**3.1 Classification of lymphoma**

The earliest classifications of lymphoma were based entirely on the morphological features of the neoplastic cells involved. Historically, lymphomas represented by large cells were known as *reticulosarcomas* and those by small cells were *lymphosarcomas* (Diebold, 2001). Later, lymphomas began to be distinguished according to their origin from B or T lymphocytes. With the development of immunophenotyping and cytogenetics, as well as an appreciation of differences in prognosis and patient stratification, more complex classification systems have developed. The World Health Organisation (WHO) Classification of Tumours of Haemopoietic and Lymphoid Tissues, updated in 2008 (see Table 1), is now widely accepted (Swerdlow et al., 2008) and categorises lymphoid neoplasms in to those derived from:


314 New Advances in the Basic and Clinical Gastroenterology

studies have proven their efficacy (Hanauer et al., 2006, Hanauer et al., 2002, Jarnerot et al., 2005). A third, pegylated anti-TNF drug, certolizumab has also been studied and appears to have equivalent clinical efficacy (Sandborn et al., 2007a). Despite medical therapy, up to 50- 70% of patients with CD will undergo surgery within 5 years of diagnosis and UC patients

The increased risk of colonic adenocarcinoma in patients with ulcerative colitis and Crohn's colitis is well documented (Rutter et al., 2006, Jess et al., 2006). One study has suggested a protective role for thiopurines in this context (Beaugerie et al., 2009b) though these patients were not corrected for co-administration of 5ASA preparations which may also have a

There also appears to be an increased risk of certain non-colorectal malignancies amongst IBD patients. In the same cohort of patients from the CESAME study, prospective data suggested a 20-fold increased risk of small bowel adenocarcinoma and suggestion of an increased risk of skin and cervical malignancy (Beaugerie et al., 2009c). In a database of over 27,000 UC patients from Sweden, the standardised incidence ratio (SIR) for all cancers was 1.46 with increased risk of malignancy of the liver, small bowel (carcinoid), prostate and breast (Hemminki et al., 2008). In a recent review of malignancies associated with thiopurine therapy, Smith et al concluded that these drugs did not increase the risk of cervical dysplasia, colonic cancer or solid organ tumours in IBD patients (Smith et al., 2010). A retrospective cohort study of over 50,000 IBD patients from the US suggested an increased risk of non-melanomatous skin cancer and that this risk was highest in patients treated with thiopurines (Odds Ratio 4.27) and biological therapies (Odds Ratio 2.18) (Long et al., 2010). Many of these studies have also shown an increased risk of lymphoma and this will be

Lymphoma is a broad term used to describe a variety of neoplasms due to proliferation of lymphoid cells. Traditionally, lymphoid neoplasms that presented with bone marrow and blood involvement were referred to by the term *leukaemia* and those that presented with a mass would be called a *lymphoma*. However, it is now appreciated that any *lymphoma* can present with or evolve in to a leukaemic picture and occasionally, *leukaemia* can present with

The earliest classifications of lymphoma were based entirely on the morphological features of the neoplastic cells involved. Historically, lymphomas represented by large cells were known as *reticulosarcomas* and those by small cells were *lymphosarcomas* (Diebold, 2001). Later, lymphomas began to be distinguished according to their origin from B or T lymphocytes. With the development of immunophenotyping and cytogenetics, as well as an appreciation of differences in prognosis and patient stratification, more complex classification systems have developed. The World Health Organisation (WHO)

have a 20-30% lifetime risk of colectomy (Cosnes et al., 2005).

**2.4 Cancer risk in IBD** 

protective role in this setting.

discussed further in this chapter.

**3.1 Classification of lymphoma** 

**3. Lymphoma** 

a mass lesion.


#### **Non-Hodgkin's Lymphoma**


Evaluating Lymphoma Risk in Inflammatory Bowel Disease 317

A B

C D

Fig. 2. Figures adapted from Cancer Research UK 2011. A: Incidence of non-Hodgkin's lymphoma by gender. B: Incidence of Hodgkin's lymphoma by gender. C: Age standardised incidence rates for non-Hodgkin's lymphoma. D: Age standardised incidence rates for

nodal NHL presents in the GI tract (Newton et al., 1997).

