**7. Population and cohort studies**

A number of population and cohort studies have been published and are described below. The standardised incidence ratio (SIR) is defined as the ratio between observed and

Frizzi et al., 2000, Nyam et al., 1997) and one publication suggests EBV may be involved in the aetiology (Schwartz et al., 2006). Lymphoma at an ileostomy site has also been reported (Pranesh, 2002). Metachronous colonic lymphoma (Hill et al., 1993) as well as synchronous colonic adenocarcinoma and lymphoma (Hope-Ross et al., 1985, Nishigami et al., 2010) have

In addition, a number of extra-intestinal sites of lymphoma amongst IBD patients have been reported. Hepatosplenic T-cell lymphoma (HSTCL) has become a concern amongst IBD physicians and this will be discussed in further detail. Owen et al reports a patient with UC treated with azathioprine who develops a B-cell lymphoproliferative disorder on her eyelid following a recent illness diagnosed as infectious mononucleosis (Owen et al., 2010). Deneau et al recently described the case of a child with an EBV-driven NK-cell lymphoma involving the skin and GI tract causing hepatosplenomegaly (Deneau et al., 2010). Other cutaneous lymphomas are described in the literature (Adams et al., 2004, Martinez Tirado et al., 2001). Vulval and peri-anal lymphoma has also been identified (Winnicki et al., 2009, Sivarajasingham et al., 2003). Kastner et al present a young lady with ulcerative colitis, previously treated with azathioprine, who presents with seizures and is found to have cerebral lesions of high grade B cell lymphoma (Kastner et al., 2007). Plamacytoma (a

mature B-cell lymphoma) can present as a paravertebral mass (Redmond et al., 2007).

appearances can be diverse, manifesting as ulceration, polyps or masses.

lymphoma diagnosis (Beaugerie et al., 2009a).

IBD (DeBenedet et al., 2008).

**7. Population and cohort studies** 

Many of the symptoms of intestinal lymphoma are very similar to those caused by inflammatory bowel disease. The most commonly presenting symptom is bloody diarrhoea occurring in almost three quarters of cases (Holubar et al., 2010, Wong and Eu, 2006). Other common symptoms include abdominal pain, weight loss and sweats. Presentation with bowel obstruction and perforation occurs less frequently (Holubar et al., 2010, Bourikas et al., 2008). Diagnosis of lymphoma is frequently made following laparotomy. Endoscopic

Duration of IBD before development of lymphoma appears to be very variable between individual cases. Shepherd et al reported 10 cases of colorectal lymphoma complicating inflammatory bowel disease (6 patients with UC and 4 with CD) (Shepherd et al., 1989). The duration of inflammatory bowel disease varied from 30 months to 20 years in these cases. In the CESAME study, there was between 1 to 16 years of exposure to thiopurines before

More unusual presentations of lymphoma include jaundice due to a nodal mass at the porta hepatis in a patient with Crohn's disease (Parasher et al., 1999), spontaneous tumour lysis syndrome in a Crohn's patient with a plasmacytoma (Froilan Torres et al., 2009), nephrotic syndrome in a patient with Hodgkin's lymphoma and UC (Basic-Jukic et al., 2002), and jaundice due to vanishing bile duct syndrome in a patient with Hodgkin's lymphoma and

A number of population and cohort studies have been published and are described below. The standardised incidence ratio (SIR) is defined as the ratio between observed and

been described in IBD patients.

**6.2 Clinical presentation** 

expected events in a study population. This is a useful comparator to analyse the risk of lymphoma in IBD patients and has been used in much of the literature.

