1. DIAGNOSING LYMPHOMA AND THE GMCHMDS
INTRODUCTION TOTHE NATURE AND MANAGEMENT OF LYMPHOMA
Dr Andrew J Norton

2. Thomas Hodgkin

4. Case 4: Thomas Westcott

5. Samuel Wilks

6. Reed-Sternberg cell or Sternberg-Reed cell
Carl von Sternberg
Reed-Sternberg cell or Sternberg-Reed cell
Dorothy Reed Mendenhall

7. Cancer 1966;19:317

8. HODGKIN’S DISEASE HISTOLOGICAL SUBTYPES
Lymphocyte predominant
Mixed cellularity
Lymphocyte depleted
Nodular sclerosis

11. RELATIVE PROPORTIONS OF HODGKIN LYMPHOMA SUBTYPES
n=882 (Barts)

12. CLASSICAL HODGKIN LYMPHOMA
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.

13. NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA
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.

14. LYMPHOMAS OTHER THAN HODGKIN’S DISEASE
Non-Hodgkin lymphomas:
14% Hodgkin lymphoma
80% B-cell lymphomas
6% T-cell lymphomas

15. B-areas and cell types
T-areas and cell types

16. Incidence is increasing in Europe and N America, and there is evidence the rise is global.

17. 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

18. 2001

19. 2008

20. 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

21. T-cell and NK-cell neoplasms
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
Primary cutaneous 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

22. IMPORTANT PRACTICAL DIAGNOSTIC POINTS
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

24. Follicular Lymphoma
CD10, CD20, bcl-2, bcl-6 positive

25. BURKITT LYMPHOMA
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

26. IMPORTANT DIAGNOSTIC POINTS
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

27. “Low grade” or small cell lymphomas – age incidence
“High grade” or large cell lymphomas – age incidence

28. Infectious Agents and Lymphoma
HIV infection
Epstein Barr Virus
Human Herpes-8
HTLV-1
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

29. Frequencies of Extranodal Lymphomas by Site of Origin (Barts & London)

30. Diffuse large B cell lymphoma is not an homogeneous entity

31. Alizadeh AA et al.
Nature 2000; 403:

32. Germinal Centre profile DLBCL have a superior survival to Activated B-cell profile DLBCL
Lymphochip
Affymetrix
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 August 19; 100(17): 9991–9996.

33. Global incidence of non-Hodgkin lymphoma in men: age standardized incidence / 100,000 population
World Cancer Report 2003

34. Diffuse Large B-cell Lymphoma
Follicular Lymphoma
Diffuse Large B-cell Lymphoma
USA and Europe
Middle East, Far East, India
3.5 / 100,000
~0.5 / 100,000
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

35. Henry Rappaport on Lymphoma Classification
“(A classification should be) … clinically useful, scientifically accurate, reproducible, easily taught and readily learnt.”

36. Haematological Cancers
NHS
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

37. • All 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

38. Greater Manchester & Cheshire
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:

39. Population >3.5M

40. RESULTS OF AN AUDIT OF FIRST SIX MONTH’S ACTIVITY
Total Errors - all Trusts (n=198)
15.2% errors with an impact on patient management

41. THE DIAGNOSTIC ALGORITHM
Clinical data
Tissue biopsy
Morphological assessment
Immunophenotyping
Cytogenetics / FISH
Molecular genetics / PCR
Integrated report
Multidisciplinary Team Meeting

42. THE DIAGNOSTIC ALGORITHM
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