A number of risk factors for the development of NHL have been studied:

with an increase of 35% during the 20 year interval between 1988 and 2007 (see Figure 2C). This trend seems to be reflected throughout the world. Mortality in the UK is estimated at 6.9 per 100,000 from NHL and with improvements in treatment, it is estimated that over half of patients now survive for at least 10 years following diagnosis. Up to 15% of all extra-

 **Infectious agents** – It is thought that a proportion of the worldwide rise in incidence of NHL parallels, but is not completely explained by, the HIV epidemic. The risk of NHL in HIV and AIDS is well documented but only 3-5% of these patients will develop NHL (Serraino et al., 1992). Epstein-Barr virus has been linked to Burkitt's lymphoma and post-transplant lymphoma (Epstein et al., 1964). Other infections associated with an increased risk of NHL include *Helicobacter Pylori* (Xue et al., 2001), Hepatitis C (Dal Maso and Franceschi, 2006) and Human T-cell Lymphotropic Virus (HTLV-1) (Parkin,

 **Immunosuppression** – The use of immunosuppression following organ transplant has been shown to increase the risk of NHL and in a significant proportion of these, EBV

Hodgkin's lymphoma.

2006).


Table 1. WHO Classification of Non-Hodgkin's and Hodgkin's Lymphoma (Swerdlow et al, 2008). (MALT – mucosa-associated lymphoid tissue; HL – Hodgkin's Lymphoma; NK – Natural Killer).

Hodgkin's lymphoma (formerly known as Hodgkin's disease) arises from B-cells of germinal or post-germinal centres of peripheral lymph nodes. It is pathologically and clinically distinct from other lymphoid neoplasia and generally has a good prognosis. Hodgkin's lymphoma has a distinguishing cellular composition on biopsy of lymphomatous tissues with abundant inflammatory cells and only a minority of neoplastic cells, known as Reed-Sternberg cells. Reed-Sternberg cells are large, binucleated or multinucleated containing multiple eosinophilic nucleoli and have prominent cytoplasm. Hodgkin's lymphoma (HL) is classified in to *nodular lymphocyte predominant HL* and *classical HL*, which is further subdivided in to *nodular sclerosis*, *mixed cellularity*, *lymphocyte-rich* and *lymphocytedepleted* types (see Table 1).

The term Non-Hodgkin's lymphoma encompasses all other types of lymphoma. Although the WHO classification does not distinguish NHL on the basis of disease activity, it has classically been divided in to two subtypes:


### **3.2 Non-Hodgkin's lymphoma**

NHL can occur in children and adults but over two-thirds are diagnosed in people aged over 60 years. There is a male preponderance with a ratio of up to 1.5 in older age groups. NHL is the fifth most common cancer in the UK with over 10,000 people diagnosed with the condition in 2007 and an age-standardised rate of 14.2 per 100,000 population (Cancer-Research-UK, 2011) (see Figure 2A). In the United States, the Surveillance Epidemiology & End Results (SEER) registry provides an age-standardised rate of 19.6 per 100,000 between 2003 and 2007 (Altekruse et al., 2010). The incidence of NHL seems to be rising in the UK

**Hodgkin's Lymphoma** 

**Classical Hodgkin's lymphoma** 

Nodular sclerosis classical HL Mixed cellularity classical HL

Lymphocyte rich classical HL Lymphocyte depleted classical HL

**Nodular lymphocyte predominant HL** 

Table 1. WHO Classification of Non-Hodgkin's and Hodgkin's Lymphoma (Swerdlow et al, 2008). (MALT – mucosa-associated lymphoid tissue; HL – Hodgkin's Lymphoma; NK –

Hodgkin's lymphoma (formerly known as Hodgkin's disease) arises from B-cells of germinal or post-germinal centres of peripheral lymph nodes. It is pathologically and clinically distinct from other lymphoid neoplasia and generally has a good prognosis. Hodgkin's lymphoma has a distinguishing cellular composition on biopsy of lymphomatous tissues with abundant inflammatory cells and only a minority of neoplastic cells, known as Reed-Sternberg cells. Reed-Sternberg cells are large, binucleated or multinucleated containing multiple eosinophilic nucleoli and have prominent cytoplasm. Hodgkin's lymphoma (HL) is classified in to *nodular lymphocyte predominant HL* and *classical HL*, which is further subdivided in to *nodular sclerosis*, *mixed cellularity*, *lymphocyte-rich* and *lymphocyte-*

The term Non-Hodgkin's lymphoma encompasses all other types of lymphoma. Although the WHO classification does not distinguish NHL on the basis of disease activity, it has

Low-grade or indolent NHL develops slowly and there may be no symptoms for many

NHL can occur in children and adults but over two-thirds are diagnosed in people aged over 60 years. There is a male preponderance with a ratio of up to 1.5 in older age groups. NHL is the fifth most common cancer in the UK with over 10,000 people diagnosed with the condition in 2007 and an age-standardised rate of 14.2 per 100,000 population (Cancer-Research-UK, 2011) (see Figure 2A). In the United States, the Surveillance Epidemiology & End Results (SEER) registry provides an age-standardised rate of 19.6 per 100,000 between 2003 and 2007 (Altekruse et al., 2010). The incidence of NHL seems to be rising in the UK

Natural Killer).

