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 a

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