UK Non-Hodgkin lymphoma incidence statistics

This section contains the latest cancer incidence statistics on non-Hodgkin lymphoma (NHL) in adults by age and sex, trends over time, geographic variation and sub-types (including WHO classification table for NHL). Statistics on lymphomas in children are presented in the childhood cancer section. The ICD code for non-Hodgkin lymphoma is ICD9 200+202, ICD10 C82-85, and C96.

Non-Hodgkin lymphoma incidence by age and sex

In 2006 there were 10,569 people diagnosed with non-Hodgkin lymphoma in the UK ( Table 1.1). 1-4

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While there are roughly equal numbers of cases diagnosed in males and females, because there are more women than men in the population, the male age-standardised incidence rate per 100,000 population (16.3) is higher than the female rate (11.7). 1-4

The incidence of NHL increases with age, rates increase sharply in people over 50 and more than two thirds (70%) of all cases are diagnosed in people over 60 years ( Figure 1.1). 1-4

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Non-Hodgkin lymphoma incidence trends

The non-Hodgkin lymphoma incidence trend in Great Britain is shown in Figure 1.2. The age-standardised incidence rate for NHL increased by over 40% in the twenty-year period between 1987-2006. 1-3

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The UK non-Hodgkin lymphoma incidence trend is shown in Figure 1.3.

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This pattern of increase has also been seen in the US 11 and Western Europe 12. There have also been increases in India, Japan, Brazil and Singapore. 13-14 In Britain the biggest increases in incidence have been in older people. Rates in those over 75 are three times higher than they were in 1975 ( Figure 1.4). 1-3

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These trends need to be interpreted with caution as at least some of the increase in incidence can be explained by changes in the diagnosis, classification and patient registration rates for NHL. 13, 15 However there is evidence to suggest that increases in incidence are real. 16, 17

American data show the incidence of high-grade NHL tripled among males and doubled among females between the late 1970s and mid 1990s. Immunoblastic NHL was the fastest growing high-grade subtype, followed by small noncleaved and lymphoblastic NHL. 18

Elsewhere extra-nodal B-cell lymphomas, nodal T-cell lymphomas, ‘high grade’ lymphoma and follicular lymphoma, are reported to have increased in incidence more than others. 12, 19 In countries hit worst by HIV, increases in immunoblastic and Burkitt-like NHL have been striking. 20, 21

Geographic variation in Non-Hodgkin lymphoma incidence

While there are no significant variations in the incidence of NHL across the UK, there are significant international variations in the incidence and types of NHL, with the highest rates in Northern America, Australia, New Zealand and Western Europe and the lowest rates in Eastern and South Central Asia ( Figure 1.5). 5

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Notable variations exist within the types of lymphoma seen, examples being the endemic Burkitt lymphoma prevalent in Africa, T-cell lymphomas which are much more common in the Far East and the Carribean 6 and Gastric lymphoma in Northern Italy 7. The international variation in the incidence and mortality of NHL in males and females are very similar 5. The UK comes 20th in the world ranking of NHL.

Within the EU the highest incidence rates are in Finland and France and the lowest rates in Latvia and Lithuania ( Figure 1.6). 5 The UK ranks 6th in the EU ranking of NHL.

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Sub-types of Non-Hodgkin lymphoma

A reliable classification system for haematological malignancies has only recently been developed and agreed by oncologists and pathologists: this is the World Health Organisation (WHO) classification ( Table 1.2). 8

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No single marker can be used as the ‘gold standard’ for diagnosis, a combination of techniques is needed, including morphology, immunophenotype, genetic features and clinical features, including symptoms. Confirmation of diagnosis requires a lymph node or other tissue biopsy, ideally with analysis of fresh tissue for patterns of protein expression on the cell surface as well as genetic changes at the molecular level. Retrospective analysis of different lymphoma types is difficult in practice and progress in targeted therapies may mean future developments in tumour classification 9.

The percentage of all NHLs coded as being of extra-nodal origin is between 25% and 35% in most countries, with the stomach, skin and small intestine being the most common extra-nodal sites.

In general, the pattern of incidence rates for extra-nodal lymphomas tends to reflect that of other lymphomas. For example, the age incidence curve of each site-specific extra-nodal lymphoma is similar to that of nodal lymphomas, and in countries where total lymphoma incidence is high the incidence of lymphomas at each extra-nodal site also tends to be relatively high.

