Syed Z A Zaidi

WHO Classification of Leukemias and Lymphomas

HISTORY

Thomas Hodgkin(1798-1866)

Thomas Hodgkin published in 1832 the first description of lymphoma, specifically of the form named after him, Hodgkin's lymphoma.

Name Hodgkin's Disease proposed in 1865 by Wiks.

HISTORY

HISTORY - IMPORTANT LAND MARKSSince Thomas Hodgkin’s first description of lymphoma in

1832, many other forms of lymphoma have been described, grouped under several proposed classifications.

1956, 1966 Rappaport’s Classification of NHL1966 Lukes-Butler (American) modern classification of

HL Kiel classification: in 1974, Karl Lennert proposed a

new system of classifying lymphomas based on cellular morphology and their relationship to cells of the normal peripheral lymphoid system.

The very popular 1982 Working formulation classification introduced the category Non-Hodgkin Lymphoma (NHL), itself divided into 16 different diseases.

REAL classification: In 1994 the Revised European-American Lymphoma (REAL) Classification attempted to apply immunophenotypic and genetic features in identifying distinct clinico-pathologic NHL entities.

The latest classification by the WHO (2001 updated in 2008) lists 43 different forms of lymphoma divided in four broad groups.

BLOOD, 1 DECEMBER 2008 VOLUME 112, NUMBER 12

MILESTONES

Need for classification of Lymphomas and Leukemia :

Classification is a language of medicine: diseases must be described, defined and named before they can be diagnosed, treated and studied.

A consensus on definitions and terminology is essential for both clinical practice and investigation.

A classification should contain diseases that are clearly defined, clinically distinctive, non-overlapping and that together comprise all known entities.

WHO classification of tumours of the haematopoietic and lymphoid tissues 4th edition, 2008 – true worldwide consensus classification of hematological malignancies:

WHO classification is based on the principles initially defined in REAL classification by the ILSG.

Guiding principle of the REAL and WHO classification is the attempt to define “real diseases” that can be recognised by available techniques and that appear to be distinct clinical entities.

Three important components to the process of developing classification of Hema Malignancies:

First, recognising that the underlying causes of the neoplasm are often unknown and may vary. So, we use morphology, immunophenotype, genetic features, and clinical features to define diseases.

Second principle is that classification relies on building a consensus among as many experts as possible on the definition and nomenclature of the disease.

Third, while pathologists must take primary responsibility for developing a primary classification, involvement of clinicians is essential to ensure its usefulness and acceptance in daily practice.

There is no one “gold standard” by which all diseases are defined in the WHO classification. So:

1. Morphology is always important. 2. Immuno-phenotype and 3. Genetic features are an important part of the definition

of hematologic tumors. Some diseases have a characteristic immunophenotype. Similarly in some lymphoid and many myeloid neoplasms

a specific genetic abnormality is the key defining criteria, while others lack specific known genetic abnormality.

Some genetic abnormalities serve as prognostic factors (such as TP53 mutations or FLT3 – ITD).

Most of the diseases in WHO classification are considered to be distinct entities. However, some are not clearly defined and these are listed as provisional entities.

In July 2009, some more explanations have been published in Blood Journal (Blood.2009: Vol 114: 937-951).

Precursor B & T cell Neoplasms: Precursor B Lymphoblastic Leukemia/LBL, NOSPrecursor B Lymphoblastic Leukemia/LBL with

recurrent cytogenetic abnormalitiesB Lymphoblastic Leukemia/LBL with t(9;22)B Lymphoblastic Leukemia/LBL with t(v;11q23)B Lymphoblastic Leukemia/LBL with t(12;21)B Lymphoblastic Leukemia/LBL with HyperdiploidyB Lymphoblastic Leukemia/LBL with HypodiploidyB Lymphoblastic Leukemia/LBL with t(5;14)B Lymphoblastic Leukemia/LBL with t(1;19)

