Integrated Diagnostic Services for Haematogical Malignancies

- Why wouldn’t you?

Robin Ireland King’s Integrated Diagnostic Centre

Haematological Malignancy and Bone Marrow Failure Syndromes

Unipath 2014

What is the problem?

Size of the problem

UK Haematological Malignancy Incidence

(5th most common malignancy)

Haematological Cancers; estimated annual UK incidence

20,000/yr

Precursor and peripheral:Multiple differentiating lineages

12 Major Malignancy Groups (143 subdiagnoses)

1. Myeloproliferative neoplasms2. Myeloid and lymphoid neoplasms with eosinophilia3. Myelodysplastic/myeloproliferative neoplasms4. Myelodysplastic syndromes5. AML6. Acute leukaemias of ambiguous lineage7. ALL -B and -T8. Mature B-neoplasms including all NHL and |Myeloma9. Mature -T and -NK neoplasms10. Hodgkin lymphoma11. Immunodeficiency associated lymphoproliferative

disorders.12. Histiocytic and dendritic neoplasms.

UK Relative incidences – International geographical variations

UK Haematological Malignancy Subtype Data – HMRN

The History of Haematopathology in the UK

• The unified concept of haematological malignancy is recent:– Understanding of cellular pathology of the

haematopoietic and lymphoreticular systems– UK model dates from the early 1960’s

• Pathology subspecialisation– Laboratory Haematology and Histopathology split– Haematologists begin treating leukaemias– Lymphoma and myeloma treated by various specialities

• Separation of liquid and solid tissue reporting• Rise of non-morphological techniques

– Flow Cytometry– Cytogenetics and Molecular Diagnostics

>> FRAGMENTED MODEL

The WHO classification defines diseases as clinico-pathological entities:

• Clinical Features• Morphology• Immunohistochemistry• Immunophenotype• Cytogenetics• Molecular genetics

Diagnostic accuracy?

UK NICE Improving Outcomes Guidance: 2003 Diagnosis of Haematological Malignancy

• Pathology reviews, audit and trial data suggested significant error rates in diagnosis– Welsh NHS Audit

• Accurate diagnosis is increasingly important with changes in treatment and more disease specific directed therapies.

• Increasing requirement for cellular prognostic factors and detection of minimal residual disease.– NICE Guidance: ‘Improving Outcomes in Haematological Cancers’

(2003)

What was the evidence?

USA experience Comparison of referring and tertiary cancer center physician's diagnoses in patients with leukemia. (DeLima M et al. Am J Med. 1998 Mar;104(3):246-51)

– 409 patients referred to the M.D. Anderson Leukemia Service

– And 100 cases, including 84 of the 409 referred patients for whom the diagnostic outside bone marrow slide had been sent for review.

•Overall concordance rate was 73%– 18% discordances were present and considered of major

importance (affecting treatment and/or prognosis)– 9% there were minor discordances

•Major discordance rates:CLL 2%HCL 57%ALL 19%

AML 29% APML 43%MDS 23%CML 5%

Changing Expectation of Diagnostic Services

1. The Patient and Haemato-oncologist need to have confidence in the accuracy of diagnosis.

2. The diagnosis needs to be correct and timely.

3. The morphological opinion of an ‘expert’ is no longer. enough.

4. Quality is a whole-system process not just NEQAS.

5. Diagnostic strategies: A systematic approach is essential defining choice and order of testing..

10 years on, is there still a problem?

1. A recent audit carried out in Greater Manchester (A Norton and R Byers 2008) found the serious and critical error rate to be 15%. These data refer to the diagnosis of lymphoma.

2. Review was undertaken in a North London Cancer Network. JCO 2011 ……..

Have raised awareness and improved immunohistological techniques reduced diagnostic errors?

Proctor, C. McNamara, M. Rodriguez-Justo, P. Isaacson, and A. Ramsay. Importance of Expert Central Review in the Diagnosis of Lymphoid Malignancies in a Regional Cancer Network, North Central London Lymphoma

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.

Journal of Clinical Oncology April 10, 2011 vol. 29 no. 11 1431-1435

NICE Guidance: Still holds true!

1. “Improving the consistency and accuracy is probably the single most important aspect of improving outcomes in haematological cancers’’

2. “In order to reduced errors, every diagnosis of possible haematological malignancy should be reviewed by specialists”

3. “Results of tests should be integrated and interpreted by experts” who-

-Work with local Clinicians and Pathologists (the final Quality check)

to provide a specialised service at network level’

What does this mean in practice?

How can it be provided?

• Management of patients should be based on sound and comprehensive diagnostic information:

– An integrated diagnostic process is required

• Best achieved by co-locating all specialist haematopatholology diagnostic services in a single laboratory.

– Integration of results into a single final report.

