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