The 2008 World Health Organization Classification System for Myeloproliferative Neoplasms

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1 Review Article The 2008 World Health Organization Classification System for Myeloproliferative Neoplasms Order Out of Chaos Ayalew Tefferi, MD 1 ; Juergen Thiele, MD 2 ; and James W. Vardiman, MD 3 The first formal classification of chronic myeloid neoplasms is credited to William Dameshek, who in 1951 described the concept of myeloproliferative disorders (MPD) by grouping together chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2001 World Health Organization (WHO) classification of myeloid malignancies included these MPDs under the broader category of chronic myeloproliferative diseases (CMPD), which also included chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), and CMPD, unclassifiable. The revised 2008 WHO classification system featured the following changes: 1) the term CMPD was replaced by myeloproliferative neoplasm (MPN), 2) mast cell disease was formally included under the category of MPN, and 3) the subcategory of CEL/HES was reorganized into CEL not otherwise specified (CEL-NOS) and myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 ; CEL-NOS remained a subcategory of MPN, whereas the latter neoplasms were now assigned a new category of their own. Furthermore, diagnostic criteria for PV, ET, and PMF were revised by incorporating recently described molecular markers (eg, JAK2 and MPL mutations) as well as underscoring the role of histology in differentiating reactive from clonal myeloproliferations. As a result, red cell mass measurement is no longer necessary for the diagnosis of PV, and ET can now be diagnosed at a lower platelet count threshold. The revised WHO document continues to promote the recognition of histologic categories as a necessary first step toward the genetic characterization of myeloid malignancies. Cancer 2009;115: VC 2009 American Cancer Society. KEY WORDS: myeloproliferative, polycythemia, thrombocythemia, myelofibrosis, JAK2. Myeloid malignancies are stem cell-derived clonal disorders and include 3 broad clinicopathologic categories: acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN). However, such classification is not precise; for example, some patients present with features that are characteristic of both MPN and MDS, and are assigned to an overlap category of MDS/ MPN. 1-4 Corresponding author: Ayalew Tefferi, MD, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; Fax: (507) ; tefferi.ayalew@mayo.edu 1 Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; 2 Institute of Pathology, University of Cologne, Cologne, Germany; 3 Department of Pathology, University of Chicago, Chicago, Illinois Received: December 29, 2008; Revised: January 15, 2009; Accepted: January 22, 2009 Published online May 26, 2009 in Wiley InterScience ( DOI: /cncr.24440, Cancer September 1, 2009

2 WHO Classification of MPNs/Tefferi et al The history of MPNs dates back to 1951, when William Dameshek coined the term myeloproliferative disorders (MPD) as a clinicopathologic category that included chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and erythroleukemia (Di Guglielmo syndrome). 5 Over the years, erythroleukemia has been redefined as acute erythroid leukemia or its variants, whereas the other 4 entities have continued to be referred to as MPDs. In 2001, the World Health Organization (WHO) classification of myeloid neoplasms included the Dameshek-defined MPDs under the broader category of chronic myeloproliferative diseases (CMPDs), and also included chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), and CMPD, unclassifiable. 1 At the time, the CMPDs were in turn considered to be 1 of 4 major categories of chronic myeloid neoplasms; the other 3 were MDS, MDS/MPD overlap, and mast cell disease (MCD). The WHO classification of hematopoietic and lymphoid neoplasms was published in September, 2008 It is now well established that chronic myeloid neoplasms share a common stem cell-derived clonal heritage, 6 and their phenotypic diversity is attributed to differences in the specific genetic rearrangements or mutation(s) that underlie the clonal myeloproliferation. 7 For example, the CML phenotype is invariably associated with BCR-ABL1 fusion proteins, whereas a spectrum of abnormal PDGFRA/B proteins that are the products of intrachromosomal (eg, FIP1L1-PDGFRA) or interchromosomal (eg, ETV6-PDGFRB) gene fusions almost invariably display a MPN phenotype that is characterized by prominent blood and bone marrow eosinophilia. 8 Other MPN-associated abnormalities have involved mutations of KIT (associated with mastocytosis), 9 FGFR1 (associated with the 8p11 leukemia/lymphoma syndrome), 10 and RAS/ PTPN11/NF1 (associated with juvenile myelomonocytic leukemia). 11 Conversely, the molecular pathogenesis of the BCR-ABL-negative MPDs remained elusive until 2005, when a JAK2 gain-of-function mutation (JAK2V617F) was discovered in the majority of affected patients In the ensuing 2 years, other JAK2 and MPL mutations were described in JAK2V617F-negative patients with PV, ET, and PMF These discoveries Table 1. Classification of Myeloid Neoplasms According to the 2008 World Health Organization Classification Scheme 1. Myeloproliferative neoplasms (MPN) 1.1. Chronic myelogenous leukemia, BCR-ABL1 positive (CML) 1.2. Polycythemia vera (PV) 1.3. Essential thrombocythemia (ET) 1.4. Primary myelofibrosis (PMF) 1.5. Chronic neutrophilic leukemia (CNL) 1.6. Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS) 1.7. Mast cell disease (MCD) 1.8. MPN, unclassifiable 2. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 3. MDS/MPN 3.1. Chronic myelomonocytic leukemia (CMML) 3.2. Juvenile myelomonocytic leukemia (JMML) 3.3. Atypical chronic myeloid leukemia, BCR-ABL negative (acml) 3.4. MDS/MPN, unclassifiable 4. Myelodysplastic syndromes (MDS) 5. Acute myeloid leukemia (AML) played a major role in the 2008 revision of the classification and diagnostic criteria for chronic myeloid neoplasms. 20 The WHO Classification System for Chronic Myeloid Neoplasms The 2001 WHO classification system defined 4 separate categories of chronic myeloid disorders: CMPD, MDS, MDS/MPD, and MCD. As mentioned earlier, the CMPD category included the 4 classic MPDs (ie, CML, PV, ET, and PMF) as well as CNL, CEL/HES, and CMPD, unclassifiable. 1 In the revised 2008 WHO classification system, the word disease in the context of both CMPD and MDS/MPD was replaced by neoplasm (ie, CMPD was replaced by myeloproliferative neoplasm [MPN] and MDS/MPD was replaced by MDS/MPN ). In addition, MCD was formally included in the MPN category (Table 1). These changes take into account current evidence that strongly supports the common feature of stem cell-derived clonal myeloproliferation noted among CMPDs and in MCD. 21,22 Another major change in the 2008 WHO classification system was the reorganization of CEL/HES into CEL not otherwise specified (CEL-NOS) and myeloid and lymphoid neoplasms with eosinophilia and Cancer September 1,