#### **Incidence and Risk Factors for Lymphoma in a Single-Center Inflammatory Bowel Disease Population (Chiorean et al 2010)**

A cohort study identified 3,585 patients attending a single IBD centre in Indianapolis, USA. Data was collected retrospectively between 1990 and 2005. Since 2005, the registry was updated prospectively. An electronic database was interrogated for diagnoses of Hodgkin's and non-Hodgkin's lymphoma and compared to expected age-standardised incident rates from the SEER registry. This study also used a case matched control group with a ratio of 1:10 to determine risk factors for lymphoma development. The population consisted of 2,277 Crohn's patients and 1,308 UC patients with no significant demographic differences between groups. 8 patients were identified with a diagnosis of lymphoma (6 NHL and 2 HL). Only 3 patients had thiopurine exposure but 2 of these patients had also received TNF antagonists and were EBV positive. The study did not find any statistically significant relationship between diagnosis of lymphoma with demographics, drug therapy, duration of treatment and length of diagnosis. Based on SEER statistics, the overall SIR for lymphoma was 1.6 (95% CI 0.6 to 3.0) but this was not significant. (Chiorean et al., 2010)

#### **Risk of Cancer in Inflammatory Bowel Disease Treated with Azathioprine: A UK Population-Based Case-Control Study (Armstrong et al 2010)**

This was a nested case-control study using the General Practice Research Database (GPRD) in the UK which was interrogated for patients with a diagnosis of IBD, any previous prescriptions for azathioprine or mercaptopurine and a subsequent diagnosis of any cancer. The GPRD is the largest longitudinal primary care database in the world containing approximately 50 million patient years of data. The control group consisted of all IBD patients who had not been diagnosed with a cancer. The total number of patients included in the study was 15,471 and 15 patients had diagnoses of lymphoma (2 HL, 6 NHL and 7 unspecified). The group found the risk of lymphoma for patients who had ever received thiopurines versus those that had never received such drugs was increased by an OR of 3.22 (95% CI 1.01 to 10.18). An SIR was not calculated for the risk of lymphoma compared to the background population in this study. (Armstrong et al., 2010)

#### **Lymphoproliferative Disorders in an Inflammatory Bowel Disease Unit (Van Domselaar et al 2010)**

This was a retrospective study of 911 patients attending a tertiary IBD clinic in Madrid followed up for a mean of 32.3 months. There were 7 cases of lymphoma identified in the cohort (6 NHL and 1 HL). The mean age at diagnosis was 53 years and the mean time from IBD to lymphoma diagnosis was 4.82 years (range 0 to 20 years). Three cases were associated with EBV. An SIR of 3.72 can be calculated from the figures presented though this was not calculated by the authors. (Van Domselaar et al., 2010)

#### **Risk of Malignant Lymphoma in Patients with Inflammatory Bowel Diseases: A Dutch Nationwide Study (Vos et al)**

The authors identified all IBD patients diagnosed with lymphoma between 1997 and 2004 from a Dutch nationwide histo- and cyto-pathology database known as PALGA. Age adjusted incidence of lymphoma was obtained from the Netherlands Central Bureau for

Evaluating Lymphoma Risk in Inflammatory Bowel Disease 327

This is an important large retrospective cohort study utilising the General Practice Research Database that was also used by Armstrong et al above. All patients coded with a diagnosis of UC or CD were eligible for inclusion and cross-matched for a diagnosis of HL and NHL. Prescriptions for AZA and 6MP were also analysed and an average dose per day was calculated. A control cohort was randomly selected but matched for age, sex and primary care practice. The study identified 6,605 patients with CD, 10,391 patients with UC and there were 60,506 patients in the control group. 18 patients were identified with lymphoma in this cohort compared with an expected 13.6 cases and an SIR of 1.32 (95% CI 0.78 to 2.10). The relative risk compared to the control group was 1.20 (96% CI 0.67 to 2.06). The authors concluded that IBD was not associated with an increased risk of lymphoma. Even on sub-analysis of patients prescribed thiopurines, there was no significant increased risk of lymphoma. (Lewis et al., 2001) **Cancer Risk in Patients with Inflammatory Bowel Disease – A Population-based Study** 

Population-based data was obtained from the University of Manitoba IBD database which was extracted from the Manitoba Health administrative databases in Winnipeg, Canada. An age and gender matched non-IBD control group was randomly selected with a ratio of 1:10. 5,529 patients were included in the study and the overall incidence of cancer was 690.2 per 100,000 population. 16 cases of NHL were identified but no cases of HL. This study found an incident rate ratio of 1.59 (95% CI 0.6 to 3.3) for the risk of lymphoma. The risk of developing lymphoma was highest in male patients with Crohn's disease where the IRR was calculated

