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Abstract
Haematological malignancies are a diverse group of cancers that affect the blood, bone marrow and lymphatic systems. Laboratory diagnosis of haematological malignancies is dependent on combining several technologies, including morphology, immunophenotyping, cytogenetics and molecular genetics correlated clinical details and classification according to the current WHO guidelines. The concept of the Specialised Integrated Haematological Malignancy Diagnostic Services (SIHMDS) has evolved since the UK National Institute for Health and Care Excellence (NICE) Improving Outcomes Guidance (IOG) in 2003 and subsequently various models of delivery have been established. As part of the 2016 update to the NICE IOG, these models were systematically evaluated and recommendations produced to form the basis for quality standards for future development of SIHMDS. We provide a summary of the systematic review and recommendations. Although the recommendations pertain to the UK National Health Service (NHS), they have relevance to the modern delivery of diagnostic services internationally.
- HAEMATO-ONCOLOGY
- HAEMATOPATHOLOGY
- MOLECULAR GENETICS
- CYTOGENETICS
- FLOW CYTOMETRY
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Introduction
The National Institute for Health and Care Excellence (NICE) service guidance is based on the best available evidence of clinical and cost-effectiveness, and is produced to help commissioners, NHS Trusts, managers, healthcare professionals and patients make informed choices about appropriate healthcare to improve the effectiveness and efficiency of healthcare services.
Haematological malignancies include leukaemias, lymphomas and myeloma and originate mainly in the bone marrow and lymph nodes. They are a diverse group of diseases affecting people of all ages, but with highest incidence among the elderly. Prognosis and responsiveness to treatment of these conditions also varies widely. Haematological malignancies accounted for 8.4% of all malignant disease (excluding non-melanoma skin cancer) diagnosed in England in the years 2001–2010.1
Accurate diagnosis of haematological malignancies involves haematological and histopathological cytomorphology, immunophenotyping by flow cytometry and/or immunohistochemistry, cytogenetics and molecular genetics, including cutting-edge technologies, such as next-generation sequencing. Clinical information is also essential, both at the time of specimen analysis and when discussing diagnostic reports in a multidisciplinary team meeting. This approach is built into the WHO classification for all haematological malignancies and updates of this classification2–4 provide a diagnostic framework that emphasises the importance of integrating all these modern diagnostic tests.
Historical evidence, based principally on lymphoma, supports between 5% and 15% of haematological malignancies being misdiagnosed, sometimes with major clinical consequences.5–7 Such errors can be difficult to detect after a patient has been treated and so it is very important that the initial diagnosis is correct and supported by strong evidence from several independent investigative modalities.
In the UK, the 2003 NICE Improving Outcomes Guidance (IOG) for Haematological Malignancies emphasised the importance of an integrated diagnostic approach to haematological malignancies.8 The original guidance defined two levels of haematological malignancy diagnostic service—a local service, which provides initial assessment of specimens and a specialist laboratory service. A specialist service uses predefined diagnostic pathways to analyse specimens using a variety of diagnostic modalities, then validates and correlates the results to produce an integrated diagnostic report. This approach has been gradually adopted across the country and the specialist laboratories are now known as Specialist Integrated Haematological Malignancy Diagnostic Services (SIHMDS).
Despite the 2003 NICE IOG for haematological malignancy recommendations that all diagnostic technologies should be provided by a single laboratory (‘co-located’ services), the adoption of a single co-located SIHMDS structure has been variable across England with little progress beyond local reporting by separate laboratories in some regions.
In 2016, the IOG was revised and included an economic appraisal of SIHMDS as well as additional guidance relating to these laboratories.1 The original IOG was limited to adult patients (aged 16 years or more) despite a similar requirement for integrated diagnostic technologies in the diagnosis of haematological cancers in childhood in accordance with the WHO classification. The updated NICE IOG applies to all ages.
The aim of this best practice review is to summarise the evidence and recommendations for SIHMDS laboratories included in the revised IOG for haematological malignancies. Although the NICE guidance will be most relevant to SIHMDS in England, the general principles will be relevant to specialised laboratory practitioners and healthcare providers who work in the field of cancer internationally.