Although specific factors are known to increase the risk of lymphomas at certain anatomical sites, these data suggest that the aetiology of extra-nodal lymphomas is not entirely independent from that of nodal lymphomas 10.

UK Non-Hodgkin lymphoma mortality statistics

This page presents non-Hodgkin lymphoma mortality statistics including by age and sex and trends over time

Non-Hodgkin lymphoma mortality rates by age and sex

In 2007 there were 4,533 deaths from non-Hodgkin lymphoma (NHL) in the UK and, reflecting the incidence of the disease, the numbers of deaths in males and females are roughly equal (M:F ratio is 1.2:1.0), however, the male age-standardised mortality rate is higher ( Table 2.1). 1-3

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Mortality statistics for lymphoma are particularly unreliable because many patients die from infections and these, rather than the underlying disease, may be recorded as the cause of death.

As Figure 2.1 shows, the majority of deaths from non-Hodgkin lymphoma occur in older people, over three-quarters in those aged 65 and over and a third in the over 80s. 1-3

 

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Trends in non-Hodgkin lymphoma mortality rates

Reflecting the increases in incidence, the age-standardised mortality rates for NHL in the UK increased by an average of around 3% per year in males and females up to the mid 1990s. At this point the mortality rates peaked, and for the last few years have been showing signs of a decrease, currently reaching 6.5 per 100,000 males and 4.1 per 100,000 females in 2007 ( Figure 2.2). 1-3

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Non-Hodgkin lymphoma survival statistics

This page presents Non-Hodgkin lymphoma survival statistics including one, five and ten year survival rates, and survival rates in EU countries.

Non-Hodgkin lymphoma - one, five and ten year survival rates

There have been significant improvements in one-, five- and ten-year survival from NHL over the past 30 years. For patients diagnosed with NHL in England and Wales in the early 1970s the five-year survival rate was around 30%, but for patients diagnosed in the late 1990s it was around 50% ( Figure 3.1 ). 1 Survival rates are consistently higher in women than men.

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Survival rates for NHL vary significantly by age, the five-year survival rate for those diagnosed aged 15-44 is 65%, while for those aged 65-74 it is 37% and those aged 85+ it is 13%. 2

Non-Hodgkin lymphoma survival rates in EU countries

The age-standardised relative five-year survival rates for male patients diagnosed with NHL 1990-1994 for the European countries participating in the EUROCARE 3 project are shown in Figure 3.2. 3 Survival rates in Wales and Scotland are significantly lower than the European average but rates in England are not significantly different.

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Non-Hodgkin Lymphoma risk factors

This page presents information on non-Hodgkin lymphoma (NHL) risk factors including infectious agents, immunosuppression, genetic susceptibility and environmental factors.

There are a number of well-established risk factors for the development of NHL, although the majority of cases have no clearly identifiable cause. A number of reviews have concluded that the large increases in incidence could not be wholly explained by known risk factors. 1-3

NHL risk factors - infectious agents

Various microbial agents have been associated with NHL, although infection is only one step in the complex chain of events required for cancer development and NHL is not in any sense an infectious disease.

Some of the worldwide increase in NHL is associated with immunodeficiency 4, increasingly common with the HIV infection epidemic. However, the rising incidence of NHL in many countries predates the HIV epidemic. The increased risk of NHL in patients with HIV is well documented, although only approximately 3-5% of people with HIV and AIDS will develop NHL. 5-7

The relative risks of NHL in people with AIDS ranges between 15 for low-grade and T-cell NHL and 400 for high-grade NHL. 8, 9

Infection with Epstein-Barr virus (EBV) is associated with both Burkitt lymphoma, prevalent in malarial areas of sub-Saharan Africa but rare in developed countries, and ‘post-transplant’ lymphoma. 10

There is growing evidence for a causal link between infections and lymphomas of mucosa-associated lymphoid tissue (MALT) such as Helicobacter pylori and primary gastric lymphoma. 11 and Chlamydia psittaci with orbital lymphoma 12.

NHL risk factors - immunosuppression

The use of immunosuppression with organ transplantation is associated with an increased risk of non-Hodgkin lymphoma and in a proportion of cases EBV is implicated 13. The risk of lymphoma rises with the duration and depth of immunosuppression. Around 13% of heart, and 33% of heart/lung recipients have been reported to develop NHL in one series. 14, 15

The chronic immunosuppression associated with rheumatoid arthritis and its treatment also carries a slightly increased risk of lymphoma. 16

NHL risk factors - genetic susceptibility

The role of genetic susceptibility is poorly defined at present. A high incidence of B cell lymphomas has been associated with ataxia telangiectasia and with genetically determined immune deficiency states such as common variable hypogammaglobulinaemia. 17 Familial clusters of NHL are also known to occur, although the relative contribution of genetic and environmental factors is undefined. Coeliac disease is a known predisposing factor to intestinal T cell lymphoma.

