Keywords:

Haematological malignancies; the rationale for integrated Haematopathology services, key elements of organisation and wider contribution to patient care.

Introduction

The 1995 Calman-Hine report of oncology services [START_REF]Cancer to the Chief Medical Officers of England and Wales[END_REF] in the United Kingdom began a process of service improvement driven by the recognition that UK cancer outcomes were inferior to those achieved in comparable countries [START_REF] Woodman | Are differences in stage at presentation a credible explanation for reported differences in the survival of patients with colorectal cancer on Europe?[END_REF][START_REF] Gatta | Towards a comparison of survival in American and European cancer patients[END_REF][START_REF] Capocaccia | The Eurocare Working Group. Cancer survival increases in Europe but international differences remain wide[END_REF] . The approach taken was to re-design the delivery of care around the patient, local multi-disciplinary teams and regional cancer networks. The process of care was later defined by the National Institute of Clinical Excellence (NICE) in Improving Outcomes Guidance for Haematological Oncology 2003 [START_REF]Improving Outcomes in Haematological Cancers[END_REF] and its implementation audited through the Cancer Peer Review process. The process of implementation has been difficult and seven years later, many cancer networks have not complied fully with some of the key recommendations. The most challenging recommendation has been the requirement to develop integrated laboratories for the diagnosis of haematological malignancy and this is an area of NICE guidance that has not been achieved.

The unified concept of haematological malignancy is recent and based on understanding cellular pathology of the bone marrow and immune systems. Historical UK pathology practice has previously resulted in the separation of laboratory haematology from histopathology and separation of liquid and tissue specimens. Proposals for re-integration and centralisation with specialist-led 3 centralised diagnostic services and reporting [START_REF] Richards | The development of integrated haematopathology laboratories: a new approach to the diagnosis of leukaemia and lymphoma[END_REF] challenged the historical model with its fragmentation of processes and techniques.

Accuracy and certainty of diagnosis remains an ongoing problem which particularly applies to lymphomas with evidence that concordance of diagnosis for lymphomas is slowly improving but still only approaching 85% in two recent reviews [START_REF] Proctor | The importance of expert central review in the diagnosis of lymphoid malignancies in a regional cancer network[END_REF] (personal communication Byers and Norton 2008). The financial costs of a precise diagnosis are a small fraction of treatment costs and there is a potentially significant human and financial cost of diagnostic errors.

Finally, no nationwide, validated and comparable epidemiology/population based data exist for accurate and complete ascertainment of new cases of haematological cancers, service planning or clinical outcomes monitoring.

This article examines the original rationale behind the NICE guidance and outlines the key components and processes of an integrated diagnostic service.

Original Rationale and Evidence -NICE guidance 2003

The National Institute for Clinical Excellence laid out the rationale, evidence and recommendations for haemato-oncology services in 'Improving Outcomes in Haematological Cancers -The Manual' in 2003 [START_REF]Improving Outcomes in Haematological Cancers[END_REF] .

The NICE guidance clearly identified that the haematological malignancies are a complex group of neoplastic diseases and the current WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2008 [START_REF] Swerdlow | World Health Organisation Classification of Tumours: Pathology and Genetics[END_REF] identifies over 140 diagnoses and subtypes in 12 major disease groups. Scientific advances have challenged and transformed diagnosis, classification and patient management so that specialist immunophenotyping, cytogenetics and molecular methods have become essential adjuncts to traditional morphology for accurate disease classification. Accurate diagnosis and sub-classification requires integration of the morphological, immunophenotypic and genetic features [START_REF]Pathology and Genetics of Tumours of Haemopoietic and Lymphoid Tissues[END_REF] . These techniques are now fundamental not only for diagnosis but also for patient treatment and monitoring in the era of targeted monoclonal antibodies and novel agents for specific molecular abnormalities. Unlike most other solid tumours which are initially biopsied and then surgically removed, there is no second tissue sample for confirmation of most haematological tumours, the bulk of which remains in the patient at the time of treatment. Thus the maximum amount of diagnostic, therapeutic and prognostic information must be generated by the laboratory on the initial biopsy sample.

A central conclusion from NICE was that 'Individual patient management should be based on sound and comprehensive information to define the most appropriate treatment' which recognised that consistency and accuracy of diagnosis was not only the starting point but probably 'the single most important aspect of improving outcomes in haematological cancers'. There is consistent evidence of a significant level of inaccuracy of diagnosis and that expert review improves diagnostic accuracy. This was derived from audit and reviews which showed significant errors in diagnosis that would affect treatment and these are summarised in Table 1.

Insert table1

Extrapolation of the evidence derived from the Welsh review (up to 5% of patients treated for lymphoma in Wales had benign disease) suggests that annually 400 people might receive an inappropriate cancer diagnosis and unnecessary treatment in England. Cost savings from avoided misdiagnosis in England are unknown but could be substantial. In addition, many more patients may have received sub-optimal treatment because their disease is incorrectly classified.

These problems are by no means limited to the United Kingdom and similar problems in the diagnosis of lymphoma [START_REF] Wolf | Evaluation of pathology review of malignant lymphomas and Hodgkin's disease in cooperative clinical trials. The Eastern Cooperative Oncology Group experience[END_REF] and acute leukaemias (15) were reported from the USA and support the view that expert review of pathology improves diagnostic accuracy. The financial costs of a precise diagnosis are a small fraction of the cost of treatment and the human cost of diagnostic error is potentially enormous

If progress was to be made as part of the National Cancer Plan, how was this to be achieved? NICE guidance challenged the current organisation of the NHS and made important recommendations about service organisation and delivery. It supported local initial assessment of specimens leading to appropriate referral to identified specialist immunophenotyping, molecular biology and cytogenetics services and facilities. This was incorporated in the Cancer Peer Review measures (1A-248, 249 and 250) [START_REF]Measures for the Manual for Cancer Services 2004: Haematology, head and neck and cancer registry[END_REF] . The guidance supported the Department of Health's development of clinical networks in pathology across Trusts to build capacity reduce fragmentation and provide enhanced levels of equipment and expertise (Carter Report (17) ). Finally, it recommended the organisation of clinical and pathology haematological services at network level, with collaboration between networks to achieve economies of scale and with specialist diagnostic services serving one or more networks.

In order to reduce errors, the guidance recommended that every diagnosis should be reviewed by specialists in haematological malignancy. This was to be achieved by integrating the results of specialist tests into a final report with an overall interpretation and diagnostic opinion which is authorised by a single designated pathologist (CPR Measure 1C-122) [START_REF]Measures for the Manual for Cancer Services 2004: Haematology, head and neck and cancer registry[END_REF] . This is most easily achieved by co-locating all specialist haemato-pathology diagnostic services in single laboratories, having integrated diagnostic processes with a systematic approach to the choice and With this way of working, the results can be integrated into a single interpretative report containing all the information relevant to the management of the patient and avoid the duplication and possible contradictions that may arise when these key investigations are carried out in separate laboratories.

Quality of the new organisation and diagnostic systems is assured by all laboratories participating in CPA and external quality assurance schemes as well as a systematic approach to diagnostic testing with a specified range of tests carried out on each sample in a systematic way, following protocols that define order and choice of test.