Precursor T Lymphoblastic Leukemia/TLBL

WHO classification (4th Edition- 2008) of myeloid neoplasms and acute

leukemia• Myeloproliferative neoplasms (MPN)

• Myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1

• Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)

• Myelodysplastic syndrome (MDS)

• Acute myeloid leukemia and related neoplasms

• Acute leukemias of ambiguous lineage

• B lymphoblastic leukemia/lymphoma

• T lymphoblastic leukemia/lymphoma

WHO classification of myeloid neoplasms and acute leukemia

WHO classification of myeloid neoplasms and acute leukemia

WHO classification of myeloid neoplasms and acute leukemia

WHO classification of myeloid neoplasms and acute leukemia

Requirements for assigning more than one lineage to asingle blast population in mixed phenotype acute leukemia (MPAL)

Blood. 2009;114:937-951

Conceptualizing lymphoma and its Classificationneoplasms of lymphoid origin, typically

causing lymphadenopathyleukemia vs lymphoma (extent of BM

involvement)lymphomas as clonal expansions of cells at

certain developmental stages

ALLALL MM MM CLLCLL LymphomasLymphomas

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Myeloproliferative disordersMyeloproliferative disordersAMLAML

Lymphoidprogenitor T-lymphocytes

Plasmacells

B-lymphocytes

nanaïïveve

stemcell

lymphoidprogenitor

progenitor-B

pre-B

immatureB-cell

memoryB-cell

plasma cellplasma cell

DLBCL,FL, HL

ALL

CLL

MM

germinalgerminalcentercenterB-cellB-cell

maturenaiveB-cell

A practical way to think of lymphomaCategory Survival

of untreate

d patients

Curability

To treat or not to

treat

Non-Hodgkin lymphoma

Indolent Years Generally not curable

Generally defer Rx if asymptomatic

Aggressive

Months Curable in some

Treat

Very aggressive

Weeks Curable in some

Treat

Hodgkin lymphoma

All types Variable – months to years

Curable in most

Treat

Clinically useful classification

Diseases that have distinct• clinical features• natural history• prognosis• treatment

Biologically rational

classificationDiseases that have distinct• morphology• immunophenotype• genetic features• clinical features

WHO classificationThe WHO Classification, published in 2001

and updated in 2008, is the latest classification of lymphoma and is based upon the foundations laid within the “REAL” classification.

This system attempts to group lymphomas by cell type (i.e. the normal cell type that most resembles the tumour) and defining phenotypic, molecular or cytogenetic characteristics.

There are three large groups: the B cell, T cell, and natural killer cell tumors.

Hodgkin's lymphoma, although considered separately within the WHO (and preceding) classifications, is now recognised as being a tumour of, albeit markedly abnormal, lymphocytes of mature B cell lineage.

Table 9: Requirements for assigning more than one lineage to asingle blast population in mixed phenotype acute leukemia (MPAL)

Blood. 2009;114:937-951

Blood. 2009;114:937-951

Blood. 2009;114:937-951

Cytogenetic abnormalities sufficient for diagnosis of AML with myelodysplasia-related changes when 20% or more PB or BMblasts are present

Blood. 2009;114:937-951

Recurring chromosomal abnormalities considered as presumptive evidence of MDS in the setting of persistent cytopenia of undetermined origin, but in the absence of definitive morphologic features of MDS

Blood. 2009;114:937-951

Blood. 2009;114:937-951

Blood. 2009;114:937-951

Provisional entity: refractory anemia with ring sideroblasts and thrombocytosis

Blood. 2009;114:937-951

Criteria for primary myelofibrosis (PMF)

Blood. 2009;114:937-951

Criteria for essential thrombocythemia (ET):

