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DIAGNOSING LYMPHOMA AND THE GMCHMDS
Dr Andrew J Norton
INTRODUCTION TOTHE NATURE AND MANAGEMENT OF LYMPHOMA
Thomas Hodgkin 1798-1866
Case 4: Thomas Westcott
Samuel Wilks 1824-1911
Dorothy Reed Mendenhall 1874-1964
Carl von Sternberg 1872-1935
Reed-Sternberg cell or Sternberg-Reed cell
Cancer 1966;19:317
Nodular sclerosis Lymphocyte depleted
Lymphocyte predominant
Mixed cellularity
HODGKIN’S DISEASE HISTOLOGICAL SUBTYPES
RELATIVE PROPORTIONS OF HODGKIN LYMPHOMA SUBTYPES
0
10
20
30
40
50
60
70
%
Nodular LP
Lymphocyte-rich
Mixed cellularity
Nodular sclerosis
Lymphocyte depleted
Composite HD & NHL
n=882 (Barts)
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 LymphomasInternational 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 lymphomaB-cell prolymphocytic leukaemiaLymphoplasmacytic lymphoma
Splenic B-cell marginal zone lymphomaHairy cell leukaemiaPlasma cell myeloma / plasmacytoma - solitary osseous, extraosseous
Extranodal marginal zone B-cell lymphoma of MALTNodal marginal zone B-cell lymphomaFollicular lymphoma, grades 1-3a & 3b
Mantle cell lymphomaDiffuse large B-cell lymphoma (12 specific variants and NOS)Burkitt lymphoma
Primary cutaneous follicle centre lymphoma
World Health Organization Classification of Neoplastic Diseases of the Haematopoietic and Lymphoid Tissues
T-cell and NK-cell neoplasms
T-cell prolymphocytic leukaemia
Aggressive NK-cell leukaemia
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
Peripheral T-cell lymphoma, NOS
T-cell large granular lymphocytic leukaemia
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma, ALK positiveAnaplastic large cell lymphoma, ALK negative
Hydroa vaccineforme-like lymphoma
Primary cutaneous gamma delta T-cell lymphoma
Systemic EBV positive lymphoproliferative disease of childhood
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 MalariaSporadic (Western type) – EBV usually –veHIV – 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
0
10
20
30
40
50
60
70
80
90
Stomach
Small gut
Large gutO
ral
PharyngealTonsilsNose
Orbit+
Larynx-lungPleura
SpleenPancreasBreastO
vary
Testis
UrologicalCervix/vaginaThyroidSalivaryBrain
Bone
Skin
ExtraduralM
ediastinumLiver
Soft tissue
B-CLL Lymphoplasmacytic FollicularMantle cell Marginal zone (MALT) Diffuse large BT-cell NK/T, nasal type
Frequencies of Extranodal Lymphomas by Site of Origin (Barts & London)
5
20
35
50
65
80
950
20
40
60
80
100
120
Diffuse large B cell Lymphoma
+ B- LymphocyticBlastic mantle cell+Nodular L&H HDHIV related NHL+Lymphoplasmacytic+Marginal zone MALTMediastinal large B+Follicular lymphomaDiffuse large B cell NOS
Diffuse large B cell lymphoma is not an homogeneous entity
Alizadeh AA et al. Nature 2000; 403: 503-511
A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphomaWright G, et alProc Natl Acad Sci U S A. 2003 August 19; 100(17): 9991–9996.
Lymphochip Affymetrix
Germinal Centre profile DLBCL have a superior survival to Activated B-cell profile DLBCL
Global incidence of non-Hodgkin lymphoma in men: age standardized incidence / 100,000 population World Cancer Report 2003
Follicular Lymphoma
• USA and Europe• Middle East, Far East, India
• 3.5 / 100,000• ~0.5 / 100,000
Diffuse Large B-cell Lymphoma
Europe and USA.Middle East, Far East, India
5.0 / 100,0002-3 / 100,000
NK/T-cell lymphoma, nasal type
Europe and USAHong Kong, Taiwan S. America, etc
0.04 /100,0000.4 / 100,000
Henry Rappaport on Lymphoma Classification
“(A classification should be) … clinically useful, scientifically accurate, reproducible, easily taught and readily learnt.”
Guidance on Cancer Services
Improving Outcomes inHaematological Cancers
The Manual
NHS
National Institute forClinical Excellence
Guidance on C
ancer Services – Im
proving Outcom
es in Haem
atological Cancers – T
he Manual
Haematological cancers service guidanceCancer 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 ExcellenceOctober 2003
• All patients with haematological cancer should be managed bymulti-disciplinary haemato-oncology teams which servepopulations 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 C
ancer Services – Im
proving Outcom
es in Haem
atological Cancers – T
he Manual
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.
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
Christie Hospital Manchester Royal Infirmary
Population >3.5M
6.1
7.1
2
6.6
16.2
62.1
Critical - benign vs.malignant
Major - error affectingtreatment
Minor - missedcomponent
Minimal -terminological
Refined
No change
Total Errors - all Trusts (n=198)15.2% errors with an impact on patient management
RESULTS OF AN AUDIT OF FIRST SIX MONTH’S ACTIVITY
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: 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