*depleted* types (see Table 1).

**3.2 Non-Hodgkin's lymphoma** 

years.

classically been divided in to two subtypes:

High-grade NHL develops quickly and aggressively.

Fig. 2. Figures adapted from Cancer Research UK 2011. A: Incidence of non-Hodgkin's lymphoma by gender. B: Incidence of Hodgkin's lymphoma by gender. C: Age standardised incidence rates for non-Hodgkin's lymphoma. D: Age standardised incidence rates for Hodgkin's lymphoma.

with an increase of 35% during the 20 year interval between 1988 and 2007 (see Figure 2C). This trend seems to be reflected throughout the world. Mortality in the UK is estimated at 6.9 per 100,000 from NHL and with improvements in treatment, it is estimated that over half of patients now survive for at least 10 years following diagnosis. Up to 15% of all extranodal NHL presents in the GI tract (Newton et al., 1997).

A number of risk factors for the development of NHL have been studied:


Evaluating Lymphoma Risk in Inflammatory Bowel Disease 319

 **Epstein-Barr virus** – EBV infection has long been implicated in the development of Hodgkin's lymphoma. EBV DNA can be found in 40% of cases with higher rates of association found in the paediatric population (Jarrett et al., 1996). EBV positivity is more commonly found in the Mixed Cellularity than the Nodular Sclerosis subtypes of classical HL. A previous history of infectious mononucleosis confers an increased risk

of HL with an SIR of 3.49 in patients aged 15 to 34 years (Hjalgrim et al., 2000). **Previous non-Hodgkin's lymphoma** – Studies suggest that patients who have previously been treated for NHL are at increased risk of subsequently developing HL with a magnitude in the order of four- to twelve-fold (Travis et al., 1991, Travis et al.,

Lymphoma is a clonal expansion of B- and T- lymphocytes caused by the accumulation of a series of genetic mutations affecting proto-oncogenes and tumour suppressor genes. This results in dysregulated proliferation, evasion of immune surveillance mechanisms and inhibition of apoptosis (Jaffe et al., 2001). Significant progress has been made in to the understanding of these mechanisms at a molecular level. The activation of oncogenes by aberrant chromosomal translocations as well as the inactivation of tumour suppressor genes by chromosomal deletion or mutation are both important mechanisms of lymphomagenesis (Kuppers et al., 1999). Oncogenic viruses such as EBV and HTLV1 can also introduce foreign genetic sequences into the lymphocyte genome causing disruption of normal function (Neri

There are a number of genetic, environmental, infectious and iatrogenic factors amongst patients with inflammatory bowel disease which can predispose to increased susceptibility

 **Chronic inflammation** – The pathogenesis of IBD is not completely understood but aberrations in the innate and adaptive immune response to luminal antigens has been the focus of much research. It can be postulated that the dysregulation of these immune systems seen in the chronic inflammation associated with IBD may lead to antigendriven lymphocyte proliferation and a relatively unhindered risk of genetic and chromosomal deviations (Sokol and Beaugerie, 2009). Another possibility is that the combination of metabolites, cytokines and chemokines seen in the mucosa of IBD patients promotes mutagenesis in bystander cells. These theories may help to explain the increased risk of lymphoma seen in a variety of different auto-immune conditions and their concordance to sites of inflammation (Smedby et al., 2006). EBV related lymphoma has been reported in longstanding pyothorax of over 20 years duration (Aozasa et al., 2005). This is a condition which is regarded to be due to chronic suppuration with no autoimmunity and it is suggested that any chronic inflammatory

 **Genetic susceptibility** – Linkage studies and genome wide association studies have identified a large array of susceptibility genes for IBD (Barrett et al., 2008). These genetic changes may also be involved in the pathogenesis of lymphoma in certain individuals. For example, the first susceptibility gene identified, IBD1, encodes for the protein

susceptibility with lower risk in blacks than whites (Glaser, 1991).

1993).

et al., 1991).

**4. Pathogenesis of lymphoma in IBD** 

to these mechanisms for the development of lymphoma:

state may predispose to lymphoma development.

et al., 2005, Goldin et al., 2004). Studies from the USA suggest racial differences in

infection has been implicated (Kawashima et al., 1994). A recent meta-analysis suggests an 8-fold increased risk of NHL in post-transplant patients (Grulich et al., 2007b).

