WHO Classification of Leukemias and Lymphomas

Syed Z A Zaidi

HISTORY

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 - IMPORTANT LAND MARKS

Since Thomas Hodgkins first description of lymphoma in

1832, many other forms of lymphoma have been described, grouped under several proposed classifications. 1956, 1966 Rappaports Classification of NHL 1966 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 EuropeanAmerican 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.

MILESTONES

BLOOD, 1 DECEMBER 2008 VOLUME 112, NUMBER 12

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, nonoverlapping 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, NOS Precursor B Lymphoblastic Leukemia/LBL with

recurrent cytogenetic abnormalities

B 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 Hyperdiploidy B Lymphoblastic Leukemia/LBL with Hypodiploidy B 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 a single blast population in mixed phenotype acute leukemia (MPAL)

Blood. 2009;114:937-951

Conceptualizing lymphoma and its Classification

neoplasms of lymphoid origin, typically causing

lymphadenopathy leukemia vs lymphoma (extent of BM involvement) lymphomas as clonal expansions of cells at certain developmental stages

ALL

CLL
nave

Lymphomas

MM

B-lymphocytes Lymphoid progenitor Plasma cells T-lymphocytes

AML
Hematopoietic stem cell Myeloid progenitor

Myeloproliferative disorders
Neutrophils Eosinophils Basophils Monocytes Platelets

Red cells

B-cell development
stem cell lymphoid progenitor
progenitor-B

CLL

mature naive B-cell

germinal center B-cell

memory B-cell

MM DLBCL, FL, HL

ALL

pre-B immature B-cell

plasma cell

A practical way to think of lymphoma

Category Survival of untreated patients

Curability

To treat or not to treat

NonHodgkin lymphoma

Indolent

Years

Generally not curable

Curable in some
Curable in some

Generally defer Rx if asymptomatic

Aggressive

Months

Treat

Very

aggressive
Hodgkin lymphoma All types

Weeks

Treat

Variable months to years

Curable in most

Treat

Classification
Biologically rational classification
Diseases that have distinct morphology immunophenotype genetic features clinical features

Clinically useful classification

Diseases that have distinct clinical features natural history prognosis treatment

 WHO classification The 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 a single 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 BM blasts 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

Provisional entity: refractory anemia with ring sideroblasts and thrombocytosis

Blood. 2009;114:937-951

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 differentiation and 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 or develop into mature naive B cells that, following exposure to antigen and blast transformation, may develop

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

A practical way to think of lymphoma

Category Survival of untreated patients

Curability

To treat or not to treat

NonHodgkin lymphoma

Indolent

Years

Generally not curable

Curable in some
Curable in some

Generally defer Rx if asymptomatic

Aggressive

Months

Treat

Very

aggressive
Hodgkin lymphoma All types

Weeks

Treat

Variable months to years

Curable in most

Treat

Three common lymphomas

Follicular lymphoma Diffuse large B-cell lymphoma

Hodgkin lymphoma

Relative frequencies of different lymphomas

Non-Hodgkin Lymphomas Diffuse large B-cell Hodgkin lymphoma NHL Follicular Other NHL ~85% of NHL are B-lineage

Follicular lymphoma
most common type of indolent lymphoma usually widespread at presentation often asymptomatic not 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: years despite indolent label, morbidity and mortality can be considerable transformation to aggressive lymphoma can occur

Diffuse large B-cell lymphoma

most common type of aggressive

lymphoma usually symptomatic extranodal involvement is common cell of origin: germinal center B-cell treatment should be offered curable in ~ 40%

Hodgkin lymphoma
Classical Hodgkin lymphomas:
Nodular sclerosis Mixed cellularity Lymphocyte-rich

Lymphocyte depleted or not depleted

Nodular lymphocyte-predominant Hodgkin

lymphoma

Hodgkin lymphoma
cell of origin: germinal centre B-cell
Reed-Sternberg cells (or RS variants) in the

affected tissues most cells in affected lymph node are polyclonal reactive lymphoid cells, not neoplastic cells

Reed-Sternberg cell

RS cell and variants

classic RS cell
(mixed cellularity)

lacunar cell
(nodular sclerosis)

popcorn cell
(lymphocyte predominance)

A possible model of pathogenesis

transforming event(s) EBV? loss of apoptosis

cytokines

germinal centre B cell

RS cell

inflammatory response