**The Incidence of Lymphoid and Myeloid Malignancies Among Hospitalized Crohn's** 

This was a retrospective cohort study. Discharge data for all in-patients in the Commonwealth of Virginia and the State of California was analysed to identify patients who were admitted to hospital with a diagnosis code for Crohn's disease. These patients were then followed up for 2 years examining for new diagnostic codes for lymphoma. The patients were matched with a control group who had admissions to hospital over the same period with no history of CD. 5,426 patients were discharged from hospital in the study period with a diagnosis of CD. 10 cases of NHL were identified and an OR of 2.04 (95% CI

**Hodgkin's Disease Risk is Increased in Patients with Ulcerative Colitis (Palli et al 2000)**  This is a population based study of all patients with IBD residing in Florence, Italy between 1978 and 1992. A total of 920 patients were followed up for a median of 11 years. An increased risk of Hodgkin's disease was observed in patients with UC with 6 cases identified and an SIR calculated at 9.3 (95% CI 2.5 to 23.8). The broad confidence interval makes it difficult to assess the validity of these findings in this study. (Palli et al., 2000)

This was a retrospective study of all incidence cases of IBD in Olmsted County, Minnesota between 1950 and 1993 examined for the diagnosis of lymphoma. The authors comment that

**Risk of Lymphoma in Inflammatory Bowel Disease (Loftus et al 2000)** 

**Inflammatory Bowel Disease is not Associated with an Increased Risk of Lymphoma** 

**(Lewis et al 2001)** 

**(Bernstein et al 2001)** 

at 3.63 (95% CI 1.53 to 8.62). (Bernstein et al., 2001)

1.33 to 3.14) was calculated. (Arseneau et al., 2001)

**Disease Patients (Arseneau et al 2001)**

Statistics between these years. After excluding incomplete data, 44 cases of lymphoma were identified in 17,834 IBD patients. The calculated SIR was 1.27 (95% CI 0.92 to 1.68) and the authors concluded that there was no increased risk of lymphoma in IBD patients. However, the SIRs in the age groups 35-39 years and 45-49 years were 9.32 and 3.99 respectively and these did reach significance. Only 43% of patients were exposed to thiopurines. Of the patients in whom EBV status could be obtained, 92% (11/12) with EBV positive lymphoma were taking a thiopurine compared to 19% (4/21) who were EBV negative (p<0.001). (Vos et al., 2010)

#### **Lymphoproliferative Disorders in Patients Receiving Thiopurines for Inflammatory Bowel Disease: A Prospective Observational Cohort Study (Beaugerie et al 2009)**

This is a frequently quoted study which set out to objectively clarify the risk of cancer in IBD patients. 19,486 patients were enrolled into a prospective French nationwide database called CESAME (Cancers et Surrisque Associé aux Maladies inflammatoires intestinales En France) between May 2004 and June 2005 and followed up until 31st December 2007. This equated to almost 50,000 patient-years of follow up. Details regarding patient demographics, type of IBD, date of diagnosis, disease location, history of malignancy and exposure to immunosuppressive therapy including thiopurines, methotrexate and anti-TNF agents were collected. A total of 23 patients were identified who developed lymphoma (22 NHL, 1 HL). The SIR is not presented in this study but later discussed in a review article by the same author at 1.86 (95% CI 1.1 to 3.0) (Sokol and Beaugerie, 2009). The HR for patients taking AZA versus those who were not was 5.28 (95% CI 2.01 to 13.9). There was a trend towards increased risk of lymphoma with anti-TNF therapy but this did not reach statistical significance. No patients taking methotrexate developed lymphoma in this study. (Beaugerie et al., 2009a)

#### **Risk of Haematopoietic Cancer in Patients with Inflammatory Bowel Disease (Askling et al 2005)**

This was a huge population based cohort study using prospectively recorded data from a number of large Swedish IBD databases (Uppsala cohort, Stockholm County cohort, Stockholm pan-colitis register and Swedish in-patient register). 47, 679 patients were recruited in total and 180 lymphomas were detected. Compared to national Swedish cancer statistics, the calculated SIR was 1.09 in this study. (Askling et al., 2005)

