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DIAGNOSING LYMPHOMA AND THE GMCHMDS. INTRODUCTION TOTHE NATURE AND MANAGEMENT OF LYMPHOMA. Dr Andrew J Norton. Thomas Hodgkin 1798-1866. Case 4: Thomas Westcott. Samuel Wilks 1824-1911. Carl von Sternberg 1872-1935. Reed-Sternberg cell or Sternberg-Reed cell.

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Dr Andrew J Norton

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Carl von Sternberg 1872-1935

Reed-Sternberg cell or Sternberg-Reed cell

Dorothy Reed Mendenhall 1874-1964

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Lymphocyte predominant

Mixed cellularity

Lymphocyte depleted

Nodular sclerosis

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  • A term to cover all types of HD other than nodular LP due to shared phenotypic and genetic properties.

  • Presents in axial nodes with contiguous nodal spread. Splenic disease tends to precede bone marrow and/or liver disease.

  • Primary mesenteric nodal or extranodal disease is hardly ever seen.

  • RS-cells are variably mixed with lymphocytes, plasma cells, eosinophils, neutrophils and histiocytes.

  • CD15+ (75%), CD30+ (100%). EBV mainly in MC-HD (75%).

  • >95% of cases arise from a “crippled” B-cell precursor:

    • Infrequent expression of B-cell markers, no Ig synthesis.

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  • Commonly presents with stage 1A disease – often below the diaphragm.

  • The most B-cell committed form of HD:

    • Architecturally tumour arises in abnormal follicles / nodules.

    • Expression of wide range of B-cell markers including Ig.

    • Does not express markers of classical HD and is EBV –ve.

    • Transformation to DLBCL in ~7% over time.

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  • Non-Hodgkin lymphomas:

    • 14% Hodgkin lymphoma

    • 80% B-cell lymphomas

    • 6% T-cell lymphomas

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B-areas and cell types

T-areas and cell types

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Proposal for an International Consensus on the Classification of Lymphomas

International Lymphoma Study Group

We came to the conclusion that the most practical approach to lymphoma categorization at this time is simply to define the diseases that we think we can recognize with available morphologic, immunologic, and genetic techniques. Thus, a lymphoma classification becomes simply a list of well-defined, “real” disease entities.

Blood 84: 1361, 1994

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2001 Classification of Lymphomas

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2008 Classification of Lymphomas

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World Health Organization Classification of Neoplastic Diseases of the Haematopoietic and Lymphoid Tissues

B-cell neoplasms

Chronic lymphocytic leukaemia / small lymphocytic lymphoma

B-cell prolymphocytic leukaemia

Lymphoplasmacytic lymphoma

Splenic B-cell marginal zone lymphoma

Hairy cell leukaemia

Plasma cell myeloma / plasmacytoma - solitary osseous, extraosseous

Extranodal marginal zone B-cell lymphoma of MALT

Nodal marginal zone B-cell lymphoma

Follicular lymphoma, grades 1-3a & 3b

Primary cutaneous follicle centre lymphoma

Mantle cell lymphoma

Diffuse large B-cell lymphoma (12 specific variants and NOS)

Burkitt lymphoma

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World Health Organization Classification of Neoplastic Diseases of the Haematopoietic and Lymphoid Tissues

T-cell and NK-cell neoplasms

T-cell prolymphocytic leukaemia

T-cell large granular lymphocytic leukaemia

Aggressive NK-cell leukaemia

Systemic EBV positive lymphoproliferative disease of childhood

Hydroa vaccineforme-like lymphoma

Adult T-cell leukaemia / lymphoma

Extranodal NK / T-cell lymphoma, nasal type

Enteropathy-associated T-cell lymphoma

Hepatosplenic T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma

Mycosis fungoides

Sézary syndrome

Primarycutaneous anaplastic large cell lymphoma

Primary cutaneous gamma delta T-cell lymphoma

Peripheral T-cell lymphoma, NOS

Angioimmunoblastic T-cell lymphoma

Anaplastic large cell lymphoma, ALK positive

Anaplastic large cell lymphoma, ALK negative

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IMPORTANT PRACTICAL DIAGNOSTIC POINTS Diseases of the Haematopoietic and Lymphoid Tissues

  • Immunophenotyping for cell surface antigens is mandatory.

  • Certain entities require evidence of a marker chromosomal abnormality for a firm diagnosis:

    • Mantle cell lymphoma; t(11;14)

    • Burkitt lymphoma; CMYC translocation, t(8;14) or variants.

  • Certain entities require clonal cytogenetic or molecular evidence for diagnosis:

    • Cutaneous and nodal mycosis fungoides

    • Sézary syndrome

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Follicular Lymphoma Diseases of the Haematopoietic and Lymphoid Tissues

CD10, CD20, bcl-2, bcl-6 positive

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BURKITT LYMPHOMA Diseases of the Haematopoietic and Lymphoid Tissues

Endemic type – EBV+ associated with Falciparum Malaria

Sporadic (Western type) – EBV usually –ve

HIV – related – EBV ~30%

IGH/MYC translocation or variant with no IGH/BCL2, BCL6 or complex karyotype

CD10 positive. MIB1 100%. bcl-2, MUM1 negative

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IMPORTANT DIAGNOSTIC POINTS Diseases of the Haematopoietic and Lymphoid Tissues

  • Certain entities require a multidisciplinary approach to establish a diagnosis e.g.:

