**1. Introduction**

310 New Advances in the Basic and Clinical Gastroenterology

Rivière, PJ.; Farmer, SC.; Burks, TF. & Porreca, F. (1991). Prostaglandin E2-induced diarrhea

Sengupta, A.; Ghosh, S.; Bhattacharjee, S. & Das, S. (2004). Indian food ingredients and

Sirisha, N.; Sreenivasulu, M.; Sangeeta, K. & Madhusudhana Chetty C. (2010). Antioxidant

Spangler, BD. (1992). Structure and function of cholera toxin and the related Escherichia coli

Suzuki, H.; Inadomi, JM. & Hibi, T. (2009). Japanese herbal medicine in functional

Viswanatha, GL.; Hanumanthappa, S.; Krishnadas, N. & Rangappa, S. (2011). Antidiarrheal

Wallace, JL. (2001). Pathogenesis of NSAID-induced gastroduodenal mucosal injury. *Best* 

Zaware, BB.; Nirmal, SA.; Baheti, DG.; Patil, AN. & Mandal, SC. (2011). Potential of *Vitex* 

Vol.2, No.4 (October 2010), pp. 2174-2182. ISSN 0974-4304

Vol.4, No.6 (June 2011), pp. 451-456. ISSN 1995-7645

Vol.49, No.8 (August 2011), pp. 874-878. ISSN 1388-0209

*therapeutics*, Vol.256, No.2 (February 1991), pp. 547-552. ISSN 0022-3565 Rosenbloom, RA.; Chaudhary, J. & Castro-Eschenbach, D. (2011). Traditional botanical

2011), pp. 158-161. ISSN 1075-2765

126-132. ISSN 1513-7368

622-647. ISSN 0146-0749

ISSN 1521-6918

pp. 688-696. ISSN 1350-1925

in mice: importance of colonic secretion. *The Journal of pharmacology and experimental* 

medicine: an introduction. *American journal of therapeutics*, Vol.18, No.2 (March

cancer prevention - an experimental evaluation of anticarcinogenic effects of garlic in rat colon. *Asian Pacific journal of cancer prevention,* Vol.5, No.2 (April 2004), pp.

properties of Ficus species- A review. *International journal of pharmtech research*,

heat-labile enterotoxin. *Microbiological reviews*, Vol.56, No.4 (December 1992), pp.

gastrointestinal disorders. *Neurogastroenterology and motility,* Vol.21, No.7 (Jul 2009),

effect of fractions from stem bark of *Thespesia populnea* in rodents: Possible antimotility and antisecretory mechanisms. *Asian Pacific journal of tropical medicine*,

*practice & research. Clinical gastroenterology,* Vol.15, No.5 (October 2001), pp. 691-703.

*negundo* roots in the treatment of ulcerative colitis in mice. *Pharmaceutical biology*,

The risk of lymphoma in inflammatory bowel disease (IBD) has been a topic of great interest for many years. In 1928, the first published series of colorectal malignancies in ulcerative colitis (UC) patients included a case of lymphosarcoma, the name given to an early classification of lymphoma (Bargen, 1928). Since then a huge number of case reports, case series, cohort studies, population-based studies and meta-analyses have been presented on the topic but the matter remains controversial with conflicting results based on poor quality evidence. Most recently, a type of non-Hodgkin's lymphoma (NHL) known as hepatosplenic T-cell lymphoma (HSTCL) has understandably drawn much attention despite its rarity. HSTCL has an invariably fatal outcome despite reports of early response to treatment, it almost exclusively affects young men with Crohn's disease (CD) and seems to be linked to commonly used drugs for the management of IBD, the thiopurines and tumour necrosis factor (TNF) antagonists (Kotlyar et al., 2011). A further source of concern stems from a trend by IBD physicians to use these drugs earlier in the course of disease and also in combination because recent studies suggest that these strategies may improve outcomes (Colombel et al., 2010, D'Haens, 2009).

Proving causality has been difficult because it is difficult to separate the multiple factors involved in lymphomagenesis using the evidence that is available (see Figure 1). It has long been suspected that the chronic inflammation seen in IBD itself may be the cause of lymphoma in this setting but there has been growing concern that it is in fact the drugs used in the treatment of IBD which confers this risk. One could also speculate that it is the combination of both these factors which results in the development of lymphoma.

The case of lymphosarcoma identified by Bargen in 1928 was in an era when immunomodulators were not available for the treatment of IBD suggesting that the disease itself may predispose to lymphoma development. There are other reports of lymphoma in drug-naïve IBD patients (Aydogan et al., 2010). There does appear to be an increased risk of lymphoma in other chronic inflammatory and autoimmune conditions as well including rheumatoid arthritis (RA), primary Sjögren's syndrome, systemic lupus erythematosus (SLE) and Hashimoto's thyroiditis (Smedby et al., 2006). There is some evidence that increased severity of the disease may increase the risk of lymphoma in these conditions (Baecklund et al., 2006, Theander et al., 2006, Lofstrom et al., 2007).

