Nodal Diffuse Large B-cell Lymphoma

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DIAGNOSING LYMPHOMA AND THE GMCHMDS
INTRODUCTION TOTHE NATURE AND MANAGEMENT OF
LYMPHOMA
Dr Andrew J Norton
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Thomas Hodgkin 1798-1866
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Case 4 Thomas Westcott
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Samuel Wilks 1824-1911
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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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Cancer 196619317
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HODGKINS DISEASE HISTOLOGICAL SUBTYPES
Lymphocyte predominant
Mixed cellularity
Lymphocyte depleted
Nodular sclerosis
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RELATIVE PROPORTIONS OF HODGKIN LYMPHOMA SUBTYPES
n882 (Barts)
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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).
• gt95 of cases arise from a crippled B-cell
  precursor
• Infrequent expression of B-cell markers, no Ig
  synthesis.

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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.

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LYMPHOMAS OTHER THAN HODGKINS DISEASE

• 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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Incidence is increasing in Europe and N America,
and there is evidence the rise is global.
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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
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2008
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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
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
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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(1114)
• Burkitt lymphoma CMYC translocation, t(814) 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
CD10, CD20, bcl-2, bcl-6 positive
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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
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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

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Low grade or small cell lymphomas age
incidence
High grade or large cell lymphomas age
incidence
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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 Castlemans
• Adult T-cell lymphoma
• Gastric MALT type lymphoma
• Cutaneous MZL
• A variety of small B

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Frequencies of Extranodal Lymphomas by Site of
Origin (Barts London)
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Diffuse large B cell lymphoma is not an
homogeneous entity
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Alizadeh AA 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
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) 99919996.
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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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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
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Henry Rappaport on Lymphoma Classification
(A classification should be) clinically
useful, scientifically accurate, reproducible,
easily taught and readily learnt.
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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
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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
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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 Childrens
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 gt3.5M
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RESULTS OF AN AUDIT OF FIRST SIX MONTHS ACTIVITY
Total Errors - all Trusts (n198) 15.2 errors
with an impact on patient management
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THE DIAGNOSTIC ALGORITHM
Clinical data
Tissue biopsy
Morphological assessment
Immunophenotyping
Cytogenetics / FISH
Molecular genetics / PCR
Integrated report
Multidisciplinary Team Meeting
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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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