**5. Lymphoma risk in the literature**

In order to evaluate any causality between IBD and the risk of lymphoma, it is extremely important to appreciate the quality of safety data available. Frequently, this information is flawed and difficult to interpret.

#### **5.1 Quality of data**

Randomised controlled drug trials collate information regarding adverse events but they are powered to elucidate differences in efficacy and not safety. They also tend to have relatively small numbers and a short follow up period which may not reflect the true incidence of late or delayed adverse events. Some useful safety information is available from observational studies of large populations. These have large numbers and long follow up but are susceptible to indication bias and often have other confounding factors. Case controlled series have an efficient methodology but may be hampered by the shortcomings of control selection. The most common form of safety data comes from case reports and case series which are able to identify rare risks. However, the inherent positive bias with this form of evidence, does not allow it to be utilised for risk quantification or for providing proof of causality. Post marketing surveillance, a form of *pharmaco-vigilence*, is another important source of safety data. This information may be made available through institutional

Evaluating Lymphoma Risk in Inflammatory Bowel Disease 323

Fig. 3. Medline cited publications regarding lymphoma risk in IBD patients since 1950.

(Holubar et al., 2010). These cases are not discussed further here.

**6.1 Intestinal and extra-intestinal lymphoma** 

classified as intestinal and extra-intestinal.

McCullough et al., 1992, Pohl et al., 1991, Bartram and Chrispin, 1973) and ulcerative colitis (Isomoto et al., 2003, Luo et al., 1997, Wagonfeld et al., 1976, Myerson et al., 1974, Parnes et al., 1974, Friedman et al., 1968, Federman et al., 1963). Clearly, lymphoma of the GI tract frequently occurs in the absence of inflammatory bowel disease. In a series from the Mayo Clinic spanning 40 years in the pre-biologic era, of the 2,332 cases of primary intestinal lymphoma identified, only 15 patients had concomitant inflammatory bowel disease

Lymphoma may present at a variety of sites amongst IBD patient but these can broadly be

Up to 15% of extra-nodal lymphoma involves the GI tract (Newton et al., 1997). In a series of 15 cases of intestinal lymphoma, 60% were colorectal, 27% involved the small bowel and there were individual cases in the stomach, duodenum and ileal pouch, each constituting 6.25% of this series (Holubar et al., 2010). In 80% of these cases, the location of the lymphoma was congruous to the site of IBD. In another series of 14 colorectal lymphomas, the commonest sites were the caecum and rectosigmoid but these were not IBD patients (Wong and Eu, 2006). Gastric mantle cell lymphoma has also been reported by Raderer et al in a patient with a 14 year history of Crohn's disease (Raderer et al., 2004). Ileal pouch lymphoma has also been reported in a number of other publications (Sengul et al., 2008,

reporting schemes, such as the FDA's Adverse Events Recording System (AERS) in the United States (FDA, 2011) or the MHRA's Yellow Card System in the United Kingdom (MHRA, 2011). Important information may come from drug specific data such as the TREAT registry (Lichtenstein et al., 2006), which is an on-going large-scale observational registry that was designed to examine the safety of Crohn's Disease therapies including infliximab. This type of data provides a *real world* experience with a heterogeneous group of patients suffering a variety of co-morbidities and taking concomitant medication. However, such schemes are generally voluntary systems which are prone to under-reporting and hence an under estimation of true incidence.

The low incidence of lymphoma, even in higher risk populations, poses a challenge to evaluating this risk. The incidence of all types of lymphoma diagnosed in the United Kingdom in 2007 was about 17 cases per 100,000 population (Cancer-Research-UK, 2011). A study of almost 3 million individuals would be necessary to detect an adverse event of this frequency with a confidence interval of 95%. No studies of this magnitude are available nor are likely to be available in the future.

#### **5.2 Available data**

The literature pertaining to the risk of lymphoma amongst IBD patients is dominated by case reports and case series. However, a number of large population studies have also been published over the last three decades which have been extremely valuable because they allow approximation of the risk of lymphoma (Loftus et al., 2000, Lewis et al., 2001, Beaugerie et al., 2009a, Greenstein et al., 1985). This information must be considered within the limitations of this type of study. A small number of meta-analyses have attempted to combine information from these population-based studies (Kandiel et al., 2005, Siegel et al., 2009). Post-marketing surveillance for drugs such as azathioprine, mercaptopurine and methotrexate are not available but some data regarding the newer anti-TNF therapies in IBD now exists (Lichtenstein et al., 2006).

Interest in the risk of developing lymphoma in the context of IBD and its treatment has grown exponentially (see Figure 3). This coincides with increasing use of immunomodulators in the management of IBD and concerns over their safety. Prior to the 1990s, only sporadic case reports and case series were available. More recently, a number of population based studies, review articles and meta-analyses have been published which are discussed in this report.

Additionally, changes in the classification of lymphoid neoplasia makes evaluation of the literature difficult in certain circumstances where there are overlapping features between diagnoses (Swerdlow et al., 2008).