#### **Intestinal and Extra-Intestinal Cancer in Crohn's Disease: Follow-up of a Populationbased Cohort in Copenhagen, Denmark (Jess et al 2004)**

374 patients with a diagnosis of Crohn's disease were followed up for a median of 17 years in Copenhagen County. No lymphomas were observed in this population. (Jess et al., 2004)

#### **Long-term Risk of Cancer in Ulcerative Colitis : A Population-based Cohort Study from Copenhagen County (Winther et al 2004)**

This study is from the same cohort of patients investigated in the above study by Jess et al. In the sample of 1160 UC patients, the median follow up was 19 years. A total of 124 malignancies were observed including only 1 lymphoma. The SIR for lymphoma risk works out at 0.5 ( 95% CI 0.1 to 0.8) in this study. This suggests a protective role of UC in lymphomagenesis which is not demonstrated in any other studies. This result is likely to be artefactual due to the finding of only 1 case of lymphoma in the study. (Winther et al., 2004)

Statistics between these years. After excluding incomplete data, 44 cases of lymphoma were identified in 17,834 IBD patients. The calculated SIR was 1.27 (95% CI 0.92 to 1.68) and the authors concluded that there was no increased risk of lymphoma in IBD patients. However, the SIRs in the age groups 35-39 years and 45-49 years were 9.32 and 3.99 respectively and these did reach significance. Only 43% of patients were exposed to thiopurines. Of the patients in whom EBV status could be obtained, 92% (11/12) with EBV positive lymphoma were taking a thiopurine compared to 19% (4/21) who were EBV negative (p<0.001). (Vos et

**Lymphoproliferative Disorders in Patients Receiving Thiopurines for Inflammatory Bowel Disease: A Prospective Observational Cohort Study (Beaugerie et al 2009)** 

This is a frequently quoted study which set out to objectively clarify the risk of cancer in IBD patients. 19,486 patients were enrolled into a prospective French nationwide database called CESAME (Cancers et Surrisque Associé aux Maladies inflammatoires intestinales En France) between May 2004 and June 2005 and followed up until 31st December 2007. This equated to almost 50,000 patient-years of follow up. Details regarding patient demographics, type of IBD, date of diagnosis, disease location, history of malignancy and exposure to immunosuppressive therapy including thiopurines, methotrexate and anti-TNF agents were collected. A total of 23 patients were identified who developed lymphoma (22 NHL, 1 HL). The SIR is not presented in this study but later discussed in a review article by the same author at 1.86 (95% CI 1.1 to 3.0) (Sokol and Beaugerie, 2009). The HR for patients taking AZA versus those who were not was 5.28 (95% CI 2.01 to 13.9). There was a trend towards increased risk of lymphoma with anti-TNF therapy but this did not reach statistical significance. No patients taking methotrexate developed lymphoma in this study.

**Risk of Haematopoietic Cancer in Patients with Inflammatory Bowel Disease (Askling et** 

This was a huge population based cohort study using prospectively recorded data from a number of large Swedish IBD databases (Uppsala cohort, Stockholm County cohort, Stockholm pan-colitis register and Swedish in-patient register). 47, 679 patients were recruited in total and 180 lymphomas were detected. Compared to national Swedish cancer

**Intestinal and Extra-Intestinal Cancer in Crohn's Disease: Follow-up of a Population-**

374 patients with a diagnosis of Crohn's disease were followed up for a median of 17 years in Copenhagen County. No lymphomas were observed in this population. (Jess et al., 2004) **Long-term Risk of Cancer in Ulcerative Colitis : A Population-based Cohort Study from** 

This study is from the same cohort of patients investigated in the above study by Jess et al. In the sample of 1160 UC patients, the median follow up was 19 years. A total of 124 malignancies were observed including only 1 lymphoma. The SIR for lymphoma risk works out at 0.5 ( 95% CI 0.1 to 0.8) in this study. This suggests a protective role of UC in lymphomagenesis which is not demonstrated in any other studies. This result is likely to be artefactual due to the finding of only 1 case of lymphoma in the study. (Winther et al., 2004)

statistics, the calculated SIR was 1.09 in this study. (Askling et al., 2005)