    • Mediastinal large B-cell lymphoma

    • Cutaneous follicle centre lymphoma

    • Diffuse large B-cell lymphoma, leg-type

    • Primary effusion lymphoma

    • Post-transplant lymphoproliferative disorders

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“Low grade” or small cell lymphomas – age incidence Diseases of the Haematopoietic and Lymphoid Tissues

“High grade” or large cell lymphomas – age incidence

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HIV infection Diseases of the Haematopoietic and Lymphoid Tissues

Epstein Barr Virus

Human Herpes-8


Helicobacter pylori

Borrelia Burgdorferi

Hepatitis C

Various types -

PTLD, Hodgkin lymphoma, DLBCL, NK/T-cell lymphoma

PEL, PTLD, Plasmablastic lymphoma in Castleman’s

Adult T-cell lymphoma

Gastric MALT type lymphoma

Cutaneous MZL

A variety of small B

Infectious Agents and Lymphoma

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Alizadeh AA & London)et al.

Nature 2000; 403: 503-511

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Germinal Centre profile DLBCL have a superior survival to Activated B-cell profile DLBCL



A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma

Wright G, et al

Proc Natl Acad Sci U S A. 2003 August 19; 100(17): 9991–9996.

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Global incidence of non-Hodgkin lymphoma in men: age standardized incidence / 100,000 population

World Cancer Report 2003

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USA and Europe standardized incidence / 100,000 population

Middle East, Far East, India

3.5 / 100,000

~0.5 / 100,000

Diffuse Large B-cell Lymphoma

Follicular Lymphoma

Europe and USA.

Middle East, Far East, India

5.0 / 100,000

2-3 / 100,000

NK/T-cell lymphoma, nasal type

Europe and USA

Hong Kong, Taiwan S. America, etc

0.04 /100,000

0.4 / 100,000

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Henry Rappaport on Lymphoma Classification standardized incidence / 100,000 population

“(A classification should be) … clinically useful, scientifically accurate, reproducible, easily taught and readily learnt.”

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NHS standardized incidence / 100,000 population

National Institute for

Clinical Excellence

Guidance on Cancer Services

Improving Outcomes in

Haematological Cancers

The Manual

Guidance on Cancer Services – Improving Outcomes in Haematological Cancers – The Manual

Haematological cancers service guidance

Cancer service guidance supports the implementation of The NHS Cancer Plan for England,and the NHS Plan for Wales Improving Health in Wales.The service guidance programme was initiated in 1995 to follow on from the Calman and Hine Report, A Policy Framework for Commissioning Cancer Services.3 The focus of the cancer service guidance is to guide the Commissioning of services and is therefore different from clinical practice guidelines. Health services in England and Wales have organisational arrangements in place for securing improvements in cancer services and those responsible for their operation should take this guidance into account when planning, commissioning and organising services for cancer patients. The recommendations in the guidance concentrate on aspects of services that are likely to have significant impact on health outcomes. Both the anticipated benefits and the resource implications of implementing the recommendations are considered. This guidance can be used to identify gaps in local provision and to check the appropriateness of existing services.

Published by the National Institute for Clinical Excellence

October 2003

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standardized incidence / 100,000 populationAll patients with haematological cancer should be managed by

multi-disciplinary haemato-oncology teams which serve

populations of 500,000 or more.

• In order to reduce errors, every diagnosis of possible haematological malignancy should be reviewed by specialists in diagnosis of haematological malignancy. Results of tests should be integrated and interpreted by experts who work with local haemato-oncology multi-disciplinary teams (MDTs) and provide a specialised service at network level. This is most easily achieved by locating all specialist haemato-pathology diagnostic services in a single laboratory.

Guidance on Cancer Services – Improving Outcomes in Haematological Cancers – The Manual

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Greater Manchester & Cheshire standardized incidence / 100,000 population

Haematological Malignancy Diagnostic Service (GMCHMD)

A regional service for the diagnosis of lymphoma on paraffin embedded blocks in Phase 1 for the Greater Manchester & Cheshire Cancer Network.

Christie Hospital Manchester Royal Infirmary

The GMCHMD service is a joint initiative between Central Manchester and Manchester Children’s University NHS Trust and The Christie NHS Foundation Trust and is in line with current NICE Improving Outcomes Guidance for Haematological cancers.

Information packs have been sent to all hospitals in the Greater Manchester area.

If further information is required, please phone the GMCHMD enquiry Tel No: 0161 446 3277

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Population >3.5M standardized incidence / 100,000 population

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RESULTS OF AN AUDIT OF FIRST SIX MONTH’S ACTIVITY standardized incidence / 100,000 population

Total Errors - all Trusts (n=198)

15.2% errors with an impact on patient management

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THE DIAGNOSTIC ALGORITHM standardized incidence / 100,000 population

Clinical data

Tissue biopsy

Morphological assessment


Cytogenetics / FISH

Molecular genetics / PCR

Integrated report

Multidisciplinary Team Meeting

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THE DIAGNOSTIC ALGORITHM standardized incidence / 100,000 population

Clinical data: extradural tumour

Tissue biopsy: neurosurgical resection

Morphological assessment: highly proliferative large cell tumour

Immunophenotyping: CD20, MUM1 +; CD5,10,23-. No EBV by ISH

Cytogenetics / FISH: no IGH/BCL-2, IGH/MYC, C-MYC, or BCL6 gene rearrangements

Molecular genetics / PCR: N/A

Integrated report: activated type large B-cell lymphoma, EBV negative

Multidisciplinary Team Meeting: CNS and visceral disease

HIV test recommended – result +ve; patient transferred to specialist HIV team