NHL risk factors - environmental factors

Occupational exposure to chemicals, particularly agricultural chemicals, has been suggested by several studies as a risk factor for NHL. 18-20 Immunosuppression can also be caused by agricultural and industrial chemicals, and these could be responsible for at least some of the rise in incidence of NHL.

There are local excesses of NHL in rural areas, relatively high incidence rates among farmers and horticulturalists 21, and associations between exposure to agricultural biocides and risk of NHL.

However, whilst atrazine, lindane and phenoxy herbicides such as 2,4D have all been implicated in some studies, current evidence does not show a clear-cut association between any specific agricultural chemical and lymphoma. 22-25

Associations have also been found between exposure to tetrachloroethylene, a solvent widely used for dry cleaning and degreasing, and various forms of cancer including non-Hodgkin lymphoma. Although the published evidence for increased risk of NHL among people working with tetrachloroethylene is limited to three cohort studies, their results are consistent. 26, 27

Non-Hodgkin lymphoma classification and staging

This page presents information on non-Hodgkin lymphoma (NHL) classification and staging.

Classification of non-Hodgkin lymphoma

In the World Health Organisation (WHO) system, 1 non-Hodgkin lymphomas are classified as far as possible according to their normal counterparts in B or T lymphocyte lineage. In addition to its biological relevance, this system has direct clinical applicability and is becoming the accepted international standard.

An increasing number of cytogenetic and molecular abnormalities are now being identified in various subtypes of NHL. These abnormalities often result in the over-expression of oncogenes, or of anti-apoptotic genes. Although their clinical significance remains unclear, there is emerging evidence that some of these abnormalities may provide prognostic information, and that they may prove useful ‘tumour markers’ for monitoring the presence of residual disease ( Table 5.1)

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Despite the complex nature of the classification system, many of the major subtypes of NHL can be grouped into low-, intermediate-, or high-grade categories, reflecting their clinical behaviour.

NHL Staging and Prognostic factors

Until recently, the Ann Arbor staging system, which is based entirely on anatomical extent of disease, was the major determinant of therapy in NHL. Although it remains an important factor in treatment decisions, it is now recognised that several other presenting features of the disease are important predictors of outcome.

The International Prognostic Index (IPI) 2 was constructed to provide a predictive model for aggressive NHL, based on presenting features. Patients can be stratified into four risk groups according to their presenting characteristics.

A similar index has now been developed for risk stratification in follicular lymphoma. 3

In addition to the clinical and morphologic features of NHL, aspects of the immunophenotype, genotype and patterns of gene expression are emerging as carrying important prognostic information. For example the expression of Bcl-2 protein is known to carry an adverse prognostic significance in large B-cell NHL, whilst expression of germinal centre markers such as CD10 and Bcl-6 are favourable. 4

Such distinctions have been carried further in microarray-based analysis of gene expression, and the separation into germinal centre type versus activated B-cell type large cell lymphoma on this basis has been described as giving prognostic information independent of the normal clinical index. 5

Interestingly a similar analysis of gene expression in material from follicular lymphoma suggested that the presence of infiltrating immune cells rather than expression of genes by the lymphoma cells themselves gave the most accurate prognostic information, suggesting an important role for the host response. 6

Non-Hodgkin lymphoma symptoms and treatment

This page presents information on Non-Hodgkin lymphoma (NHL) symptoms and treatment including radiotherapy, chemotherapy, monoclonal antibodies, immunotherapy, antimicrobials and new therapies.

Non-Hodgkin lymphoma symptoms

The most common presenting symptom of non-Hodgkin lymphoma is painless enlargement of lymph nodes, which may occur at any site in the body, although the most frequent presentation is in the neck. The disease may involve a single, or multiple groups of lymph nodes.

Systemic symptoms are common, including unexplained fevers, drenching night sweats and weight loss - known as ‘B’ symptoms.

In addition to disease at nodal sites, 15-20% of NHL occur in lymphoid tissue elsewhere in the body. Extranodal lymphomas can occur at almost any anatomical site.