**based Cohort in Copenhagen, Denmark (Jess et al 2004)** 

**Copenhagen County (Winther et al 2004)** 

al., 2010)

(Beaugerie et al., 2009a)

**al 2005)** 

#### **Inflammatory Bowel Disease is not Associated with an Increased Risk of Lymphoma (Lewis et al 2001)**

This is an important large retrospective cohort study utilising the General Practice Research Database that was also used by Armstrong et al above. All patients coded with a diagnosis of UC or CD were eligible for inclusion and cross-matched for a diagnosis of HL and NHL. Prescriptions for AZA and 6MP were also analysed and an average dose per day was calculated. A control cohort was randomly selected but matched for age, sex and primary care practice. The study identified 6,605 patients with CD, 10,391 patients with UC and there were 60,506 patients in the control group. 18 patients were identified with lymphoma in this cohort compared with an expected 13.6 cases and an SIR of 1.32 (95% CI 0.78 to 2.10). The relative risk compared to the control group was 1.20 (96% CI 0.67 to 2.06). The authors concluded that IBD was not associated with an increased risk of lymphoma. Even on sub-analysis of patients prescribed thiopurines, there was no significant increased risk of lymphoma. (Lewis et al., 2001)

#### **Cancer Risk in Patients with Inflammatory Bowel Disease – A Population-based Study (Bernstein et al 2001)**

Population-based data was obtained from the University of Manitoba IBD database which was extracted from the Manitoba Health administrative databases in Winnipeg, Canada. An age and gender matched non-IBD control group was randomly selected with a ratio of 1:10. 5,529 patients were included in the study and the overall incidence of cancer was 690.2 per 100,000 population. 16 cases of NHL were identified but no cases of HL. This study found an incident rate ratio of 1.59 (95% CI 0.6 to 3.3) for the risk of lymphoma. The risk of developing lymphoma was highest in male patients with Crohn's disease where the IRR was calculated at 3.63 (95% CI 1.53 to 8.62). (Bernstein et al., 2001)

#### **The Incidence of Lymphoid and Myeloid Malignancies Among Hospitalized Crohn's Disease Patients (Arseneau et al 2001)**

This was a retrospective cohort study. Discharge data for all in-patients in the Commonwealth of Virginia and the State of California was analysed to identify patients who were admitted to hospital with a diagnosis code for Crohn's disease. These patients were then followed up for 2 years examining for new diagnostic codes for lymphoma. The patients were matched with a control group who had admissions to hospital over the same period with no history of CD. 5,426 patients were discharged from hospital in the study period with a diagnosis of CD. 10 cases of NHL were identified and an OR of 2.04 (95% CI 1.33 to 3.14) was calculated. (Arseneau et al., 2001)

#### **Hodgkin's Disease Risk is Increased in Patients with Ulcerative Colitis (Palli et al 2000)**

This is a population based study of all patients with IBD residing in Florence, Italy between 1978 and 1992. A total of 920 patients were followed up for a median of 11 years. An increased risk of Hodgkin's disease was observed in patients with UC with 6 cases identified and an SIR calculated at 9.3 (95% CI 2.5 to 23.8). The broad confidence interval makes it difficult to assess the validity of these findings in this study. (Palli et al., 2000)

#### **Risk of Lymphoma in Inflammatory Bowel Disease (Loftus et al 2000)**

This was a retrospective study of all incidence cases of IBD in Olmsted County, Minnesota between 1950 and 1993 examined for the diagnosis of lymphoma. The authors comment that

Evaluating Lymphoma Risk in Inflammatory Bowel Disease 329

lymphoma were found in this cohort with an expected 8.9 cases. The SIR was 1.0 (95% CI 0.5

This was a retrospective case note review of patients with a diagnosis of IBD at the Mount Sinai Hospital, New York. 1961 patients were studied with a total of 8 lymphomas (6 NHL and 2 HL). The expected frequency of lymphoma expected was 1.67 giving an SIR of 4.79.