In addition, results of tests were to be integrated and interpreted by experts who work with local haemato-oncology multi-disciplinary teams (MDTs) and provide a specialised service at network level. The MDT is the final quality check confirming that all clinical, imaging and pathology results are concordant.

Of major concern was the fact that there were no precise or reliable figures for incidence or survival rates for the haematological cancers in England and Wales and it is not possible to judge whether clinical outcomes are better or worse than elsewhere in the world. Future service planning for the NHS requires knowledge of incidence and prevalence rates both of which are changing in the UK. Updatable computer software designed to support precise identification of haematological malignancies is required for diagnostic laboratories to facilitate accurate populationbased studies of epidemiology and clinical outcomes.

Finally, the guidance identified resource implications for setting up these services which have high capital and revenue costs. Rational selection of diagnostic tests following defined protocols can conserve resource by only selecting tests yielding useful information. There are also substantial economies of scale that can be achieved and obvious economic implications of the current guidance as these specialist laboratories have high capital and revenue costs.

Cost implications of centralising and integrating laboratories varies according to the degree of centralisation already achieved, additional equipment required, inclusion of gene sequencing facilities and size of population served.

Costing exercises predicted national capital set-up costs of approximately £5.8million with annual running costs of £7.5 million were predicted but with cost-effectiveness linked to the size of population served; i.e. a low-cost scenario with an anticipated catchment population of 3 million or more and a high-cost scenario for smaller populations down to 1.5 million. The original NICE guidance has been misinterpreted by some as simply collating the individual results into a report and at a minimal level, stapling a variety of individual reports together, with or without adding a comment. It is also clear from the NICE guidance that it is inappropriate to have a local report produced and then sent on for "central review" or "integration" into the final diagnostic report. This undermines the integrated diagnostic process and immediacy of access to samples for additional testing as well as the internal validation and quality assurance given by systematic investigation processes. Inevitably it will lead to delays in the turn around of a meaningful, high quality diagnostic report within a time-frame that allows for timely decision making and this will impact on cancer pathways which all trusts are under pressure to comply with.

The Integrated Diagnostic

The underlying principle is that effective working requires an integrated diagnostic pathway and this is what was clearly intended in the original IOG publication. This process is characterised by a single point of access for all samples, registration, initial screening, investigation, reporting and authorisation. It requires a predefined diagnostic pathway that is followed systematically for each specimen type or clinical problem. The design of the pathway includes two components: 1) selection of the most appropriate diagnostic platforms for a particular clinical situation and 2) selection of a panel of investigations for each specimen to provide maximum levels of internal cross-validation using the WHO principle of multi-parameter disease definitions whilst avoiding unnecessary duplication. To achieve this requires comprehensive diagnostic testing facilities, technologies and interpretation (including cytomorphology, histology, immunocytochemistry, flow cytometry, cytogenetics and molecular technologies). This is followed by review of all of the results and compilation within the laboratory of a fully integrated report by senior laboratory staff with appropriate levels of expertise which is then released to the referring clinician. This affords the opportunity for internal validation and cross-checking at source, before a misleading or potentially dangerous report leaves the laboratory. In addition, this should be completed in a timeframe that allows additional investigations to be carried out if inconsistencies or uncertainties remain after the primary investigations have been completed. An integrated report that includes all information needed for initial patient management should be available at the multidisciplinary meeting (MDM) and the final report should summarise the results of investigations performed, contain an interpretative comment and a final diagnosis using the terminology of the WHO classification/ICDO-3 coding. An effective system of quality assurance should include an audit trail for each sample demonstrating that the diagnostic pathway has been followed, as well as traditional external quality assurance schemes.

In many cases this will require significant re-engineering of existing services to achieve the benefits described below. However, in most cases many of the core resources required to do this will already exist within the network.

Review of Rationale and Anticipated Benefits

The original rationale for the guidance was the recognition that the error rate in the diagnosis of haematological malignancies was unacceptably high and had clinical consequences. This was based on publications and audit data. Seven years later this data is challenged by some who claim that this is no longer the case. However, there is evidence that the underlying problem, although improving, still remains and this has been confirmed in two recent reviews. The first was an audit carried out in Greater Manchester (A Norton and R Byers 2008) who found the serious and critical error rate to be 15%. This data refers to the diagnosis of lymphoma but similar results would be expected in other diagnostic categories. The second review was undertaken in North London and whilst error rates have fallen between 2003 and 2008, they are still substantial (13-15%) resulting in minor or major changes in treatment or delay in treatment [START_REF] Proctor | The importance of expert central review in the diagnosis of lymphoid malignancies in a regional cancer network[END_REF]. This is the essential context for the following discussion.

Quality Assurance

These concerns about standards of diagnosis serve to highlight a more fundamental problem that is almost unique to haematological oncology. For most types of cancer, the diagnosis made on an initial biopsy or cytology specimen will result in a secondary operative procedure and specimen which provides independent validation of the original diagnosis. Visualisation of the lesion at endoscopy or operation adds further steps in the diagnostic process contributing to overall confidence in the accuracy of the original diagnosis. For leukaemia and lymphoma a diagnosis made on a pathological specimen will generally lead directly to treatment by chemotherapy or radiotherapy. This may be based primarily on subjective morphological interpretation of cytology preparations or tissue sections by a pathologist. Unless a subsequent review is undertaken serious errors will not be detected. External quality assurance schemes designed to test morphological interpretation are difficult to design for haematopathology given the very large numbers of possible diagnoses. More importantly, by their nature, they are retrospective and based on circulated material to test overall performance rather than detect and prevent errors in 'real time' diagnostic samples. A 'real time' quality assurance scheme should be a target which a network of integrated diagnostic centres could explore and exploit.

Fortunately, recent developments in classification and technology provide a solution to this problem. The WHO classification defines each type of leukaemia and lymphoma in terms of morphology, phenotype, molecular and cytogenetic features and clinical characteristics. If all of the defining features can be demonstrated there is a high probability that the diagnosis is correct. This is the rationale for the integrated diagnostic pathway described above. Technical developments mean that it is now possible to design pathways that contain multiple levels of cross-validation between techniques. Adherence to these pathways is the critical element in diagnostic quality assurance and provides clinician and patient with the level of confidence in the diagnosis that is required before proceeding to treatment. In Haemato-oncology the critical element is the ability to demonstrate that a diagnosis is likely to be correct through a process of internal validation using multiple independent diagnostic techniques. Where this process is absent, particularly where the primary diagnosis is based mainly on subjective assessments, there will be a major weakness in the quality assurance of the whole patient pathway leading to the possibility of undiscoverable errors. As retrospective audit data has demonstrated, these risks are unacceptably high. A systematic approach to the investigation of suspected leukaemia and lymphoma based around a carefully designed pathway is essential. If this is the approach taken then important entities that cannot be reliably identified by morphology alone will be mis-diagnosed. The problem is not simply a function of morphological interpretation, as shown in a recent European study of the reproducibility of immunocytochemistry (18) .