The gastro-intestinal system is the commonest primary extranodal site, although primary NHL of most other organs is well documented. Presenting symptoms may be related to extranodal disease, and may also be due to generalised metabolic complications of NHL, including hypercalcaemia ( Table 6.1)

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The treatment of NHL is undergoing rapid change, particularly with the introduction of specific therapies based upon monoclonal antibodies and small molecules. Notably, NHL is the first illness in which the use of a monoclonal antibody has been shown to improve survival, using the anti-CD20 reagent Rituximab in combination with chemotherapy. 1

In the modern era several different modalities are used for patients with NHL who require treatment:

Radiotherapy treatment for NHL

A minority (10-15%) of patients with low grade lymphomas present with disease restricted to one lymph node group, and around 50% of these may be cured using involved field irradiation. Patients with aggressive NHL are treated where possible with combination chemotherapy, but for those with localised disease an abbreviated course of chemotherapy may be used in combination with local radiotherapy.

Radiotherapy is also used frequently for primary central nervous system lymphoma and for some patients with large masses at presentation.

Chemotherapy treatment for NHL

Single agent: Single alkylating agents (eg Chlorambucil) or purine analogues (eg Fludarabine) are widely used in the treatment of advanced low grade lymphoma, where it is generally accepted that no currently-available treatment is curative, and that the disease will pursue a relapsing and remitting course. (Although around 15% of patients in large series are found to survive long-term free of disease).

Combination: Combination chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) is the standard treatment in aggressive lymphoma. It also produces higher response rates and longer remissions but without comparably increased survival in low grade lymphoma, where it is generally reserved for treatment of recurrence. 2

High dose: Very intensive therapy with autologous stem cell transplantation has been shown to improve survival for patients with recurrent large cell lymphoma who are fit enough to undertake it. 3 It is also used successfully in the treatment of some patients with low grade disease and there is some data to suggest a survival benefit in recurrent follicular lymphoma. 4

Monoclonal antibody treatment for NHL

Monoclonal antibodies which target surface molecules on non-Hodgkin lymphoma cells are now a standard part of NHL therapy.

The antibody Rituximab, which recognises the CD20 B-cell marker, can be used alone for the treatment of low grade B-cell lymphoma or in combination with chemotherapy, particularly for aggressive types. 5 An anti-CD20 antibody can also be conjugated to a radioisotope such as Iodine-131 or Yttrium-90 to deliver targeted irradiation. 6

There are antibodies which can target T-cell lymphomas, and a recombinant protein comprising part Interleukin-2 and part diphtheria toxin (denileukin diftitox) is used for cutaneous T-cell lymphoma which expresses the CD25 interleukin-2 receptor.

Immunotherapy treatment for NHL

A variety of vaccines have been developed to provoke active immunity against lymphoma, many of them using the unique surface immunoglobulin sequences (the idiotype) as a tumour-specific target. 7 These are the subject of ongoing clinical trials.

A less specific but more potent form of immunotherapy is the use of allotransplantation, in which donor stem cells are used to reconstitute the immune system after ablative therapy, giving rise to a graft-versus-lymphoma effect. The use of reduced intensity treatment regimens has made this a safer procedure recently, and for low grade NHL in particular the early results of clinical trials appear promising. 8

Antimicrobial therapy treatment for NHL

The identification of infectious agents as pathogenic in some types of lymphoma has led to testing of antimicrobial agents in their therapy.

In gastric MALT lymphoma the eradication of Helicobacter pylori has been shown to produce regression of the disease in a high proportion of cases 9, and similar findings are emerging from the use of tetracycline in patients with orbital lymphoma.

The use of antiviral agents in EBV-related lymphoproliferative diseases is also showing promising results in clinical trials.

New therapies for NHL

Small molecule targeted therapy has also been tested in lymphoma. Agents such as the anti-angiogenic thalidomide, the proteosome inhibitor bortezomib, the inhibitors of the mammalian target of rapamycin and of histone deacetylases have all entered clinical trials with interesting responses being seen. 10

The incidence of NHL is increasing which is partly due to increases in immunodeficiency, auto-immunity and viral infections. In most cases the causes of NHL are still not understood.

There have been some important advances in understanding the development of healthy lymphocytes and the pathogenesis of NHL, yielding significant improvements in the use of specifically targeted therapy. In many cases of NHL treatment results in cure, and the proportion of these is rising.