An estimate of the baseline lymphoma risk has been made for this chapter using a metaanalysis technique. Populations and cohort studies were identified using the MEDLINE database provided by the US National Library of Medicine (NLM). Statistical analysis was carried out using the Review Manager (RevMan) Version 5 software which is provided by The Cochrane Collaboration, Copenhagen, for preparing and maintaining Cochrane reviews and meta-analyses. Dichotomous data was entered and analysed using the Mantel-Haentszel statistical technique and a 95% confidence interval assuming a Poisson distribution of lymphoma incidence. Studies were only weighted by their size. Graphical representation of results is performed with a Forest plot indicating 95% confidence intervals. A total of 145,208 patients from 16 trials were included in the meta-analysis (see Figure 4). This produced a cumulative Risk Ratio of 1.29 (95% CI of 1.10 to 1.51, p=0.002). However, this included hospital-based and specialist clinic cohorts which can introduce selection bias. The meta-analysis was repeated only including the 12 population-based studies (see Figure 5). 133,463 patients were included. This did not have a very large effect on the results and the Risk Ratio falls slightly to 1.23 (95% CI 1.05 to 1.45, p=0.01). In both analyses, the test for heterogeneity was not significant and the test for overall effect was 3.15 and 2.52 respectively.

Fig. 4. Meta-analysis of population and cohort studies to evaluate the baseline risk of

**Extraintestinal Cancers in Inflammatory Bowel Disease (Greenstein et al 1985)** 

to 1.6). (Ekbom et al., 1991)

(Greenstein et al., 1985)

lymphoma.

**8. Baseline risk of lymphoma in IBD** 

the use of immunomodulators during this time frame was rare and hoped to be able to demonstrate the baseline risk of lymphoma in IBD patients. Expected cases of lymphoma were derived from published Olmsted County age-standardised incidence rates. 454 patients were diagnosed with IBD in the study period. Only 1 case of NHL was identified in the entire cohort and an SIR of 1.0 (95% CI 0.03 to 5.6) was calculated. The observed number of patients with lymphoma is so small in this study that the results are very difficult to interpret. (Loftus et al., 2000)

#### **Increased Incidence of non-Hodgkin's Lymphoma in Inflammatory Bowel Disease Patients on Immunosuppressive Therapy but Overall Risk is Low (Farrell et al 2000)**

This study interrogated an IBD database of 782 IBD patients in Dublin. 30% of patients were taking immunomodulators therapy with the majority on azathioprine. A total of 30 cancers were identified with 4 cases of NHL compared with the expected 0.53 cases. These figures produced an SIR of 31.2 (95% CI 2.0 to 85.0). All these patients were on immunosuppressive therapy (2 on MTX and 2 on AZA). Calculating an SIR for patients on immunosuppressive therapy, the authors found a 58.8 –fold increased risk. These rather alarming results have not been duplicated. The confidence intervals are very broad and difficult to interpret. A possible explanation for these outlying results is that this retrospective study was initiated shortly after two new cases of lymphoma had been identified in this cohort. This clustering of cases may have had a significant impact on risk calculations. (Farrell et al., 2000)

#### **Increased Risk of Cancer in Ulcerative Colitis: A Population-based Cohort Study (Karlén et al 1999)**

A cohort of 1547 patients with UC in Stockholm County diagnosed between 1955 and 1984 were followed on the National Cancer Register and the National Cause of Death Register until 1989. Comparisons were made with regional cancer statistics. 3 lymphomas were identified in the cohort with an SIR of 1.2 (95% CI 0.3 to 2.5). (Karlen et al., 1999)

#### **Long-term Neoplasia Risk after Azathioprine Treatment in Inflammatory Bowel Disease (Connell et al 1994)**

This study from St Mark's Hospital in London followed up 755 IBD patients taking azathioprine for a median of 12.5 months. The overall risk of cancer was similar to that of the background population with an SIR of 1.27 but there was an increased risk of colorectal malignancy with an SIR of 6.7. No cases of lymphoma were identified in this cohort. (Connell et al., 1994)

#### **Crohn's Disease and Cancer: A Population-based Cohort Study (Persson et al 1994)**

This study was performed by the same group and used similar methodology to the Karlén study from Stockholm described above. 1251 patients with Crohn's disease were followed up. There was an increased incidence of small bowel and upper GI tract malignancies. 4 cases of lymphoma were identified with an SIR of 1.4 (95% CI 0.4 to 3.5). (Persson et al., 1994)