Methods: evidence review during NICE IOG development in relation to SIHMDS
Service configuration
Most of the published research on cancer topics focuses on clinical evaluations of treatment; little direct research has been carried out on the organisation and delivery of services.
Epidemiology
This was key to the review in order to understand the routes through which patients with haematological malignancies might present initially or at relapse to healthcare services, to inform the shape of these services.
Accurate capture of information on haematological malignancies nationally, despite recent improvements, is still challenging. Haematological malignancies are diverse, ranging from highly aggressive types to incidentally identified indolent conditions. Certain chronic leukaemias rarely produce symptoms, and the recorded incidence of these conditions depends on whether blood samples are examined and on the criteria used for deciding whether there is a malignancy. Even when it is clear that there is a malignancy, identifying the specific type requires sophisticated diagnostic techniques and the integration of information from clinical and laboratory sources. These results are not always available to the Cancer Registries and so some registrations fail to capture the precise diagnosis. This is particularly true of non-Hodgkin's lymphoma (NHL), a large and varied group of conditions, for which the International Classification of Diseases-10 coding may be inadequately detailed to separate distinct entities or present other challenges for accurate classification in routine practice.
Data sources for the guideline included the National Cancer Registration Service, which is part of Public Health England, the National Cancer Intelligence Network, the Office for National Statistics, the Patient Experience Survey, National Audit of Cancer Diagnosis in Primary Care, Hospital Episode Statistics, National Cancer Data Repository and regional data taken from the Haematological Malignancies Research Network (HMRN).
Population-based national incidence rates for England (as estimated by cancer registrations) rose over the period 2001–2010 for some haematological cancers: Hodgkin's lymphoma, NHL and myeloma. There are no haematological cancers for which incidence rates declined over that period. Registration rates for haematological cancers may have changed because of better ascertainment of new cases and developments in both diagnosis and classification; therefore, the changes seen may not represent true changes in incidence.1
Relative survival improved for individuals in specific age groups who were diagnosed between 2000 and 2010 for a number of haematological cancers: acute lymphoblastic leukaemia (0–14 years males and females; 15–64 years males), acute myeloid leukaemia (AML) (15–64 years), chronic myeloid leukaemia (CML), NHL and myeloma. For the most common forms of leukaemia in older people (adults aged 65 years or more), namely AML and chronic lymphocytic leukaemia (CLL), there was no evidence of significant change in the outcome for patients over this time period.1
The incidence of haematological malignancy does not generally vary between areas with different levels of deprivation, apart from AML and Hodgkin's lymphoma. Deprivation was also associated with poorer relative survival for CLL, CML, Hodgkin's lymphoma, myeloma and NHL.1
For the majority of haematological malignancies, general practitioner (GP) referral was the most common route to diagnosis, with the exception of AML and ALL, in which over half of all patients presented to hospital as an emergency. CML and myeloma had similar proportions of GP referral and emergency presentations. All haematological malignancies with the exception of Hodgkin's lymphoma had a significantly higher proportion of emergency presentations than malignancies in general. Relative survival was significantly poorer for emergency presentations for most haematological malignancies. The exception to this was ALL, where 1-year relative survival for emergency presentations was similar to that from all other routes. For some acute haematological malignancies, emergency presentation may be the most appropriate route to diagnosis.1
Evidence review and quality grading
Searches were carried out in Medline. Premedline, Embase, Cochrane, Library, Web of Science (Science Citation Index and Social Sciences Citation Index) and Institute for Scientific Information Proceedings, Healthcare Management Information Consortium, PscyInfo, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Joanna Briggs Institute Evidence Based Practice database, OpenGrey, HMRN and British Committee for Standards in Haematology from January 2000 to April 2015. Results of the searches are detailed in figure 1. In total, 19 studies were included in the review (table 1).5–7 ,9–24
Studies included in evidence review
Search results.
The evidence was considered to be of low quality overall as all the identified studies were retrospective case series and none of them directly compared integrated diagnostic services with other forms of diagnostic service. There was a high risk of bias based on the potential lack of blinding and the possibility of selection bias.