Morphology is no longer a gold standard; though an important starting point it must be complemented by other studies. A very striking example is the recent MRC LY10 trial in Burkitt lymphoma (BL) [START_REF] Mead | A prospective clinicopathologic study of dosemodified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial)[END_REF] . This is a critical diagnostic area and about 50% of patients entered in the trial were proven not to have Burkitt Lymphoma on review and further investigation. The implications of this data are that half of the patients in the trial had the wrong treatment -in this case expensive and toxic in-patient chemotherapy. The trial took 3 years to recruit approximately 60 patients while the incidence in the UK is about 250 per year (Yorkshire and Humber Haematological Malignancy Research Network data [START_REF]Haematological Malignancy Research Network[END_REF] ). It is very likely that many patients with BL are currently not recognised. This condition is very successfully treated with intensive chemotherapy but not with CHOP-R which is the standard treatment of diffuse large B-cell lymphoma. The specific cause of this problem is the fact that Burkitt Lymphoma cannot be reliably diagnosed by morphology alone and requires systematic use of extended immunophenotyping and FISH investigations.

A similar situation pertains in a number of other types of haematological malignancies. These conditions will only be recognised reliably if a diagnostic pathway designed to sensitively detect them is applied systematically to all specimens in the appropriate setting. This particularly applies to rare, low-frequency tumours.

Finally, the assessment of prognosis is an increasing component of the workload of laboratories engaged in the diagnosis of leukaemia and lymphoma. This includes the identification of prognostic markers at the time the patient presents and the use of monitoring through therapy. This is a highly complex area involving the integration of multiple forms of investigation which should ideally be combined into a single assessment of outcome. The same considerations apply to the assessment of prognosis and response to treatment as for primary diagnosis. Clinically important decisions depend on accurate monitoring during the course of therapy.

Cost Effectiveness

The traditional approach to the diagnosis of leukaemia and lymphoma is wasteful and often ineffective. If there is no integrated diagnostic pathway samples are often sent to multiple separate laboratories specialising in individual techniques. As a matter of routine, each laboratory carries out its own series of investigations based only on the referral information and which, pre-diagnosis, may be imprecise. The data produced may be irrelevant to the clinical problem or needlessly duplicate information produced in another laboratory. Cost-effectiveness depends on rational choices of investigative techniques, balancing cross-validation against reduplication. There are 3 key examples that illustrate this problem.

(i)The demonstration of genetic abnormalities This is a central element in the diagnosis of leukaemia and lymphoma. There are many techniques available to demonstrate individual abnormalities and these are often done in different laboratories. In an integrated diagnostic laboratory the most appropriate technique for a particular clinical situation can be selected and unnecessary duplication avoided. This is particularly important in the case of metaphase cytogenetics and other very high-cost techniques. In Leeds, implementation of audit data reduced the use of conventional metaphase cytogenetics by 60% (personal communication, A Jack). For many of these specimens there was no indication for any genetic investigation while for others, a simpler more targeted technique was used in the diagnostic pathway.

(ii)Reporting of Bone Marrow Specimens

It is common practice in the UK for the bone marrow aspirate, bone marrow trephine biopsy and flow cytometry to be investigated and reported separately in different departments. Each of these components is required for the final diagnosis and examining each separately is wasteful in time and resources and is clinically ineffective. It has been suggested that reporting a trephine biopsy in isolation requires up to 45 minutes of an histopathologist's time and usually results in further immunocytochemical investigations. An additional 15mins of a consultant haematologist time would be spent separately reporting the aspirate. Reporting the trephine and aspirate together, with flow cytometry data available, reduces the time taken an average of 15-30mins (personal communication, A Jack). The availability of flow cytometry results at the time of reporting greatly reduces the need for immunocytochemistry to around 10% of cases. Even in centres with a small workload this is a very significant cost improvement.

(iii)Investigation of Lymph Node Biopsies

Most lymph node biopsies are sent in fixative to Histopathology departments. This precludes the use of flow cytometry and compromises molecular investigations even although these tests may be available in other departments of the same institution. Flow cytometry and molecular studies considerably enhance the quality of diagnosis of nodal lymphoid malignancies by providing a tumour specific phenotype and fast and reliable detection of clonal B-cell populations. The use of modern multiparameter flow techniques allows much more reliable definition of cellular population compared to a conventional approach based on morphology and immunocytochemistry. This approach is commonplace in other developed countries but not in the UK. As well as improved diagnosis, the reporting time is reduced because flow cytometry is carried out in parallel with the histology processing and the results are available when the tissue sections are examined. A turnround time of 2-3 days is readily possible.

These three examples represent a major component of haematopathology workload and demonstrate that savings are possible in an integrated model as opposed to separate laboratories based on individual techniques.

A fundamental weakness of the traditional approach is that the onus is placed on the clinician or the MDM to bring together these disparate and sometimes highly complex pieces of information. In most cases the individuals concerned do not have the experience and competence to do this to the standard required. This issue was raised as a matter of concern in the Carter Report (17) . NICE guidance highlighted four levels of diagnostic service clearly demonstrating the national variation in access to diagnostic services (Table2).

Insert Table 2

Level 3 and 4 services are still rare.

These problems of effectiveness can be overcome in a fully integrated laboratory and it would be expected that significant savings would also be made by eliminating duplication. However, a fully effective diagnostic integrated haematopathology service requires considerable investment in specialist staff and equipment and this places constraints on the minimum workload that is consistent with cost-effective operation. In this context the benchmarks for cost-effective operation should mean providing the enhanced service at unit costs equal to or less than existing services based on multiple laboratories. This is a complex calculation but is achievable where a laboratory serves a catchment population of 3-4million (Personal communication, A Jack).

Technical and Organisational Developments

Diagnostic techniques and basic concepts of disease have entered a phase of rapid evolution. This has been driven by an impressive expansion in knowledge which has, in turn, been the result of very high levels of investment in research by government, charities and the commercial sector. These developments promise very significant benefits to patients. Structures within the NHS should be specifically designed to facilitate the introduction of these techniques into clinical practice.

In Haemato-oncology the benefit to patients includes improved certainty and accuracy of diagnosis, the use of minimally invasive techniques, improved assessment of prognosis, risk stratification, the effective use of new targeted therapies and improved disease monitoring following treatment. The service described in this document is particularly suited to the introduction of the new generation of diagnostic techniques through the flexible use of skilled staff and the use of structured diagnostic pathways. Where services are fragmented and uncoordinated, appropriate research and the introduction of new technologies and concepts may be very difficult, not least because of the problems of transferring staff and resource between traditional departments and institutions. This has been clearly demonstrated in the evolution of many services. Underpinning these technical changes is a need for laboratories to have a sufficient critical mass to undertake diagnostic research, technology development and training of scientific and medical staff.