#### **Extracolonic Malignancies in Inflammatory Bowel Disease (Ekbom et al 1991)**

This was a population based cohort with IBD consisting of 4776 patients from the Uppsala Health Care Region in central Sweden. All patients were followed up in the Swedish Cancer Registry and the Registry of Causes of Death for a diagnosis of malignancy. 9 cases of

the use of immunomodulators during this time frame was rare and hoped to be able to demonstrate the baseline risk of lymphoma in IBD patients. Expected cases of lymphoma were derived from published Olmsted County age-standardised incidence rates. 454 patients were diagnosed with IBD in the study period. Only 1 case of NHL was identified in the entire cohort and an SIR of 1.0 (95% CI 0.03 to 5.6) was calculated. The observed number of patients with lymphoma is so small in this study that the results are very difficult to

**Increased Incidence of non-Hodgkin's Lymphoma in Inflammatory Bowel Disease Patients on Immunosuppressive Therapy but Overall Risk is Low (Farrell et al 2000)** 

of cases may have had a significant impact on risk calculations. (Farrell et al., 2000)

identified in the cohort with an SIR of 1.2 (95% CI 0.3 to 2.5). (Karlen et al., 1999)

**Increased Risk of Cancer in Ulcerative Colitis: A Population-based Cohort Study (Karlén** 

A cohort of 1547 patients with UC in Stockholm County diagnosed between 1955 and 1984 were followed on the National Cancer Register and the National Cause of Death Register until 1989. Comparisons were made with regional cancer statistics. 3 lymphomas were

**Long-term Neoplasia Risk after Azathioprine Treatment in Inflammatory Bowel Disease** 

This study from St Mark's Hospital in London followed up 755 IBD patients taking azathioprine for a median of 12.5 months. The overall risk of cancer was similar to that of the background population with an SIR of 1.27 but there was an increased risk of colorectal malignancy with an SIR of 6.7. No cases of lymphoma were identified in this cohort.

This study was performed by the same group and used similar methodology to the Karlén study from Stockholm described above. 1251 patients with Crohn's disease were followed up. There was an increased incidence of small bowel and upper GI tract malignancies. 4 cases of lymphoma were identified with an SIR of 1.4 (95% CI 0.4 to 3.5). (Persson et al.,

This was a population based cohort with IBD consisting of 4776 patients from the Uppsala Health Care Region in central Sweden. All patients were followed up in the Swedish Cancer Registry and the Registry of Causes of Death for a diagnosis of malignancy. 9 cases of

**Crohn's Disease and Cancer: A Population-based Cohort Study (Persson et al 1994)** 

**Extracolonic Malignancies in Inflammatory Bowel Disease (Ekbom et al 1991)** 

This study interrogated an IBD database of 782 IBD patients in Dublin. 30% of patients were taking immunomodulators therapy with the majority on azathioprine. A total of 30 cancers were identified with 4 cases of NHL compared with the expected 0.53 cases. These figures produced an SIR of 31.2 (95% CI 2.0 to 85.0). All these patients were on immunosuppressive therapy (2 on MTX and 2 on AZA). Calculating an SIR for patients on immunosuppressive therapy, the authors found a 58.8 –fold increased risk. These rather alarming results have not been duplicated. The confidence intervals are very broad and difficult to interpret. A possible explanation for these outlying results is that this retrospective study was initiated shortly after two new cases of lymphoma had been identified in this cohort. This clustering

interpret. (Loftus et al., 2000)

**et al 1999)** 

**(Connell et al 1994)** 

(Connell et al., 1994)

1994)

lymphoma were found in this cohort with an expected 8.9 cases. The SIR was 1.0 (95% CI 0.5 to 1.6). (Ekbom et al., 1991)

#### **Extraintestinal Cancers in Inflammatory Bowel Disease (Greenstein et al 1985)**

This was a retrospective case note review of patients with a diagnosis of IBD at the Mount Sinai Hospital, New York. 1961 patients were studied with a total of 8 lymphomas (6 NHL and 2 HL). The expected frequency of lymphoma expected was 1.67 giving an SIR of 4.79. (Greenstein et al., 1985)