3 Review Article abnormalities of PDGFRA, PDGFRB, and FGFR1 (Table 1). The latter group was assigned a new category of myeloid neoplasms whereas CEL-NOS remained an entity within the MPN category. This particular change reflects recognition that myeloid malignancies with prominent eosinophilia are heterozygous in their pathogenesis and include molecularly distinct subcategories The separate consideration of PDGFRA-, PDGFRB-, and FGFR1-rearranged eosinophilic disorders carries major therapeutic relevance because the efficacy of treatment with imatinib mesylate depends on the presence of a PDGFR mutation 24,27 ; in other words, neither CEL- NOS nor FGFR1-rearranged disease responds to imatinib mesylate. In addition, the new disease category reconciles the different opinions regarding the nomenclature of PDGFRA-rearranged myeloid neoplasms, which were previouslyreferredtobydifferentinvestigatorsashes, 23 systemic mastocytosis, 28 myeloproliferative variant HES, 29 or CEL. 30 Bone marrow histology remains integral to the 2008 WHO classification of MPNs and is of utmost importance in the morphologic distinction between reactive and clonal myeloproliferation as well as between MDS, MPN, MDS/MPN, and, in some cases, even AML. 4,31 In addition, for the experienced hematopathologist, it provides important clues that enable one to distinguish ET from prefibrotic PMF, an entity often associated with marked thrombocytosis. 32,33 However, recognizing the limited worldwide expertise in MPN pathology, the authors of the WHO classification system effectively incorporated molecular/cytogenetic disease markers and biologically relevant minor criteria to confirm histologic impressions. 20 Finally, the 2001 and 2008 WHO documents are similar in their content with regard to the MDS/MPN (formerly MDS/MPD) category, which displays features that are characteristic of both MDS (dyserythropoiesis or dysgranulopoiesis) and MPN (peripheral blood granulocytosis, monocytosis, eosinophilia, or thrombocytosis). 4 Included in this category were chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, BCR-ABL1- negative, and MDS/MPN, unclassifiable (Table 1). 2 The category of MDS/MPN, unclassifiable includes the WHO provisional entity of refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T). 4 The WHO Diagnostic Criteria for PV, ET, and PMF In 1967, Louis Wasserman assembled a multinational group of clinical investigators and founded the Polycythemia Vera Study Group (PVSG). 34 The PVSG mandate was to study the natural history of PV, establish diagnostic criteria, and conduct large-scale clinical trials. Accordingly, the group formulated diagnostic criteria for the purposes of uniform entry criteria for clinical trials in PV and ET. 35,36 However, these criteria were focused primarily on the exclusion of other causes of erythrocytosis and thrombocytosis and did not place adequate emphasis on bone marrow histology, which was later addressed, in part, by the 2001 WHO diagnostic criteria. 1 The 2008 WHO diagnostic criteria were further refined by the inclusion of additional histologic characterization of the entities and particularly by the addition of the recently discovered JAK2 and MPL mutations as clonal markers (Table 2). 2 For example, it is becoming apparent that nearly all patients with PV carry a JAK2 mutation (JAK2V617F or JAK2 exon 12 mutation). 18 However, although JAK2V617F is specific to PV in the context of erythrocytosis, it is also found in a substantial proportion of patients with ET, PMF, RARS-T, and other myeloid neoplasms. 37,38 Therefore, the presence of JAK2V617F excludes secondary myeloproliferation and supports a diagnosis of MPN, but cannot distinguish 1 MPN from another. However, the presence of either JAK2V617F or JAK2 exon 12 mutation might be essential for the diagnosis of PV. 39 In other words, the diagnosis of PV is based primarily on the detection of a JAK2 mutation, which is often accompanied by a subnormal serum erythropoietin level. Unlike in PV, JAK2V617F mutation screening has limited diagnostic value in ET and PMF because approximately half of the patients are negative for the mutation. 40,41 In this regard, the value of the MPLW515 mutation as a clonal marker in JAK2V617F-negative ET or PMF is undermined by the low incidence of the mutation (estimated to be 5%-10%). 16,17 Furthermore, it has been well established that the aforementioned mutations can occasionally accompany other myeloid neoplasms, including MDS/MPN and MDS. 37,38 Therefore, MPNconsistent bone marrow histology is listed as a required criterion for the diagnosis of ET, PMF, and JAK2 mutation-negative PV (Table 2). 20 Furthermore, because of 3844 Cancer September 1, 2009