The Need for Accurate Data The national datasets for leukaemia and lymphoma are extremely poor and this has been highlighted by Eurocare and others [START_REF] Sant | EUROCARE-4. Survival of cancer patients diagnosed in 1995-1999. Results and commentary[END_REF][START_REF] Gata | Cancer survival differences between European populations: the UK uneasiness[END_REF] . Publishing data on incidence and outcome for all leukaemia and lymphoma patients (current practice in the UK) is effectively meaningless (but costs a lot). The main problems in this area are incomplete ascertainment of all new cases because primary data resides in multiple laboratories and clinical databases and there is a lack of standardised approach to diagnosis. The ability to provide high ascertainment of new cases and detailed datasets that can be used for analysing outcome and service performance is a major benefit of network-based integrated laboratories that extend beyond the direct patient pathway [START_REF] Smith | The Haematology Reseach Network (HMRN) new information strategy for population based epidemiology and health services research[END_REF] . Ascertainment of new cases, as well as follow-up, is required to derive incidence and prevalence data, the latter being an important measure for healthcare planning and resource allocation which cannot be derived from Death Certification Only data. This approach is in line with the National Cancer Intelligence Network initiatives.

The points summarised above demonstrate the benefits of integrated laboratories with effective diagnostic pathways and links to effective population based cancer databases. These anticipated benefits are now much broader and with potentially greater impact across the whole patient pathway, including clinical trials support, research, biobanking, patient outcomes and service planning, than was originally envisaged in the Haematology IOG (Figure 1).

Insert Figure1

Key components and processes

The provision of an integrated diagnostic service, as set out above, is most easily achieved in a single laboratory with a full complement of specialist staff and equipment. It is possible, although much more difficult, to design a compliant service based around multiple laboratories each providing a component of the service. Irrespective of how the service is structured there are a number of essential components:

Organisation

The service should have clearly defined organisational structures including an identified person responsible for the operation of the service, design of the diagnostic pathway, the use of resources and standards of reporting. The service lead should have formal accountability to the Cancer Network Site Specific Group.

To facilitate organisational management, operation and development, managerial and financial responsibility should rest with a single Trust with defined business planning processes to ensure that diagnostic and therapeutic developments are coordinated. The speed of clinical and diagnostic technological development demands effective horizon scanning and funded implementation of new therapeutic and diagnostic technologies. A key element of organisational and operational quality is achieved through a central reception point for all specimens even if some tests may be performed at a different location. There is a logical flow of samples from registration to initial screening, systematic investigation, reporting and authorisation. There should be a full range of protocols covering sample handling, the diagnostic pathways, compilation of reports and relationships with users. The essential 'glue' that makes this possible is an Information technology (IT) system that regulates the diagnostic pathway, compilation of reports, reporting of diagnoses sub-typed by the WHO leukaemia/lymphoma classification and communication with users. This can be a commercially available system or one produced in-house. Quality is assured at several different levels; Cancer network planning, organisational integrity, systematic investigation protocols, formal accreditation by Clinical Pathology Accreditation (either as a standalone department or as part of haematology) and finally a close interface with the MDT which is the final quality check in the process with the clinicians managing the patient.

Diagnostic Pathways and Technologies

The diagnostic pathways and protocols that are agreed with networks form part of the network guidelines and be accessible to users. The key diagnostic technologies are flow cytometry, histocytopathology and immunocytochemistry, cytogenetics (including FISH) and molecular genetic PCR based techniques for detection of clonality, chromosomal translocations and mutations.

It is important to realise that these technologies each include a very wide range of options within each category and that many centres in the UK use methods and equipment that could be considered as obsolete (e.g. two colour flow cytometry).

The specification of range of acceptable techniques needs to be regularly reviewed. The need for specialist staff is also a critical consideration.

Multiple new technologies are becoming available for routine use. These include advanced 8-10 colour flow cytometry, gene expression profiling, whole genome copy number analysis and new generation high throughput sequencing. These will have a substantial impact on the nature of the service provided to patients. These technologies are capital intensive but with potential for savings in staff and recurrent costs. If implemented in centres with a high workload then there is potential to contain or reduce overall unit costs. To realise these savings, obsolete methods of investigation will need to be discarded, again emphasising the need for a coordinated approach to integrated diagnostic pathways rather than the current ad hoc approach found in many areas. The specialist diagnostic laboratory should be fully integrated with the clinical services and must be able to provide support to multi-disciplinary teams within the network. There should be clearly identifiable contacts for discussion of clinical problems and defined mechanisms for ensuring consultation with users on the organisation and performance of the service. Modern IT systems can provide secure electronic data repositories for results lookup and customised e-mails alerts to clinicians when results become available.

Conclusions

There are very significant quality improvements to be gained from implementing this service model. The central requirement is to demonstrate that diagnoses are correct through following a systematic protocol for investigation and reporting. Financial savings are also possible both from improved efficiency of the diagnostic process and from reduction in error. These financial gains are only achievable by centralised services where the effects of relatively high fixed costs are offset by a high workload and correspondingly low unit costs. Experience in several centres has shown that services can be provided by a centralised facility serving more than one network whilst maintaining a high level of integration with clinical services. This is fully consistent with the approach outlined in the Carter Report (17) and more recently in the NHS Confederation document 'Dealing with the Downturn' [START_REF]Dealing with the downturn: using the evidence[END_REF] .

To make real progress with implementation of the diagnostic aspects of NICE guidance requires a national approach to achieve uniformity of quality and equity of access to modern diagnostic technologies and expertise. This would best be achieved through the establishment of a national network collaborative with a national outline specification for the service and a revised set of Cancer Peer Review measures.

Such an approach would provide clarity of organisation, operation and function, coordinate and support development of services and reduce fragmentation. There is a need to build capacity and access with enhanced equipment and expertise as well as stimulate collaboration to achieve economies of scale, improved purchasing power and cost-effectiveness. On a national scale is it possible to implement innovative 'real-time' quality assurance schemes appropriate for malignant haematopathology to improve and assure quality of diagnostic pathways. Improved ascertainment of diagnostic data for epidemiological studies and service provision linked to population-based databases concords with the National Cancer Intelligence Network and Cancer Plan initiatives. A minimum critical mass of resources is required to maintain the research, education and training for the future needs of the service together with a strong linkage between clinical and diagnostic elements to maintain progress in patient care.

  Haematological malignancies; the rationale for integrated Haematopathology services, key elements of organisation and wider contribution to patient care.

  and implementing computer software designed to support precise identification of haematological malignancies.

  Pathway and Report -Clarification of the original NICE guidance

Page

  revised histological subtype and a resulting change in management in 10%

  NICE identified concerns about provision, access and accuracy of diagnosis as a result of heterogeneity of the current services which ranged from single-handed pathologists with little access to specialist diagnostics, through to fully integrated specialist diagnostic laboratories. When key investigations are carried out in multiple separate laboratories there may be reduplication and contradictions in results.

	F o r
	P
	e
	e r
	R
	e
	v i e
	w
	4

  Diagnostic centres need sufficient capital and capacity to fund, research, develop, evaluate and implement these new technologies in the setting of increasing clinical requirements for diagnostic sub-classification, cellular prognostic factors, targeted treatment planning (eg detection of BCR/ABL mutations in CML for Tyrosine Kinase resistance and p53 deletion in Chronic lymphocytic Leukaemia) and detection of minimal residual disease. Laboratory services need to be flexible to accommodate rapid implementation of new technologies, maintain platforms of technology research feeding diagnostic services and have capital investment capability. Associated with this is the need for changes in staffing skills mix.

