**14.1 Age**

Data from the US and UK clearly demonstrates that the incidence of non-Hodgkin's lymphoma, the predominant form of lymphoid neoplasm seen in IBD patients, increases with advancing age (see Figure 2). Most of the studies reviewed in this chapter use age standardised statistics to estimate risk of lymphoma in IBD patients. An earlier metaanalysis carried out by Kandiel et al, found a relative risk for the development of lymphoma in IBD patients treated with thiopurines of 4.18 (95% CI 2.07 to 7.51) which is comparable to the findings of the meta-analysis presented here. The authors went on to calculate the number of patients that would need to be treated for each new diagnosis of lymphoma i.e. the number needed to harm (NNH). Approximating to a relative risk of 4, the NNH varied from 4357 in 20-29 year olds to just 355 in 70-79 year olds (Kandiel et al., 2005). The risk of lymphoma is not uniform across all age groups and this needs to be taken in to account when this information is applied to a clinical setting.

### **14.2 Gender**

336 New Advances in the Basic and Clinical Gastroenterology

previously received both infliximab and adalimumab and an additional patient had received a third biologic, natalizumab. There were no patients who had received an anti-TNF drug alone. Most patients had received at least 2 years therapy with a thiopurine and of those patients who had received infliximab, the number of previous infusions ranged from 1 to 20 up to 5 years prior to the diagnosis of HSTCL. The age range of patients was 12 to 58 years with a median of 23 years. The majority of patients were under 35 years old and the older patient appears to be

From the limited information available, HSTCL seems to be linked to previous prolonged thiopurine exposure and the risk may be higher in those who have also received an anti-TNF drug. This seems to compete with conclusions drawn from recent efficacy trials. The SONIC trial found that combination therapy with azathioprine and infliximab reached significantly higher rates of steroid-free clinical remission than either of these drugs as monotherapy for a cohort of naïve patients with moderate to severe Crohn's disease (24.1%

Whilst it is not possible to estimate the relative risk of HSTCL in IBD patients, Kotlyar et al attempted to derive the absolute risk of HSTCL in men using epidemiology data from the US and Europe as well as an estimate of thiopurine use in IBD patients from the French CESAME trial (Beaugerie et al., 2009a, Kotlyar et al., 2010). The group concluded that more than 99.99% of patients in immunomodulatory treatment will not develop HSTCL. Further reassurance comes from the CESAME study in that no cases of HSTCL were found despite

A vigilant approach must be taken when using thiopurines for the treatment of male patients under 35 years. Kotlyar et al recommended careful monitoring in patients who have been on thiopurine treatment for more than 2 years but this may be difficult to put in to practice as no pre-malignant markers have been identified. Decisions between the use of combination or monotherapy must be made in the context of clinical severity of disease and poor prognostic markers for complicated IBD. The risk of HSTCL is extremely low and patients should be made aware of this when making choices regarding their treatment. Highly efficacious therapeutic strategies should not be rejected based entirely on the low risk of HSTCL. Somewhat reassuringly, despite the rapidly increasing number of patients on anti-TNF drugs, exceeding 5 million patient-years exposure, the rate at which new cases of

There are a number of limitations to the data which has been pooled for the meta-analyses presented in this chapter. There are also confounding factors which are not taken in to

Data from the US and UK clearly demonstrates that the incidence of non-Hodgkin's lymphoma, the predominant form of lymphoid neoplasm seen in IBD patients, increases

an isolated case. Of the 31 patients in whom gender was known, only two were female.

vs 34.9% vs 46.2% AZA vs IXB vs AZA+IXB at 50 weeks) (Colombel et al., 2010).

HSTCL have been diagnosed has not changed over the last 15 years.

**13.4 Clinical application** 

analysis of over 50,000 patient-years follow up.

**14. Confounding factors and limitations** 

account by the source studies.

**14.1 Age** 

Gender also appears to be a further factor when analysing the risk of both Hodgkin's and non-Hodgkin's lymphoma. Although other autoimmune conditions tend to affect more women, the gender difference for IBD is small. Men have an increased risk of lymphoma (see Figure 2 and Figure 3) but the magnitude of the gender difference varies with age and type of lymphoma. In NHL there is only a slight preponderance for males but in HL, the incidence is three times greater in males in certain age groups. As discussed, HSTCL occurs almost exclusively in young men. Many of the studies in this analysis did not separate results for male and female patients but this may have made analysis difficult because of the generally small number of cases of lymphoma detected in these cohorts. Vos et al, in their nationwide Dutch study, calculated SIRs for male and female patients separately but did not find a substantial difference when they took both groups as a whole. However, in the 35-39 years age range, males had an SIR of 10.25 (95% CI 2.56 to 23.05) and females, 6.74 (95% CI 1.20 to 16.77) and this difference was significant (Vos et al., 2010).