One study11 however compared diagnostic outcomes between specialist haematology laboratories and other commercial laboratories, reporting that patients in the specialist laboratory cohort were more likely to undergo more complex diagnostic testing with 26% of patients undergoing molecular diagnostics compared with 9.3% in community-based hospital laboratories. Patients in the specialist laboratory cohort were 23% more likely to reach a final diagnosis within a 30-day testing period when compared with community-based hospital laboratories.
Cost-effectiveness analysis
No previous studies of cost-effectiveness were identified as part of the evidence review. An economic model was therefore developed to inform the guideline. The economic model considered the cost-effectiveness of two overall models of haematological malignancy diagnostic service delivery: (a) local reporting of diagnostic results with a proportion of tests being referred to SIHMDS for review and (b) referring all samples immediately to SIHMDS for suspected haematological malignancies. When considering the SIHMDS itself, two comparative configurations of SIHMDS were considered: (a) networked and (b) co-located. Health outcomes were calculated as lifetime Quality Adjusted Life Years (QALYs) and all costs to the NHS and Personal Social Services were considered. Costs were predominantly taken from accounting data of one networked and one co-located SIHMDS. Health outcomes were based on the Guideline Committee's assumptions on the impact of misdiagnoses informed by clinical evidence of treatment for haematological malignancies. In the absence of strong evidence differentiating the two SIHMDS approaches, their health outcomes were assumed identical. A range of sensitivity analyses were performed to test differing assumptions and to assess the robustness of and uncertainty around outcomes.
In the model, both approaches of SIHMDS had a lower cost per diagnosis and higher QALYs per patient compared with local reporting with subsequent referral of a proportion of cases to the SIHMDS. When comparing SIHMDS structure, a co-located approach was estimated to be £19 cheaper per diagnosis compared with a networked approach, although this was not robust during sensitivity analysis.
Change in staffing, capital and set-up costs were not considered as part of the economic modelling with this varying widely across England. It was acknowledged that there may be a significant initial resource impact on some centres around obtaining laboratory accommodation, implementation of integrated IT systems and the appointment of dedicated SIHMDS staff.
There was no evidence to directly compare outcomes from co-located and networked haematology diagnostic services and strong conclusions regarding the preferred configuration of SIHMDS could not be drawn solely from the results of the economic model. One study11 reported significantly better clinical outcomes for a specialist haematology diagnostic laboratory, but it was unclear from the information provided, whether this study directly compared co-located and networked services. Communication with the author of the study added extra information about the comparisons made and the Guideline Committee debated whether this warranted a recommendation for a co-located diagnostic service to optimise integration of the increasingly complex range of tests involved in the diagnosis of haematological malignancies required to fulfil the WHO specifications. There was consensus in the Guideline Committee that a co-located service was the optimal approach and that, because it allowed more effective processes and procedures to be put in place, better communication between laboratory personnel and better quality control, it should be recommended, despite the lack of strong evidence.
The Guideline Committee agreed that there were a number of geographical and infrastructural barriers to establishing a co-located service and that the priority in any diagnostic service was delivering a high-quality service that produced timely integrated reports. Although this was likely to be best met through a service with all the component parts located on a single site, this would not always be feasible and so a networked service might be a more appropriate option for certain parts of England. To clarify the key service requirements, the Guideline Committee developed a set of consensus-based recommendations outlining the key organisational, structural and managerial parameters, which should be fulfilled by any SIHMDS, whether co-located or networked. No specific evidence was identified about paediatric diagnosis but the Guideline Committee considered that diagnosis of paediatric patients would follow the same diagnostic pathways as that of adult patients and so the recommendations should cover all age groups.
Recommendations
The following is a list of the new, updated recommendations for 2016. For all recommendations, the quality of the evidence was considered to be low.
The Guideline Committee considered that recommendations are most likely to be achieved if the component parts of the SIHMDS are located at a single site.