	Interface with Clinical Haemato-oncology
	F o r
	P
	e
	e r
	R
	e
	v i e
	w

Table 1 .

 1 Summary of lymphoma histology audits and reviews from 'Improving Outcomes in Haematological Cancers -The Manual' 2003 from NHL to HL or vice versa.-16 cases of NHL assigned to a different prognostic group.-21% diagnosed as lymphoma but no REAL classification -17 cases would have had a change in management strategy and first-line treatment was altered in 12.

	All Wales	2 year central	Major diagnostic discordance in 20% of cases:
	Lymphoma Pathology Review Panel (10) -15cases changed Lancashire review of 275 -5 cases diagnosed as benign were lymphoma. lymph -13 cases diagnosed as lymphoma were benign or a non-nodes(1998-haematological malignancy. 2000) Hospital centre review (11) Regional -36% had major discrepancies
	NE	100 lymph	-26% diagnostic discrepancy rate that would have changed
	England audit (12)	nodes	management
	Scottish
	and
	Newcastle
	Group


Eve Roman
email: eve.roman@egu.york.ac.uk

Alexandra G Smith

Keywords: Hodgkin lymphoma, Diffuse large b-cell lymphoma, epidemiology, haematological maligancy

Introduction

Epidemiology is the basic quantitative science of public health; and as such is concerned with the distribution, determinants, treatment, management and potential control of disease.

Concentrating on the first two of these, this article aims to review the epidemiology of the lymphomas -a heterogeneous group of malignancies that are estimated to account for around 3-4% of cancers world-wide (Figure 1) [START_REF] Ferlay | Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008[END_REF] . Before considering their epidemiology in any depth, the issue of disease classification -which permeates the discussion throughout is touched on below.

In order to originate and test hypotheses about pathogenesis it is vitally important to accurately describe and understand underlying disease patterns [START_REF] Boyle | World cancer report[END_REF] . Implicit in this is the need to use appropriate disease classifications; and it is this requirement that continues to beleaguer epidemiological research into lymphoid malignancies. In short, the classification of haematological malignancies has changed markedly over recent decades, and will continue to do so as new diagnostic methods and techniques are developed [START_REF] Swerdlow | WHO classification of tumours of haematopoietic and lymphoid tissues[END_REF] . In 2001 the World Health Organisation (WHO) produced, for the first time, a consensus classification that defined malignancies of the haematopoetic and lymphoid systems in terms of immunophenotype, genetic abnormalities and clinical features [START_REF] Jaffe | Pathology and genetics of tumours of haematopoietic and lymphoid tissues[END_REF] . Up until then, competing classifications had often made meaningful comparison of results between epidemiological studies virtually impossible. Although WHO's 2001 classification was adopted into clinical practice almost uniformly around the world, it did not have an immediate effect on population-based epidemiological research. This is because unlike many other cancers, haematological neoplasms are diagnosed using multiple parameters including a combination of histology, cytology, immunophenotyping, cytogenetics, imaging and clinical data. Furthermore, in practice, even within some of the best defined WHO categories there is a need to qualify the final diagnosis even further using additional clinical and biological prognostic factors before valid outcome comparisons can be made [START_REF] Barrans | Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab[END_REF][START_REF] Relander | Prognostic factors in follicular lymphoma[END_REF] . This range and depth of data is difficult for cancer registries and other researchers to access systematically, forming a barrier both to complete ascertainment and to the collection of diagnostic data at the level of detail required to systematically implement the latest WHO classification [START_REF] Jaffe | Pathology and genetics of tumours of haematopoietic and lymphoid tissues[END_REF][START_REF] Swerdlow | WHO classification of tumours of haematopoietic and lymphoid tissues[END_REF] .

Descriptive Epidemiology

Whilst cancer registration has a long history in many countries, particularly those in the more affluent regions of the world, nearly 80% of the world's population are not covered by such systems [START_REF] Parkin | The evolution of the population-based cancer registry[END_REF] . Nonetheless, with a view to characterizing the global burden of disease, the WHO's International Agency for Research on Cancer (IARC) routinely uses the available data to estimate worldwide cancer incidence and mortality levels [START_REF] Ferlay | Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008[END_REF] . Misdiagnosis and undernumeration are, however, recognized problems for haematological cancers. The acute and rapidly fatal presentation of some leading to underenumertion in countries with less well developed health service infrastructures; and the intermittant and non-specific nature of symptoms associated with others [START_REF] Howell | Lymphoma: variations in time to diagnosis and treatment[END_REF][START_REF] Howell | Help-seeking behaviour in patients with lymphoma[END_REF] posing problems even in countries with well-developed health service systems and cancer registration processes. In addition, population-based data continue to be reported in the broad anatomical-based categories of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), myeloma and leukaemia [START_REF] Ferlay | Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008[END_REF][START_REF] Westlake | Cancer incidence and mortality in the United Kingdom and constituent countries, 2004-06[END_REF][START_REF] Jemal | Cancer Statistics[END_REF][START_REF] Sant | Incidence of hematological malignancies in Europe by morphological subtype: results of the HAEMACARE project[END_REF][START_REF] Rachet | Socioeconomic inequalities in cancer survival in England after the NHS cancer plan[END_REF]

International patterns

Incidence figures from IARC's most recent series of estimates are presented in Figures 123.

Of the 12.68 million new cancer cases estimated to have occurred around the world in 2008, 6.64 were in men and 6.04 in women -haematological malignancies comprising 7.5% of cancers in males and 6.4% in females. In both sexes, lymphomas were estimated to have accounted for around half of all newly diagnosed haematological neoplasms (Figure 1).

<Figure 1>

The age-standardized lymphoma rates (NHL + HL) for both sexes combined are globally distributed in Figure 2. With one or two exceptions, the geographical pattern is dominated by the high rates in the more economically developed regions of the world. This is seen more clearly in Figure 3, which shows the estimated regional rates and numbers of cases of NHL and HL separately for men and women (http://globocan.iarc.fr/). Less than half of all NHL and HL diagnoses occurred in the three regions with the highest rates -Northern America, Europe and Oceania -largely reflecting the underlying world population distribution. The most striking disparity is seen for Asia, which has the lowest rates but more than a third of all of the estimated cases.