4 WHO Classification of MPNs/Tefferi et al Table 2. The 2008 World Health Organization Diagnostic Criteria for Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis WHO Diagnostic Criteria PV* ET PMF Major criteria 1 Hgb >18.5 g/dl (men) >16.5 g/ dl (women) or Hgb >17 g/dl (men), or >15 g/dl (women) if associated with a sustained increase of 2 g/dl from baseline that can not be attributed to correction of iron deficiency or 2 Presence of JAK2V617F or similar mutation 1 Platelet count /L 1 Megakaryocyte proliferation and atypia accompanied by either reticulin and/or collagen fibrosis, or In the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased bone marrow cellularity, granulocytic proliferation and often decreased erythropoiesis (ie, prefibrotic PMF). 2 Megakaryocyte proliferation with large and mature morphology. No or little granulocyte or erythroid proliferation 3 Not meeting WHO criteria for CML, PV, PMF, MDS or other myeloid neoplasm 2 Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm 3 Demonstration of JAK2V617F or other clonal marker or no evidence of reactive bone marrow fibrosis 4 Demonstration of JAK2V617F or other clonal marker or no evidence of reactive thrombocytosis Minor criteria 1 BM trilineage myeloproliferation 1 Leukoerythroblastosis 2 Subnormal serum Epo level 2 Increased serum LDH 3 EEC growth 3 Anemia 4 Palpable splenomegaly WHO indicates World Health Organization; PV, polycythemia vera; ET, essential thrombocythemia; PMF, primary myelofibrosis; Hgb, hemoglobin; CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome; BM, bone marrow; Epo, erythropoietin; LDH, lactate dehydrogenase; EEC, endogenous erythroid colony. * The diagnosis of PV requires meeting either both major criteria and 1 minor criterion or the first major criterion and 2 minor criteria. y The diagnosis of ET requires meeting all 4 major criteria. z The diagnosis of PMF requires meeting all 3 major criteria and 2 minor criteria. Or Hgb or hematocrit greater than the 99th percentile of reference range for age, sex, or altitude of residence or red cell mass >25% above the mean normal predicted. Small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering. the not-so-infrequent occurrence of false-positive molecular test results and the salient features of histologic diagnosis, 33,42,43 the 2008 WHO subcommittee for the classification of MPNs included biologically relevant minor criteria to solidify the molecular diagnosis of PV and the histologic diagnosis of PMF (Table 2). 20 Finally, the availability of a molecular marker (ie, JAK2V617F) along with the increased utility of bone marrow histology has made it possible to lower the platelet count threshold for an ET diagnosis from /L to /L and to consider a PV diagnosis at a lower hemoglobin target than that determined by the WHO in the presence of a persistent increase in the hemoglobin level of >2 g/dl from baseline (Table 2). 44,45 The latter modification has further undermined the utility of red cell mass measurement in the diagnosis of PV, and the therapeutic relevance of the distinction between PV and JAK2V617Fpositive ET/PMF, in equivocal cases, remains dubious. Conclusions The recent discovery of the JAK2 and MPL mutations has rekindled interest in the approach to classic BCR-ABL1- negative MPNs in terms of both diagnostic evaluation 2 and treatment. 46 However, much remains unknown with regard to the precise pathogenetic contribution of these novel mutations 47 and their ultimate value as drug targets. 48 In the interim, the WHO group in charge of MPN classification and diagnostic criteria are taking a proactive role in translating emerging new science into clinical Cancer September 1,

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