#### **14.3 Type of lymphoma**

Non-Hodgkin's lymphoma appears to be the predominant lymphoid malignancy detected in IBD patients, particularly diffuse large B-cell lymphoma (DLBCL). The CESAME study group found 22 cases of NHL and only 1 HL in their large cohort of patients from France (Beaugerie et al., 2009a). Few studies have attempted to separate findings for HL and NHL. Palli et al did find an increased risk of HL in patients with UC but the confidence interval was large and the validity of these results has been put in to question (Palli et al., 2000).

#### **14.4 Type of IBD**

Whether Crohn's disease or ulcerative colitis confers a higher risk of lymphoma has not been established. Two publications from the same population-based cohort in Copenhagen, Denmark distinguished their analysis between CD and UC patients. In the CD group no lymphomas were identified and only 1 lymphoma was found in the UC group (SIR 0.5) (Winther et al., 2004, Jess et al., 2004). A further population-based cohort from Stockholm, Sweden also analysed UC and CD separately in two different publications. Again no cases of lymphoma were seen in the CD group but there were 3 in the UC group (SIR 1.2) (Persson et al., 1994, Karlen et al., 1999). Interpreting these findings with such small numbers is

Evaluating Lymphoma Risk in Inflammatory Bowel Disease 339

high levels of 6TG causing myelo-toxicity. Those with heterozygote mutations have

Thiopurines are also commonly used drugs for the management of acute lymphoblastic leukaemia (ALL) in paediatric patients. Following treatment, these patients have an increased risk of subsequently developing secondary myelodysplasia or acute myeloid leukaemia but it had been thought that this risk is associated with alkylating agents, epipodophyllotoxins or radiation therapy rather than due to AZA. However, Bo et al showed that paediatric patients with allelic variations of the TPMT gene (and lower TPMT levels) had a higher rate of secondary leukaemias in this setting (Bo et al., 1999). Thiopurines result in the incorporation of 6TG, a purine analogue, into lymphocyte DNA which can activate DNA repair mechanisms. This introduces the risk of point mutations and chromosomal abnormalities during repair processes. It follows that higher levels of 6TG may increase this risk further, possibly explaining the link with lymphomagenesis in IBD

Disanti et al made an interesting observation in a cohort of IBD patients treated with 6MP over a 37 year period. The investigators divided the group of over 600 patients in to those who developed a sustained leukopenia of <4.0x109/l for 20 or more days and those who did not. They found that there was an increased risk of haematological malignancies in the

Although, the TPMT levels were not known in these patients, further investigation in to the

The use of imaging modalities such as computed tomography and fluoroscopy have been an important component for the diagnosis and assessment of IBD but there has been increasing concern regarding the cancer risk associated with diagnostic ionising radiation (Brenner and Hall, 2007). Much of the risk of medical radiation exposure is extrapolated from studies of populations near nuclear explosions and occupational exposure but there is some evidence in certain medical settings (Brenner et al., 2003). For example, young patients with scoliosis who have had repeated chest x-rays were at increased risk of breast malignancy (Doody et

Recent evidence suggests that CT imaging is being used more frequently in IBD patients, particularly those with Crohn's disease (Newnham et al., 2007, Kroeker et al., 2011). Leukaemia is well recognised as a long term consequence of radiation exposure and this risk is higher in children (Darby et al., 1992, Shimizu et al., 1990). However, there is little evidence to confirm an increased risk of lymphoma in patients exposed to diagnostic ionising radiation though the mechanisms of oncogenesis may be similar. There was no increased risk of lymphoma seen in patients receiving radiotherapy for uterine cancer nor amongst tuberculosis patients with repeated pneumothorax who had an average of 77 chest x-rays on follow up (Boice, 1992). A study including 318 NHL patients found no increased exposure to diagnostic radiation compared to controls if imaging from the 12 months immediately prior to lymphoma diagnosis was excluded. The authors felt that radiological procedures within this period were performed to investigate the lymphoma rather than a

group with sustained leukopenia (p=0.014) (Disanti et al., 2006).

association between TPMT and lymphoma risk may be intriguing.

intermediate TPMT activity and dose adjustment of AZA and 6MP may be required.

patients treated with thiopurines.

**15.2 Radiation exposure** 

causative factor (Boice et al., 1991).

al., 2000).

fraught with difficulty. In the CESAME study, 16 of the 23 lymphomas were in patients with Crohn's disease (Beaugerie et al., 2009a).