<Figure 2>

Variations with age and sex

That lymphoid malignancies are generally more common in men than in women is evident in Figure 3. For both NHL and HL the age standardized rates and numbers are consistently higher for males than females -the differences tending to be slightly more pronounced in less developed regions of the world (http://globocan.iarc.fr/) . The sex rate ratios (M/F) for HL, for example, ranged from 1.8 and 1.6 in Africa and Asia through to 1.2 and 1.1 in North America and Europe. Whether or not this gradation reflects genuine differences or biases within the data cannot be ascertained form the available information. The NHL and HL age-specific incidence patterns seen in developed regions of the world are broadly similar to the UK data shown in Figure 4. The relationship with age is, however, quite different for NHL and HL. For NHL, the age-specific male and female rates increase with increasing age, the divergence between the male and female rates becoming progressively more marked as age increases. By contrast, the HL incidence distribution has two peaks -one in young adults and one in the elderly. There is a pronounced male excess in the adult years, but with a slightly earlier peak and deeper trough in females the shapes of two curves are slightly different. These patterns reflect the fact that HL comprises several disease entities, each with its own descriptive features [START_REF] Swerdlow | WHO classification of tumours of haematopoietic and lymphoid tissues[END_REF][START_REF] Mani | Hodgkin lymphoma: an update on its biology with new insights into classification[END_REF] . The impact of such differences on basic descriptive age and sex patterns can be seen more clearly in Figures 567 to be diagnosed at younger ages, but in common with the B-cell form of disease there is considerable subtype heterogeneity -the tight age band for enteropathy type t-cell contrasting with that seen for anaplastic large t-cell, for example. Lastly, with a pronounced paediatric component, HL tends to be diagnosed earlier still, but again there are differences between the subtypes -the median ages within the classical Hodgkin lymphoma (CHL) category, for example, ranging from 37 years for nodular sclerosis CHL to 60 years for mixed cellularity CHL (Figure 6).

<Figure 6>

That males are far more likely to develop lymphoma than females is conspicuously clear in Figure 7 -but it is also evident that the gender disparity is much greater for some subtypes and almost absence for others. Among B-cell NHLs, roughly equal numbers of males and females were diagnosed with follicular lymphoma and with extranodal marginal zone lymphoma; but the sex-rate ratio for all other B-cell lymphomas shows a male bias -the most striking being for Burkitt lymphoma which in these and other series, is at least three times as likely to be diagnosed in males than in females. T-cell NHLs and HLs also exhibit a male bias, but again there is considerable subtype heterogeneity, with angioimmunoblastic T-cell lymphoma running counter to the trend by being more common in women (Figure 7).

<Figure 7>

The wide diversity of descriptive patterns shown in Figures 6 and7 are indicative of different sub-type aetiologies, which many new and ongoing epidemiological studies are aiming to address. However, the continued application of site-based classification systems for routine cancer registration severely limits the use of such data in epidemiological studies. Hopefully, in the future, new insights into lymphoma epidemiology will emerge as the WHO classification becomes more widely applied.

Changes over time

Monitoring disease trends over time is fundamental to descriptive epidemiology, such analyses often yielding important aetiological clues. Indeed, there are many examples in the field of cancer epidemiology where this has been the case, particularly in relation to the

<Figure 8>

The sharp increase seen for NHL between 1970s and 1990s was reported in many developed countries and naturally captured both scientific and public attention at the time (Figure 8). In males, the doubling of the NHL rate over a 20 year period is particularly striking, and contrasts with the modest fall in HL seen in males over the same time period. Whilst it is generally recognized that changing diagnostic practises is almost certainly involved in these trends, there remains debate about whether such changes could have been responsible for all, or only part, of the increase in NHL [START_REF] Boyle | World cancer report[END_REF][START_REF] Hartge | Quantification of the impact of known risk factors on time trends in non-Hodgkin's lymphoma incidence[END_REF][START_REF] Adamson | Time trends in the registration of Hodgkin and non-Hodgkin lymphomas in Europe[END_REF][START_REF] Bosetti | The recent decline in mortality from Hodgkin lymphomas in central and eastern Europe[END_REF] . In this context, the potential aetiological role of human immunodeficiency virus (HIV) as well as other viruses and exposures attracted considerable attention -and these factors are discussed in more detail in the section on causes below.

The rate of change in NHL slowed in the US towards the end of the twentieth century, and similar plateauing has now been reported for other developed regions of the world [START_REF] Bosetti | The recent decline in mortality from Hodgkin lymphomas in central and eastern Europe[END_REF][START_REF] Pollán | Attenuation of the epidemic increase in non-Hodgkin's lymphomas in Spain[END_REF] .

Taken at face-value, this would seem to support the notion that changes in disease detection, diagnostic practise and cancer registration procedures are all likely to have contributed to the increase seen over the 1970s and 1990s. Indeed, the UK Department of Health noted in 2003 that 'There are no precise and reliable figures for incidence and survival rates for the different forms of haematological cancer in England and Wales. Whilst the Office for National Statistics (ONS) and Wales Cancer Intelligence and Surveillance Unit do publish descriptive statistics, there are many problems with these figures. For example, there is evidence that many cases are never reported to cancer registries, so the actual number of patients could be substantially higher than national figures suggest' [START_REF]Improving outcomes in haematological cancer : the manual[END_REF] . Likewise, a recent report examining incidence and survival trends across Europe concluded that 'the evolving classification and poor standardization of data collected on hematological malignancies vitiate the comparisons of disease incidence and survival over time and across regions' [START_REF] Sant | EUROCARE-4. Survival of cancer patients diagnosed in 1995-1999. Results and commentary[END_REF] . Importantly, with respect to the examination of future time-trends, the role of changing diagnostic practice will undoubtedly remain challenging to evaluate since haematological oncology is changing rapidly, with new approaches to treatment and diagnosis continually emerging as diverse patient pathways evolve. In this regard, the use of more reliable and sensitive diagnostic techniques continues to lower the threshold of disease detection -the ability of flow cytometry to detect small populations of abnormal cells, for example, as well as the introduction of polymerase chain reaction (PCR) allowing the detection of disease at a molecular level. Hence, proportionately more of the patients diagnosed today have indolent or asymptomatic disease [START_REF] Relander | Prognostic factors in follicular lymphoma[END_REF][START_REF] Smith | The Haematological Malignancy Research Network (HMRN): a new information strategy for population based epidemiology and health service research[END_REF] , and it remains possible that the increasing numbers of registrations may be due, at least in part, to the recognition of new group(s) of patients that would not have been diagnosed in previous decades.

Aetiology

As discussed above the use of appropriate disease classifications is critical to the research process; and many studies conducted in previous decades have been hampered by the need to aggregate their data into the broad groupings of NHL or HL, either because primary source information was recorded in that way or because diagnostic standards were inconsistently applied. Hence, given the underlying variations in pathologies and prognosis it is perhaps not surprising that many epidemiological reports on lymphomas often begin, and sometimes end, by stating that little is known about the causes of the condition(s) under study. However, this is beginning to change as evidence about the pathological and clinical diversity of lymphoma subtypes continues to accumulate, not only revealing descriptive differences such as those outlined in the previous section, but also other potentially immune-mediated associations. In this regard, it is generally agreed that immune dysregulation plays a pivotal role in lymphogenesis, and most epidemiological research has concentrated on factors and exposures that interact with the immune system.

Infection

It has been known for some time that immunodeficiency syndromes (inherited and acquired) predispose towards lymphoproliferative disorders; and in this regard, the strong association between human immunodeficiency virus /acquired immunodeficiency syndrome (HIV/AIDS) and several B-cell lymphomas has been examined in numerous studies -the increased risks reported ranging from 10 to 300 fold, the highest risks generally been observed for the more aggressive NHL sub-types and the lowest for the HLs [START_REF] Alexander | The non-Hodgkin lymphomas: a review of the epidemiologic literature[END_REF][START_REF] Dal Maso | Epidemiology of AIDS-related tumours in developed and developing countries[END_REF] . Unsurprisingly, the potential role of the HIV/AIDS epidemic was one of the factors evaluated in the context of the striking rise of NHL observed in the 1970s-90s discussed above. NHL rates had, however, begun rise before the onset of the HIV/AIDS epidemic in the 1980s (Figure 8), and even now the contribution of HIV/AIDS to the totality of lymphomas diagnosed in developed countries remains comparatively small [START_REF] Alexander | The non-Hodgkin lymphomas: a review of the epidemiologic literature[END_REF] .