All SIHMDS should:
have clearly defined organisational structures;
have a formally appointed SIHMDS director who is responsible for the operation of the service, including the design of the diagnostic pathway, resource use and reporting standards;
have a single quality management system;
be formally accredited as a SIHMDS by a recognised independent organisation;
be managed by a single trust/organisation;
assess the clinical benefit and the financial and resource impact of new diagnostic and therapeutic technologies before introducing them;
have a central reception point for all specimens;
have a full range of age-appropriate specialist haematology and haematopathology input for diagnosis and the authorisation of integrated reports;
have a full range of protocols covering specimen handling, diagnostic pathways and compilation of integrated reports;
ensure that their location, organisation, infrastructure and culture allow effective day-to-day and ad hoc communication for rapid resolution of diagnostic uncertainty and accurate diagnosis;
have clear and reliable systems for communicating with relevant healthcare professionals outside the SIHMDS;
produce integrated reports that include all information needed for disease management, and share these with the relevant multidisciplinary team;
report diagnoses subtyped by the current WHO classification.
All SIHMDS should have a predefined diagnostic pathway that is followed for each specimen type or clinical problem. The pathway should ensure that:
the most appropriate diagnostic platforms are selected for a particular clinical situation to avoid unnecessary duplication;
tests for each specimen are used to provide maximum levels of internal cross-validation, using the current WHO principle of multiparameter disease definitions;
there is a robust process for report validation, including double reporting.
All SIHMDS should have an IT system that allows:
specimen booking and registration at source;
input and update of clinical information;
integrated reporting;
two-way communication between SIHMDS and healthcare professionals using the SIHMDS.
The SIHMDS director should be responsible for the overall quality management system, including:
laboratory processes and the quality of diagnostic reporting;
ongoing assessment of staff competencies;
training provision;
communication within the SIHMDS and with relevant healthcare professionals;
audit and quality assurance;
research and development.
If an urgent treatment decision is not needed, local diagnostic laboratories should send all specimens (including lymph node and other tissue material) directly to a SIHMDS without any local diagnostic workup:
as soon as a haematological malignancy is suspected;
during active investigation of a suspected haematological malignancy;
if patients with an established or previous malignancy have suspected relapse or disease progression.
If an urgent treatment decision is needed and local diagnostic workup will not reduce the speed or quality of the SIHMDS assessment and integrated reporting, local diagnostic laboratories should process and report on blood film, bone marrow aspirate and cerebrospinal fluid cytology specimens.
SIHMDS should release individual laboratory reports before the integrated report is produced, if there is an urgent clinical need.
SIHMDS should be responsible for specimens that are sent to external labs and should integrate the results into the relevant report (unless there are exceptional arrangements in place for clinical trials).
Disease monitoring
When flow cytometry, molecular diagnostics or cytogenetics are needed for disease monitoring, local diagnostic laboratories should send all relevant specimens directly to a SIHMDS without any local diagnostic workup.
Discussion
The concept of SIHMDS is not new and was a result of recognition that haematological malignancy diagnosis is increasingly complex and dependent on new sophisticated laboratory technology. Separate laboratory reporting and reliance on clinicians to interpret and synthesise each result and stay up-to-date with ongoing revisions in classification is likely to compromise diagnostic quality despite the dual clinical and laboratory training and certification achieved by the majority of haematologists in the UK. This is due to the complexity of current diagnostic methods and the requirement to internally validate and cross-check information, at source, in order to prevent reporting of erroneous results.
From the late 1990s, some UK centres adopted an integrated approach which was incorporated into the NICE IOG in 2003 and subsequent cancer peer review standards. Despite this, many services did not progress integrated reporting beyond an elementary stage, consistent with local reporting. Additionally, although modern diagnostic technology and classifications are relevant to all age groups, patients aged under 16 years had a different standard of care to those aged over 16 years. Others developed different models; some using co-located facilities and others using networked but geographically distinct laboratory facilities to produce integrated reports. As there were pros and cons associated with both models, the Guideline Committee considered an economic analysis as well as clinically important aspects in formulating their recommendations.
