Transcript Nodal Diffuse Large B-cell Lymphoma

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
Dorothy Reed Mendenhall 1874-1964
Cancer 1966;19:317
HODGKIN’S DISEASE HISTOLOGICAL
SUBTYPES
Lymphocyte predominant
Mixed cellularity
Nodular sclerosis
Lymphocyte depleted
RELATIVE PROPORTIONS OF HODGKIN
LYMPHOMA SUBTYPES
70
Nodular LP
60
Lymphocyte-rich
50
Mixed cellularity
40
Nodular sclerosis
30
Lymphocyte depleted
Composite HD & NHL
20
10
n=882 (Barts)
0
%
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.
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.
LYMPHOMAS OTHER THAN
HODGKIN’S DISEASE
• Non-Hodgkin lymphomas:
– 14% Hodgkin lymphoma
– 80% B-cell lymphomas
– 6% T-cell lymphomas
B-areas and cell types
T-areas and cell types
Incidence is increasing in Europe and N America, and there is evidence the rise is global.
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
2001
2008
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
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
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
Follicular Lymphoma
CD10, CD20, bcl-2, bcl-6 positive
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
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
“Low grade” or small cell
lymphomas – age incidence
“High grade” or large cell
lymphomas – age incidence
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
Frequencies of Extranodal Lymphomas by Site of Origin (Barts & London)
90
80
70
60
50
40
30
20
10
0
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Lymphoplasmacytic
Marginal zone (MALT)
NK/T, nasal type
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B-CLL
Mantle cell
T-cell
Diffuse large B cell Lymphoma
120
100
80
60
40
95
80
65
50
35
5
0
20
20
+ B- Lymphocytic
Blastic mantle cell
+Nodular L&H HD
HIV related NHL
+Lymphoplasmacytic
+Marginal zone MALT
Mediastinal large B
+Follicular lymphoma
Diffuse large B cell NOS
Diffuse large B cell lymphoma is not an homogeneous entity
Alizadeh AA et al.
Nature 2000; 403: 503-511
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.
Global incidence of non-Hodgkin lymphoma in men: age standardized incidence /
100,000 population
World Cancer Report 2003
Diffuse Large B-cell Lymphoma
Follicular 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
Henry Rappaport on Lymphoma Classification
“(A classification should be) …
clinically useful, scientifically
accurate, reproducible, easily taught
and readily learnt.”
NHS
Guidance on Cancer Services – Improving Outcomes in Haematological Cancers – The Manual
National Institute for
Clinical Excellence
Guidance on Cancer Services
Improving Outcomes in
Haematological Cancers
The Manual
Published by the National Institute for Clinical Excellence
October 2003
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.
Guidance on Cancer Services – Improving Outcomes in Haematological Cancers – The Manual
• 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.
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
Population >3.5M
RESULTS OF AN AUDIT OF FIRST SIX MONTH’S ACTIVITY
16.2
Critical - benign vs.
malignant
6.6
Major - error affecting
treatment
2
Minor - missed
component
7.1
Minimal terminological
62.1
6.1
Refined
No change
Total Errors - all Trusts (n=198)
15.2% errors with an impact on patient management
THE DIAGNOSTIC ALGORITHM
Clinical data
Tissue biopsy
Morphological assessment
Immunophenotyping
Cytogenetics / FISH
Molecular genetics / PCR
Integrated report
Multidisciplinary Team Meeting
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:
Molecular genetics / PCR: N/A
no IGH/BCL-2, IGH/MYC, CMYC, or BCL6 gene
rearrangements
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