In addition to HIV, a number of other viruses have been suggested to impact on lymphoma risk, albeit by different mechanisms. The most accepted viral associations are those with human t-cell leukaemia virus type 1 (HTLV-1) and the two herpesviruses, Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8) -also known as Kaposi's sarcoma herpesvirus (KSHV). Infection with HTLV_1 is a necessary but not sufficient cause of adult t-cell leukaemia/lymphoma (ATLL), with ATLL developing in around 3% of those infected. ATLL principally occurs in areas where HTLV-1 is endemic, including Japan, the Caribbean and parts of central Africa; and like most other lymphomas it is more common in males than females [START_REF] Swerdlow | WHO classification of tumours of haematopoietic and lymphoid tissues[END_REF][START_REF] Alexander | The non-Hodgkin lymphomas: a review of the epidemiologic literature[END_REF][START_REF] Magrath | The lymphoid neoplasms[END_REF][START_REF] Jarrett | Viruses and lymphoma/leukaemia[END_REF] .

In contrast to the specific nature of the HTLV-1/ATLL association, the globally ubiquitous EBV features in several lymphoma subtypes including Burkitt lymphoma and CHL, as well as those occurring in immunosuppressed individuals. EBV is invariably associated with the endemic form of Burkitt lymphoma that occurs in equatorial Africa and New Guinea; where, with a median age of around 7 years and a male to female ratio of 2:1, it is the commonest childhood malignancy. However, as can be seen from Figure 6, the median age at onset of the comparatively rare sporadic form of Burkitt lymphoma seen in other areas of the world is much later, and the male predominance is much greater (Figure 7). In contrast to endemic Burkitt's, EBV is only associated with around a third of all sporadic cases and the role of EBV in these tumours is a continuing area of research [START_REF] Swerdlow | WHO classification of tumours of haematopoietic and lymphoid tissues[END_REF][START_REF] Magrath | The lymphoid neoplasms[END_REF][START_REF] Orem | Burkitt's lymphoma in Africa, a review of the epidemiology and etiology[END_REF] . Likewise, the significance of the well-established association between EBV and CHL, observed most frequently in children and the elderly in around a third of all cases in resource rich countries -but even more commonly in less affluent parts of the world -remains an area of current investigation [START_REF] Swerdlow | WHO classification of tumours of haematopoietic and lymphoid tissues[END_REF][START_REF] Magrath | The lymphoid neoplasms[END_REF][START_REF] Jarrett | Viruses and lymphoma/leukaemia[END_REF][START_REF] Glaser | Racial/ethnic variation in EBV-positive classical Hodgkin lymphoma in California populations[END_REF] . HHV-8 has been found in several comparatively rare tumour sub-types, where it sometimes occurs with EBV [START_REF] Jarrett | Viruses and lymphoma/leukaemia[END_REF] . The nature of this association, and that of a number of other viruses, including Hepatitis C [START_REF] Jarrett | Viruses and lymphoma/leukaemia[END_REF][START_REF] De Sanjose | Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium[END_REF] , are topics of ongoing research. Bacterial infection resulting in chronic inflammation has been consistently linked with a marked increase in risk of some NHL subtypes -one of the best known associations being that between Helicobacter pylori and gastric mucosa-associated lymphoid tissue (MALT) extranodal marginal zone lymphoma; the presence of the bacteria increasing lymphoma risk by about 6-fold [START_REF] Swerdlow | WHO classification of tumours of haematopoietic and lymphoid tissues[END_REF][START_REF] Parsonnet | Helicobacter pylori infection and gastric lymphoma[END_REF][START_REF] Sagaert | Gastric MALT lymphoma: a model of chronic inflammation-induced tumor development[END_REF] . As with the viral associations (e.g. HTLV-1 and ATLL), bacterial infection very often occurs many years before MALT lymphoma development -the median age of diagnosis of all extra-marginal zone lymphomas combined in the HMRN series being just under 70 years (Figure 6) with no obvious sex bias (Figure 7). Helicobacter pylori infection generally occurs in childhood -the prevalence being highest in developing countries and falling as socio-economic status increases [START_REF] Suerbaum | Helicobacter pylori infection[END_REF] . In the future, the introduction of effective Helicobacter pylori treatments, coupled with increasing affluence developed regions of the world, may well lead to a reduction in incidence of Helicobacter pylori positive gastric marginal zone lymphomas [START_REF] Luminari | Decreasing incidence of gastric MALT lymphomas in the era of anti-Helicobacter pylori interventions: results from a population-based study on extranodal marginal zone lymphomas[END_REF] .

Interestingly, detailed analysis of medical records collected in a UK case-control study revealed significant increases in the frequency of non-specific infectious illness episodes more than 10 years before the diagnosis of CHL, but not of DLBCL and FL [START_REF] Newton | Hodgkin's lymphoma and infection: findings from a UK case-control study[END_REF][START_REF] Crouch | Illness patterns prior to diagnosis of lymphoma: Analysis of UK medical records[END_REF] . Whether or not the excess seen for CHL was a consequence of an underlying immune abnormality, or whether infection played a causal role could not be determined from the available data.

Autoimmune disease

Several well documented links between autoimmune disease based chronic inflammation and MALT lymphoma are also recognized -two of the strongest and most well described being that between Hashimoto thyroiditis and thyroid lymphoma and between Sjögren's syndrome and salivary gland lymphoma [START_REF] Swerdlow | WHO classification of tumours of haematopoietic and lymphoid tissues[END_REF][START_REF] Anderson | Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies[END_REF][START_REF] Smedby | Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium[END_REF][START_REF] Kristinsson | Autoimmunity and risk for Hodgkin's lymphoma by subtype[END_REF] . Consistent associations have also been reported for other chronic inflammatory rheumatic diseases, for example rheumatoid arthritis and systemic lupus erythematosus with both marginal zone and diffuse large B-cell lymphomas [START_REF] Anderson | Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies[END_REF][START_REF] Hansen | B-cell lymphoproliferation in chronic inflammatory rheumatic diseases[END_REF][START_REF] Franklin | Incidence of lymphoma in a large primary care derived cohort of cases of inflammatory polyarthritis[END_REF] , and gastrointestinal inflammatory autoimmune conditions, such as coeliac disease and Crohn's disease, with the T-cell lymphomas [START_REF] Smedby | Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium[END_REF][START_REF] Anderson | Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies[END_REF][START_REF] Tack | The spectrum of celiac disease: epidemiology, clinical aspects and treatment[END_REF] . Indeed, evidence linking lymphoproliferative disorders with autoimmunity continues to accumulate, the strongest associations being seen for marginal zone lymphoma, diffuse large B-cell lymphoma and Tcell lymphoma [START_REF] Smedby | Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium[END_REF][START_REF] Anderson | Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies[END_REF][START_REF] Ansell | Non-Hodgkin lymphoma and Autoimmunity: does gender matter?[END_REF] , and the weakest with the relatively indolent follicular lymphoma [START_REF] Smedby | Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium[END_REF][START_REF] Ansell | Non-Hodgkin lymphoma and Autoimmunity: does gender matter?[END_REF][START_REF] Smedby | Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype[END_REF] . Associations between chronic inflammatory rheumatic diseases and CHL, but not nodular sclerosis HL, have also been reported [START_REF] Anderson | Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies[END_REF][START_REF] Kristinsson | Autoimmunity and risk for Hodgkin's lymphoma by subtype[END_REF] .