Key NICE Recommendations

WHAT IS NEEDED TO MAKE IT WORK?

• Agree national model

• Identified integrated diagnostic centres

• Process of change to implement new model on historical practices and referral practices

An integrated Haematopatholology service is not just an integrated report

Multiple levels of integration required.– Integrated approach to the diagnostic process:

• Cluster of laboratories and ‘-ologies in an effective diagnostic network• Breakdown historical barriers between laboratories and sub-specialities• Single managerial control, appropriate staffing, organisational and

operational structures• Single point of reception for all samples• Design of systematic diagnostic protocols• Integrated IT system• Integrated Final Report combining results from all data sources• Close interface between clinical and laboratory services

Integrated diagnostic processes

• Are the best guarantee of diagnostic accuracy based on:– WHO Classification– Systematic diagnostic protocols– Diagnostic protocols designed to give

independent checks of diagnosis– Concordance of results across specimen

types and diagnostic platforms

Accurate Diagnosis Depends on the Integration of Multiple Diagnostic ModalitiesA systematic approach is essential

Morphology

Immunophenotyping

Cytochemistry

Cytogenetics

Molecular

FISH

OUTPUT: The Integrated Report:New diagnoses ICD-O/3 codedCoded comments on:

Prognostic factorsMinimal Residual Disease monitoring General descriptorsChimerism and Transplant monitoringFree text comments

•INPUTS: WHO•Clinical Features•Morphology•Immunohistochemistry•Immunophenotype•Cytogenetics•Molecular genetics

• Fully Integrated Diagnostics and Reporting since October 2007

– Staffing: ~25 staff (Excluding Consultants)• Haematological cytomorphology• Histopathology/Immunohistochemistry/

Cytopathology• Flow Cytometry• Cytogenetics/FISH• Molecular Diagnostics• IT and other infrastructures.

CURRENT KING’S SERVICES

King’s Haematological Malignancy Diagnostic Centre

• All haematological malignancies: Acute, Chronic, Myeloid, Lymphoid, Plasma Cell, Histiocytic, Dendritic.

• 3 Cancer networks– 17 Hospitals

• Specimens:– Peripheral blood– Marrow Aspirate and

Trephines– Tissue biopsies; Ln’s,

extranodal, skin, lung etc– CSF/Vitreous Humour

/Ascites/Pleural/ Pericardial fluids.

Cambridge and Huntingdon

Bedfordshire

West Hertfordshire

East KentWest Kent

East Sussex, Brighton and Hove

West SussexSouthampton and South

West Hampshire

Isle of W ight

Berkshire

North and Mid Hampshire

West SurreyEast Surrey

Buckinghamshire

Oxfordshire

East Norfolk

Suffolk

North Essex

South Essex

North W est Anglia

Hertfordshire

East North and

N ortham ptonsh ire

LONDON

Adult Population ~5.3m

~12,000 referrals and ~22,000 tests

WHAT IS NEEDED TO MAKE IT WORK?

• Laboratory services and staff need to be robust and flexible:– Rapid development/implementation of new

technologies– Challenges traditional technical/-ology borders– Platform of technology research feeding

diagnostic service– Changes in skill mix and cross-cover.

• Capital investment capability

Integrated Haematopathology Services: - Organisation

• A single Centre with overall responsibility:– Operational, managerial and financial– Identified laboratories and investigational modalities.– Minimum catchment population– May provide services to more than one Network

• Management and organisational accountability– Single Head of Service– Defined role and responsibilities including:

• Design of algorithms• Resource utilisation• Links with clinicians

• Specimen(s) sent to a single reception point– Identified optimal samples, methods of handling and transport– Speedy transfer of samples to minimise delays of diagnosis– Prevent omission of key tests and over-investigation

IHMDC Reception

NHS No. or Lifelong and Event Specific ID

Morphology/ Immunopheno

-typing

Result

Cytogenetics /FISH

Result

Molecular Genetics

Result

Histopathology /Cytology

Result

Consultant Worklist

Trafficlight results status

Integrated Results

ICD-O/3 Codes

Interpretive comments

Interim/Final Report

Authorised

Paper and Electronic issue

Initial review determines downstream

investigations

Referred SamplesIMPROVED PROCESSES

Finite cell samples –

use to maximum diagnostic benefit in shortest possible

time.

Most samples come with

diagnosis of ‘cytopenia or splenomegaly

? Cause.Even if given a diagnosis,

often incorrect!!

KCH Sample flows 2007 – Distributed model

KCH Sample flows 2013 – Centralised model

Single Reception > Testing > Integrated Report

• I.T. software is the ‘glue’ that makes it a workable and effective system:• Patient, clinical and sample details recorded.• Investigative protocols:

– Systematic, sequential test ordering protocols– Worksheet generation

• A single integrated report linking all results.• Communications with users:

• Single point direct access• Use of e-mail alerts and electronic return of results.

