**13.2 Immunophenotypic and genetic features**

The tumour cells express CD2, surface CD3, CD7 and CD16 but there is absence of CD4, CD5, CD8 and the B-cell surface marker CD20 (Swerdlow et al., 2008). Most cases express the γ/δ T-cell receptor (TCR-γ positive) but rarer cases express the α/β T-cell receptor (TCRβ positive) and studies demonstrate clonal rearrangements of the TCR gene.

A recent systematic review investigating chromosomal abnormalities in IBD patients diagnosed with HSTCL identified the development of isochrome 7q in 57.1%, aberrations of chromosome 8 in 35.7%, trisomy 8 in 21.4% and loss of the Y chromosome in 14.3 % of cases (Kotlyar et al., 2010). The group were intrigued by the cases with loss of the Y chromosome as almost all cases of HSTCL have presented in men. These chromosomal abnormalities are not specific to IBD patients.

#### **13.3 HSTCL in IBD**

HSTCL is not linked to EBV infection. However, the risk of HSTCL does seem to be related to thiopurine and anti-TNF therapy. DNA damage specific to chromosome 7 has been seen in a dose dependent manner with thiopurine agents (Piccin et al., 2010) and inhibition of TNF may result in decreased effectiveness of immune surveillance eliminating cells with aberrant abnormal chromosomal pattern (Shale et al., 2008).

Early concern was regarding a risk of HSTCL in IBD patients who had previous exposure to both thiopurines and anti-TNF drugs but more and more cases have been identified with only thiopurine exposure. Anti-TNF drugs are frequently used in non-IBD conditions, such as rheumatoid arthritis, ankylosing spondylitis and psoriasis, but they are rarely used in combination with other immunomodulators. It is interesting that, HSTCL has only been reported in a single non-IBD patient who received adalimumab for rheumatoid arthritis (Shale et al., 2008). Conversely, there are a number of case reports of patients developing HSTCL whilst on immunosuppression in the post-transplant setting (Roelandt et al., 2009, Tey et al., 2008, Steurer et al., 2002) where anti-TNF drugs are not used.

Kotlyar et al recently presented a systematic review investigating medications, duration of therapy and ages of IBD patients diagnosed with HSTCL (Kotlyar et al., 2011). 36 cases of HSTCL have occurred in IBD patients since 1996, all of whom had a history of thiopurine exposure. 20 of these patients also had also received anti-TNF therapy. Four patients had

Evaluating Lymphoma Risk in Inflammatory Bowel Disease 337

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

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

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.,

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

when this information is applied to a clinical setting.

1.20 to 16.77) and this difference was significant (Vos et al., 2010).

**14.2 Gender** 

**14.3 Type of lymphoma** 

2000).

**14.4 Type of IBD** 

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