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
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