• Quality assurance and audit

WHAT IS NEEDED TO MAKE IT WORK? -Information Technology Systems

INTERNAL IT FUNCTIONS; CONSULTANT WORKLIST

Images appended to results archive

SPECIMEN INTEGRATED REPORT

HMDC Reception

NHS No. or Lifelong and Event Specific ID

Morphology/ Immunopheno

-typing

Result

Cytogenetics /FISH

Result

Molecular Genetics

Result

Histopathology /Cytology

Result

Consultant Worklist

Trafficlight results status

Integrated Results

ICD-O/3 Codes

Interpretive comments

Interim/Final Report

Authorised

Paper and Electronic issue

Initial review determines downstream

investigations

Referred Samples

Final check of result quality, internal

consistency, concordance or DISCORDANCE of

results

WHAT IS NEEDED TO MAKE IT WORK? - Quality Assurance

• Quality and governance built into the system, facilities and processes.

• Standard Operating Protocols for order and choice of tests.

• Accuracy of reporting:• Double reporting/authorisation• Result concordance

• CPA, NEQAS, EQA• Monitoring of reporting times• Monitoring of resource utilisation and

efficiency.

• Education and training:– Technical/Scientific– Postgraduate: Trainee Registrars all rotate into

HMDC– Consultants

Supporting structures

Key Requirements: R&D Infrastructure

• Diagnostic Techniques are changing rapidly:– Relative decline of morphology (remains an important triage step)– Multicolour flow techniques (8 – 10 colour).– Gene expression profiling, Deep Sequencing capabilities, SNP-A

karyotyping, miRNA’s, whole exome sequencing etc.– Diagnostic services underpinned by large R&D infrastructure and

capability.– New skills required – Bioinformatics and mathematical algorithms

• Clinical needs are evolving:– New treatments and monitoring should be seen as a package

• Eg CML and BCR-ABL/ABL ratios

– Centre for Clinical Trials in Haematological Malignancies.– Now incorporated into Current trials – e.g. REMoDL-B…….

Concerns – Role of District Hospital Haematologists

• Haematologists should still report their own aspirate/trephine slides.

• Local Haematologists do not usually undertake the specialist tests (Immunophenotyping, Cytogenetics, FISH, Molecular Genetics) so for the majority this is not a real change.

• If there are haematologists/histopathologists who have a mainly Haem-Oncology laboratory role they could/should be incorporated into the provision of services centrally:

• Cancer Pathology Commissioners and Hospitals must be brought into the discussions so that relevant consultants can

participate in diagnostic service provision. • Will see more and access a wider range of diagnostic

technologies.

Concerns - Deskilling

– Clinicians can and should still combine their clinical and laboratory skills.

– They should continue to report bone marrows; this is an important quality assurance step where treatment decisions are made.

– IOG clarification is not about morphology skills of haematologists (which they are encouraged to maintain) but is about the proper integrated diagnostic process of specialist testing - core to the NICE guidance.

The Case for Research:

The case for a centralised model

Why would you leave a distributed (fragmented) service model?

– Difficult to implement modern, complex, integrated diagnostic approaches.

– Complex transport arrangements, delays, risks of sample loss.– Many cases come without a firm or correct diagnosis:

• Slow/difficult communication between labs to change investigations.• Slow to switch samples between labs; sample degradation and lengthened

delays.

– Inability to discuss results from discordant cases with all slides/ results/people simultaneously.

– Inhibits cohesion, communication, coordination and teamwork– Inefficient utilisation of scarce staff resources and skills

• Compromises critical mass for development, learning and research• No multi-tasking and multi-skilling = Inefficient labour force

– Does not facilitate service delivery, teaching, tissue banking or research.

Patient/Clinician/Organisation

Who wants?

•A slow result with a 10 – 25% error rate? •Laboratory reduplication with high capital costs?

•Inefficient use of resources/high revenue costs?

•Non-robust staffing?•No multiskilling?•Slow implementation of technologies?•Poor training?•Defunct research? - - especially molecular capability.

HAEMATOLOGISTSProf G MuftiDr R IrelandDr V TindellDr D YallopDr S Kassam

FLOW CYTOMETRYTim MilneAnne EtchesMelissa BullardDebbie D’Costa

CYTOGENETICSB CzepulkowskiL BrownP FordH GilbertT KontouD LadonV SimonianD Jijon

MOLECULARNic LeaA KizilorsN FolarinS BestJ Anwar

HISTOPATHJ SalisburyS PomplunC ShahH Abu-ArqoubJ Morehead

RECEPTIONC SulzdorfR Connell

THANK YOU