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DIAGNOSING LYMPHOMA AND THE GMCHMDS

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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DIAGNOSING LYMPHOMA AND THE GMCHMDS

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

  2. Thomas Hodgkin 1798-1866

  3. Case 4: Thomas Westcott

  4. Samuel Wilks 1824-1911

  5. Carl von Sternberg 1872-1935 Reed-Sternberg cell or Sternberg-Reed cell Dorothy Reed Mendenhall 1874-1964

  6. Cancer 1966;19:317

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

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

  9. 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.

  10. 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.

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

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

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

  14. 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

  15. 2001

  16. 2008

  17. 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

  18. 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

  19. 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

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

  21. 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

  22. 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

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

  24. 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 Infectious Agents and Lymphoma

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

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

  27. Alizadeh AA et al. Nature 2000; 403: 503-511

  28. 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. 2003 August 19; 100(17): 9991–9996.

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

  30. USA and Europe 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

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

  32. 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

  33. • 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

  34. 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: 0161 446 3277

  35. Population >3.5M

  36. 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

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

  38. 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

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