/day axillary hemophagocytic 5 years syndrome
32 Pt Age/ AZA/6MP Lymphoma Lymphoma Years no. Year gender dose EBV site type (IBD) Outcome /M No Duodenum Marginal zone, 0 MALT /M 6MP Yes Ileum Diffuse large B 15 Surgery and 75 mg/day 6MP stopped; 6 years no recurrence /M No Stomach Plasmacytoma /M 6MP Yes Cecum Diffuse large B 6 Died of 125 mg/day hemophagocytic 1.7 years syndrome /M 6MP Yes Rectum Diffuse large B 8 Surgery and 6MP 125 mg/day stopped; no 3 years recurrence /M No Rectum Diffuse large B /F AZA Yes Lung Classical 40 6MP stopped and 100 mg/day Hodgkin s lymphoma 1.2 years resolved /M 6MP Yes Lymph node, Diffuse large B 6 Died of 50 mg/day axillary hemophagocytic 5 years syndrome
33 PTLD-like Lymphoma in IBD Azathioprine or 6-MP EBV positive lymphoproliferation» Diffuse large B-cell lymphoma» Classical Hodgkin s lympoma All extranodal, most small bowel or colon Variable prognosis» Deaths due to hemophagocytic syndrome» Complete recovery with no treatment or surgery only
34 PTLD-like Lymphoma in IBD Magnitude of the problem? Used in pediatrics. At time of study appeared acceptable but not well defined.» Needed to be sorted by pathology (EBV). Our data suggested 6 in 1200 (0.5%).» Possible underestimate given lag period for lymphoma.» Possible overestimate if denominator too small.
35 Additional Studies Prospective and retrospective» Small finite increased risk of EBV-positive lymphoma with thiopurine treatment at all ages 4.5 to 9 cases per 10,000 treatment years» Small number, but >10-20x increase Ashworth et al. Inflamm Bowel Disease. 2012;18: Beaugerie et al. Lancet. 2009;7:
36 Related risks Anti-TNF alpha, as an example of biologics No increase in EBV-related lymphoma Increased infections Small increase in hepatosplenic T-cell lymphoma Currently recommended in combination with thiopurines for increased efficacy and decreased exposure to either Van Assche et al. Am J Gastroenterol. 2011;106:
37 Questions Is lymphoma increased in incidence in IBD?»? Due to innate immune suppression. Does 6-MP and/or azathioprine have a causal relationship with lymphoma in IBD?
38 AZA/6MP Exposure and Lymphoma Occurrence in IBD The overall number of IBD patients seen was similar between these two time frames AZA/6MP treated Untreated Number of lymphoma cases EBV-positive lymphoma EBV-positive lymphomas 2 CP
Therapy with immunosuppressive agents is associated
GASTROENTEROLOGY 2002;122:72 77 Epstein-Barr Virus Positive Lymphoma in Patients With Inflammatory Bowel Disease Treated With Azathioprine or 6-Mercaptopurine GERALD A. DAYHARSH,* EDWARD V. LOFTUS, Jr.,
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