Evaluating Lymphoma Risk in Inflammatory Bowel Disease 313

IBD affects 400 per 100,000 population in the United Kingdom but there is considerable variation worldwide with the highest prevalence in developed countries (Rubin et al., 2000). It most commonly presents in teenage or young adult life but it can affect any age and there

The aetiology is unknown but evidence suggests an immune dysfunction which is triggered by an environmental factor in a genetically susceptible individual (Cho, 2008) leading to chronic inflammation and injury to the gastrointestinal tract. Many of the susceptibility genes identified in recent studies have been shown to have important roles in immune regulation but there is increasing evidence that these genes pertain to the innate immune system and are involved in the sensing or intracellular processing of bacteria (Packey and Sartor, 2008). Potential microbial triggers which have been studied include a form of enteroadherent *Escherichia coli* and *Mycobacterium paratuberculosis,* but more recent investigation suggests that a disturbance of normal enteric microflora may play a role in aetiology (Sartor, 2008). Additionally, a number of other potential environmental factors have also been studied including diet, smoking, appendiceal inflammation, certain drugs and stress but causality has remained difficult to establish (Bernstein, 2010). The particular combination of susceptible genes and environmental triggers probably varies between

Ulcerative colitis causes a continuous mucosal inflammation of the colorectum, whereas Crohn's disease can affect any part of the GI tract, characteristically with skip lesions and transmural inflammation. Additionally, chronic inflammation in Crohn's disease can lead to

A curative treatment for inflammatory bowel disease is yet to be identified. Strategies for the management of IBD involve treatment of flares and maintenance of remission. Although a wide range of therapies including enteral nutrition (Zachos et al., 2007), antibiotics (Lal and Steinhart, 2006) and complementary medicines (Langmead and Rampton, 2006) are used in IBD, the mainstay of treatment has been with anti-inflammatory and immunomodulatory drugs. Corticosteroids, 5-aminosalicylates (5ASA), azathioprine (AZA), mercaptopurine (6MP), methotrexate (MTX) and cyclosporin A (CSA) have been the most commonly used drugs. In an attempt to reduce steroid exposure and maintain remission, immunomodulatory therapy is being used earlier, for prolonged periods and in combination. The concern is of an increased risk of side effects with this approach. Estimates suggest that up to 30% of patients may not respond to this treatment and may require more aggressive strategies. The increased understanding of the pathogenesis of IBD, has led to investigation in to a number of therapies targeted towards the abnormal cytokine expression seen in patients with IBD. Of these, only the monoclonal antibodies against tumour necrosis factor are currently in clinical use but other targets have been identified and are undergoing laboratory and clinical study. Infliximab (IXB) and adalimumab (ADA) are the two antitumour necrosis factor (anti-TNF) drugs available in the United Kingdom and a number of

individuals with IBD and leads to different patterns and severity of disease.

fistulising and stricturing disease behaviours (Satsangi et al., 2006).

**2.1 Epidemiology** 

**2.2 Aetiology** 

**2.3 Treatment** 

is an approximate equal sex distribution.

Fig. 1. Assessing the causality of lymphoma in IBD. IBD itself may be the cause of lymphoma (a), or lymphoma may be due to the medication used to treat it (b) or lymphoma may be due to a combination of the disease and the treatment (c).

Both primary and acquired immunodeficiency states have been associated with lymphoma which is important because many of the drugs used for the treatment of IBD have immunosuppressive effects. There is an increased risk of lymphoma with Human Immunodeficiency Virus (HIV) infection and in post-transplant patients treated with immunosuppressives (Serraino et al., 1992, Grulich et al., 2007b). The role of Epstein-Barr virus (EBV) is well established in lymphomagenesis in post-transplant patients and this also appears to be important in IBD patients (Dayharsh et al., 2002).

IBD is associated with significant morbidity and a small mortality (Rubin et al., 2004, Ghosh and Mitchell, 2007). It is important that IBD physicians are able to help patients weigh up the risk of lymphoma with the benefits of drugs used to treat IBD. A number of attempts have been made to quantify this risk. One of the largest population-based studies utilised a primary care database from the United Kingdom but did not find a statistically significant increased background risk of lymphoma in IBD patients (Lewis et al., 2001). A cohort study from Dublin found an alarmingly higher rate of lymphoma in their IBD patients with up to a 59-fold increase (Farrell et al., 2000). Kandiel et al performed a meta-analysis of 6 studies to evaluate the risk of lymphoma in IBD patients treated with thiopurines and found a 4-fold increased risk of lymphoma in these patients (Kandiel et al., 2005).

A number of more recent studies have been presented in the literature including large cohort studies from the United States (US) and Spain (Chiorean et al., 2010, Van Domselaar et al., 2010) as well as large population-based studies from the UK and the Netherlands (Armstrong et al., 2010, Vos et al., 2010). Most notably, the French CESAME study published in 2009 with almost 50,000 patient-years of follow up, set out to quantify the risk of lymphoma and made attempts to distinguish the background risk of lymphoma due to IBD itself from the risk conferred by its treatment (Beaugerie et al., 2009a).

This chapter aims to provide an up to date systematic review of the available literature regarding the risk of lymphoma in inflammatory bowel disease. Meta-analysis techniques have been used to pool data from multiple studies.