A fully co-located service is a logical and convenient means of delivering SIHMDS. It permits consolidation of expert diagnostic staff and expensive technologies and is more likely to result in reduced turnaround times, improved diagnostic accuracy, reduced need for repeat sampling and greater cost efficiency. This should in turn lead to more effective treatment and less anxiety for patients. However, there are a number of potential barriers to setting up co-located SIHMDS services, in particular the need to restructure services. Some laboratories such as histopathology and molecular genetics have a broad remit across all cancer and non-cancer specialties, which prevents separation of their haematological services into a co-located SIHMDS. In rural regions, geographically isolated and disparate units with relatively small populations may find this restructuring a challenge with particular regard to recruitment, job satisfaction and ability to effectively communicate and attend multidisciplinary team meetings, although modern telecommunications and developing digitalisation could mitigate some aspects.
Balancing potential benefits against challenges around service reconfiguration, staff satisfaction, haematology training provision and recruitment, there was agreement that these recommendations were in the best interests of the service and the patients.
Definitions
Local reporting: service models in which haematological cancer diagnosis is made within a local laboratory of an associated clinical department.
Co-located: service models in which haematological cancer diagnosis is provided in dedicated, purpose-built and localised laboratories.
Networked: service models in which established laboratories work on the same information network, but are geographically separate and not dedicated solely to haematological cancer diagnosis.
Integrated report: a single report summarising all elements of laboratory diagnosis for a specific patient episode, that is, based on available haematological cytology, histopathology, immunophenotyping by flow cytometry, cytogenetics, fluorescence in situ hybridisation and molecular genetics and in accordance with the current WHO diagnostic classification.
Integration: the process of producing an integrated report.
Acknowledgments
Dr Clare Rowntree, Consultant Haematologist, Cardiff and Vale NHS Trust. Mrs Sarah Steele, Senior Quality Improvement Lead, East of England Strategic Network. Dr Nia Angharad Evans, Lead Haematology Pharmacist, Cardiff and Vale University Health Board. Ms Barbara Von Barsewisch, Macmillan Lymphoma and CLL Clinical Nurse Specialist. Ms Marie Waller, Trainee Advanced Nurse Practitioner, Manchester Royal Infirmary. John Reeve, Patient/Carer Member. Alan Chant, Patient/Carer Member. Jonathan Pearce, Patient/Carer Member. Dr John Graham, Director, National Collaborating Centre for Cancer. Dr Andrew Champion, Centre Manager, National Collaborating Centre for Cancer. Angela Bennett, Assistant Centre Manager, National Collaborating Centre for Cancer. Dr Nathan Bromham, Senior Researcher, National Collaborating Centre for Cancer. Lianne Gwillam, Project Manager, National Collaborating Centre for Cancer. Stephanie Arnold, Information Specialist, National Collaborating Centre for Cancer. Matthew Prettyjohns, Senior Health Economist, National Collaborating Centre for Cancer. Verity Bellamy, Head of Cancer Intelligence, Northern and Yorkshire Knowledge and Intelligence Team, Public Health. Dr Steven Oliver, Senior Lecturer in Population Health, Department of Health Sciences, University of York and Hull, York Medical School.
References
Footnotes
Handling editor Mary Frances McMullin
Contributors All authors were members of the Guideline Committee for the updated National Institute for Health and Care Excellence Improving Outcomes Guidance in Haematological Cancer and contributed to the writing of the manuscript and approved the final version; the manuscript was led by John A Snowden (as Clinical Lead of the Guideline Committee) and Fergus Macbeth as (Chair of the Guideline Committee), and supported by Susan O'Connell (Researcher for systematic reviews) and James Hawkins (as Health Economist). CD, AJ, DM, CM, MS, GS and ES were members of the Guideline Committee with expertise in the diagnosis in haematological cancer.
Funding This work was undertaken by the National Collaborating Centre for Cancer, which received funding from the National Institute for Health and Care Excellence (NICE). The views expressed in this publication are those of the authors and not necessarily those of NICE.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.
Data sharing statement The updated National Institute for Health and Care Excellence (NICE) Improving Outcomes Guidance in Haematological Cancer is available on the NICE website.