The WHO Classification of Hematological Malignancies

Pathology Grand Rounds

April 11 2001

No, it’s not that kind of Who

So what is it?

• Classification that includes myeloid, lymphoid, histiocytic and mast cell neoplasms

• applies the principles of the REAL classification to hematological neoplasms– morphology– immunophenotype– genetic features– clinical features

WHO classification of myeloid neoplasms

• Myeloproliferative disease (MPD)• Myelodysplastic/Myeloproliferative disease• Myelodysplastic disease (MDS)• Acute myeloid leukemia (AML)

– AML w/recurrent cytogenetic translocations– AML w/ myelodysplasia-related features– Therapy-related AML and MDS– AML not otherwise categorized

Myeloproliferative Disease

• clonal stem cell disorder with “effective” hematopoiesis resulting in elevated peripheral blood cells and hepatosplenomegaly– Ph1+ CML– polycythemia vera– idiopathic myelofibrosis– essential thrombocytopenia

Juvenile myelomonocytic leukemia (JMML)

• distinct from adult CML or CMML

• classified as a MDS/MPD

• lack Ph1 or BCR/ABL translocation

• usually <3 years old at diagnosis

• dysplasia present but not prominent

Chronic myelomonocytic leukemia (CMML)

• some patients with MDS features - normal PMN counts, multilineage dysplasia, no organomegaly, and BM morphology of RAEB with monocytosis

• some patients with MPD features - neutrophilia, monocytosis, and splenomegaly

• classified as MDS/MPD

Atypical CML (aCML)

• lack Ph1 or BCR/ABL translocation

• predominantly neutrophil series

• dysplastic as well as proliferative features

• often multilineage dysplasia

• worse prognosis than Ph1+ CML

• classified as MDS/MPD

Refractory cytopenia with multilineage dysplasia (RCMD)

• RA and RARS (FAB) - dysplasia is largely limited to erythroid lineage

• MDS with <5% blasts but multilineage dysplasia have worse prognosis and are more likely to die of marrow failure or progress to acute leukemia (like RAEB)

• Multilineage dysplasia is defined as dysplastic features in the cells of two or more cell lines

What blast count should define AML?

• Recent studies have shown that patients with 20-30% blasts (RAEB-T) have similar prognosis to those who have >30% blasts (AML)

• WHO - AML is defined as >20% blasts

• RAEB-T category dropped

Cytogenetic/molecular categories of AML

• specific cytogenetic abnormalities do not correlate precisely with FAB categories

• these should be recognized as distinct entities

• include low blast count cases previously categorized as MDS (<20% blasts)

• currently include four categories

Cytogenetic/molecular categories of AML

• AML with t(8;21)(q22;q22),AML1(CBF )/ETO

• Acute promyelocytic leukemia (AML with t(15;17)(q22;q11-12) and variants, PML/RAR )

• AML with abnormal bone marrow eosinophils (inv(16)(p13q22) or t(16;16)(p13;q11), CBF /MYH11X)

• AML with 11q23 (MLL) abnormalities

Dysplasia and AML

• multilineage dysplasia associated with poor outcomes– dysplasia in two or more cell lines

• history of prior MDS associated with poor outcomes

Prior therapy and AML-Alkylating agents

• different from de novo AML• associated with characteristic

cytogenetic alterations– 3q-, -5, 5q-, -7, 7q-, +8, +9, 11q-,

12p-, -18, -19, 20q-, +21, t(1;7), t(2;11), and complex karyotypes

• associated with a worse prognosis

Prior therapy and AML-Topoisomerase II inhibitors• epipodophyllotoxins and

adriamycin• associated with secondary

leukemias (may be lymphoid)• associated with cytogenetic

abnormalities of de novo AML– 11q23 (MLL), occ. t(8;21), inv(16) or

t(15;17)

Lymphoid neoplasms

• WHO adopted the REAL classification with minor modifications

• split some categories• adopted some “provisional”

categories as “real”

Lymphoblastic neoplasms

• dropped FAB L1, L2, L3 terminology• ALL and lymphoblastic lymphoma

single disease• group by cytogenetic abnormalities

– t(9;22)(q34;q11); BCR/ABL– t(v;11q23); MLL rearranged– t(1;19)(q23;p13) E2A/PBX1– t(12;21)(p12;q22) ETV/CBF

Follicular lymphoma

• changed nomenclature from “follicle center lymphoma” to “follicular lymphoma”

• in the rare case of a purely diffuse lymphoma of follicle center cell origin retain the term “follicle center lymphoma, diffuse”– BCL2– CD10

Grading follicular lymphoma

• grade 1 and 2 are similar - grade 3 has earlier relapses

• use Berard cell counting method for grade

• grade 1: 0-5 centroblasts/hpf• grade 2: 6-15 centroblasts/hpf• grade 3: >15 centroblasts/hpf

– 3a - centrocytes still present– 3b - no centrocytes

Reporting diffuse areas

• should be reported and quantified as per ILSG recommendations– predominantly follicular - >75% follicular– follicular and diffuse - 25-75% follicular– predominantly diffuse - <25% follicular

• areas of DLBCL should be reported separately– e.g. follicular lymphoma grade 3 (75%)

with DLBCL (25%)

Large cells in marginal zone/MALT lymphomas

• recent studies suggest increased transformed cells (5-10% with clusters >20 cells) conferred a slight but significantly worse prognosis

• if DLBCL coexists a separate diagnosis should be made

Mantle cell lymphoma

• mantle zone pattern is less aggressive

• blastic morphology has worse prognosis

• since no effective treatment morphologic subtyping is not required but encouraged for research purposes

Diffuse large B-cell lymphoma

• no biological or clinical data to support subtyping

Burkitt’s vs. Burkitt’s-like lymphoma

• Burkitt’s-like is a non-reproducible category

• DDx - Burkitt’s and DLBCL• reserve Dx of Burkitt’s-like for high

grade lymphomas– morphologically resembles Burkitt’s– has more pleomorphic or large cells than

classical Burkitt’s– Ki-67 proliferative fraction >99%

ALCL definition

• ALK+ and/or t(2;5) - relatively good prognosis

• not restricted to ALK + cases• ALK should be performed on all

cases to the extent possible

Cutaneous vs. systemic ALCL

• cutaneous ALCL– indolent course– lack t(2;5)(p23;q35)– ALK negative– form spectrum with lymphomatoid

papulosis