Blood. 2009;114:937-951

Blood. 2009;114:937-951

Figure 2. Diagrammatic representation of B-cell differentiationand relationship to major B-cell neoplasms.B-cell neoplasms correspond to stages of B-cell maturation, even though the precise cell counterparts are not known in all instances. Precursor B cells that mature in the bone marrow may undergo apoptosis ordevelop into mature naive B cells that, following exposure to antigen and blast transformation, may develop into short-lived plasma cells or enter the germinal center (GC), where somatic hypermutation and heavy chain class-switching occur. Centroblasts, the transformed cells of the GC, either undergo apoptosis or develop into centrocytes. Post-GC cells include both long-lived plasmacells and memory/marginal zone B cells. Most B cells are activated within the GC, but T cell–independent activation can take place outside of the GC and also probably leads to memory-type B cells. Monocytoid B cells, many of which lack somatic hypermutation, are not illustrated.AG indicates antigen; and FDC, folllicular dendritic cell.Red bar represents immunoglobulin heavy chain gene (IGH@) rearrangement; blue bar, immunoglobulin light chain gene (IGL) rearrangement; and black insertions in the red and blue bars indicate somatic hypermutation.

Figure 3. Diagrammatic representation of T-cell differentiation and function. Lymphoid progenitors enter the thymus where precursor T cells develop into varied types of naive T cells. The cells of the innate immune system include NK cells, T cells, and NK-like T cells. These cells constitute a primitive type of immune response that lacks both specificity and memory. In the adaptive immune system, T cells leave the thymus, where, upon exposure to antigen, they may undergo blast transformation and develop further into CD4 andCD8 effector and memory T cells. T cells of the adaptive immune system are heterogeneous and functionally complex, and include naive, effector (regulatoryand cytotoxic), and memory T cells. Another specific type of effector T cells is the follicular helper T-cell that is found in GCs (TFH). Upon antigenic stimulation, T-cell responses may occur independent of the GC, or in the context of a GC reaction. The lymphomas of the innate immune system are predominantly extranodal in presentation, mirroring the distribution of the functional components of this system. T-cell lymphomas of the adaptive immune system present primarily in adults, and aremainly nodal in origin.

A practical way to think of lymphomaCategory Survival

of untreate

d patients

Curability

To treat or not to

treat

Non-Hodgkin lymphoma

Indolent Years Generally not curable

Generally defer Rx if asymptomatic

Aggressive

Months Curable in some

Treat

Very aggressive

Weeks Curable in some

Treat

Hodgkin lymphoma

All types Variable – months to years

Curable in most

Treat

Three common lymphomasFollicular lymphomaDiffuse large B-cell lymphomaHodgkin lymphoma

Relative frequencies of different lymphomas

Hodgkinlymphoma

NHL

Diffuse large B-cell

Follicular

Other NHL

Non-Hodgkin Lymphomas

~85% of NHL are B-lineage

Follicular lymphomamost common type of “indolent”

lymphomausually widespread at presentationoften asymptomaticnot curable (some exceptions)associated with BCL-2 gene

rearrangement [t(14;18)]cell of origin: germinal center B-cell

defer treatment if asymptomatic (“watch-and-wait”)

several chemotherapy options if symptomatic

median survival: yearsdespite “indolent” label, morbidity

and mortality can be considerabletransformation to aggressive

lymphoma can occur

Diffuse large B-cell lymphomamost common type of “aggressive”

lymphomausually symptomaticextranodal involvement is commoncell of origin: germinal center B-celltreatment should be offeredcurable in ~ 40%

Hodgkin lymphoma

Classical Hodgkin lymphomas:

Nodular sclerosisMixed cellularityLymphocyte-richLymphocyte depleted or not depleted

Nodular lymphocyte-predominant Hodgkin lymphoma

Hodgkin lymphomacell of origin: germinal centre B-cell Reed-Sternberg cells (or RS

variants) in the affected tissuesmost cells in affected lymph node

are polyclonal reactive lymphoid cells, not neoplastic cells

Reed-Sternberg cell

popcorn celllacunar cellclassic RS cell

(mixed cellularity) (nodular sclerosis) (lymphocytepredominance)

germinalcentreB cell

transformingevent(s)

loss of apoptosis

RS cellinflammatory

response

EBV?

cytokines