Taken as a whole, there is broad consensus that elucidating the mechanisms underpinning the link between autoimmune disease and the lymphomas could lead to fundamental insights into the biology of both groups of disorders, and there is considerable speculation about potential mechanisms in the literature [START_REF] Hansen | B-cell lymphoproliferation in chronic inflammatory rheumatic diseases[END_REF][START_REF] Goldin | Autoimmunity and lymphomagenesis[END_REF][START_REF] Smedby | Autoimmune and inflammatory disorders and risk of malignant lymphomas--an update[END_REF][START_REF] Hellgren | Do rheumatoid arthritis and lymphoma share risk factors?: a comparison of lymphoma and cancer risks before and after diagnosis of rheumatoid arthritis[END_REF] . In this regard routine examination of sex-specific associations could provide valuable information since it has long been known that most autoimmune conditions are considerably more common in women than men [START_REF] Invernizzi | Female predominance and X chromosome defects in autoimmune diseases[END_REF][START_REF] Gleicher | Gender as risk factor for autoimmune diseases[END_REF][START_REF] Fairweather | Sex differences in autoimmune disease from a pathological perspective[END_REF] , whereas the reverse is true for the majority of lymphoproliferative malignancies [START_REF] Swerdlow | WHO classification of tumours of haematopoietic and lymphoid tissues[END_REF][START_REF] Jemal | Cancer Statistics[END_REF][START_REF] Smith | The Haematological Malignancy Research Network (HMRN): a new information strategy for population based epidemiology and health service research[END_REF] . Furthermore, there are well documented sex-specific variations in immune response that may well impact on the risk of these diseases [START_REF] Fairweather | Sex differences in autoimmune disease from a pathological perspective[END_REF][START_REF] Bird | Sex differences and estrogen modulation of the cellular immune response after injury[END_REF][START_REF] Fish | The X-files in immunity: sex-based differences predispose immune responses[END_REF] .

Other factors

In addition to investigating associations with autoimmune and infectious conditions, the InterLymph consortium (http://epi.grants.cancer.gov/InterLymph/), which is an scientific forum for epidemiologic research on lymphomas established in 2001, has reviewed and published on several health related states/events and environmental exposures [START_REF] Boffetta | Consortia in cancer epidemiology: lessons from InterLymph[END_REF] . Thus far, relatively few notable associations have been reported; no consistent effects being seen for self-reported smoking [START_REF] Morton | Cigarette smoking and risk of non-Hodgkin lymphoma: a pooled analysis from the International Lymphoma Epidemiology Consortium (interlymph)[END_REF] , alcohol [START_REF] Morton | Alcohol consumption and risk of non-Hodgkin lymphoma: a pooled analysis[END_REF] , and obesity [START_REF] Willett | Non-Hodgkin lymphoma and obesity: a pooled analysis from the InterLymph Consortium[END_REF] ; and marginally reduced risks being observed for self-reported sun-exposure [START_REF] Kricker | Personal sun exposure and risk of non Hodgkin lymphoma: a pooled analysis from the Interlymph Consortium[END_REF] and history of atopic infections [START_REF] Vajdic | Atopic disease and risk of non-Hodgkin lymphoma: an InterLymph pooled analysis[END_REF] . Finally, with respect to genetic susceptibility, increased risks were confirmed among those with a selfreported family history of haematological cancers [START_REF] Wang | Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 211 cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph)[END_REF] ; and, perhaps more importantly, polymorphisms in two immune-system related genes have been identified using the candidate gene approach, associations being seen for both DLBCL and marginal zone lymphoma [START_REF] Skibola | Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) polymorphisms and risk of non-Hodgkin lymphoma in the InterLymph Consortium[END_REF][START_REF] Rothman | Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium[END_REF] .

Conclusion

This is an exciting time for epidemiological research into haematological malignancy; where the application of modern disease classifications is beginning to discriminate between subtypes revealing features that future aetiological hypotheses should seek to address.

  , which present data from the Haematological Malignancy Research Network (www.HMRN.org ). Established in 2004, HMRN is based in two UK cancer Networks (population 3.6 million) and comprises an ongoing population-based cohort of all patients (paediatric and adult) newly diagnosed by a single integrated haematopathology laboratory -over 2,000 patients each year with all diagnoses routinely coded to the latest WHO classification 15 . <Figure 4> HMRN patients newly diagnosed with lymphoma in the 5-years Sept 2004-Aug 2008 are proportionately distributed by WHO diagnostic category in Figure 5, beginning with the Bcell NHLs, moving clockwise thorough the T-cell NHLs and ending with the HLs 3 . Diffuselarge B-cell (DLBCL), Follicular (FL) and marginal zone (MZL) dominate accounting for more than 70% of the total. The corresponding box-and-whisker age distributions are shown in Figure6, and the sex-specific incidence rate-ratios (male rate/female rate) together with their standard errors in Figure7.<Figure 5>Whilst most B-cell NHLs have a median diagnostic age over 70 years, a significant minority tend to be diagnosed at younger ages -follicular, Burkitt and mediastinal lymphomas having median ages of 65, 52 and 36 years respectively. Furthermore, some have much broader age ranges than others -with no patients diagnosed before the age of 48 years and a median of 74 years, the age distribution of mantle cell lymphoma shows the least variation. By contrast, with a median diagnostic age approaching 71 years, but with several sporadic paediatric cases, DLBCL covers the largest age range -the scatter of outliers at younger ages indicative, perhaps, of diagnostic heterogeneity within this subtype category. Overall, T-cell NHLs tend

  occupational and environmental exposures[START_REF] Boyle | World cancer report[END_REF] . In this context, the temporal changes reported for NHL in recent decades are unquestionably dramatic, as can be seen from Figure8which shows the estimated age-adjusted incidence rates from the Surveillance, Epidemiology and End Results (SEER) Program in the United States (www.seer.cancer.gov).

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8

 12345678 Figure 1 Estimated global cancer frequency for a) males and b) females (Source GLOBOCAN) a) Males

  since, for reasons outlined in the introduction, the laboratory data required to classify haematological malignancies appropriately are hard for cancer registries to access in a timely and systematic fashion

	F o r
	P
	e
	e r
	R
	e
	v i e
	w

Published on behalf of the British Division of the International Academy of Pathology Histopathology