COMMENTARY Is It Chronic Idiopathic Myelofibrosis, Myelofibrosis With

COMMENTARY

Is it chronic idiopathic myeloﬁbrosis, myeloﬁbrosis with myeloid metaplasia, chronic megakaryocytic–granulocytic myelosis, or chronic megakaryocytic leukemia? Further thoughts on the nosology of the clonal myeloid disorders

MA Lichtman1

1University of Rochester Medical Center, Rochester, NY, USA

Leukemia (2005) 19, 1139–1141. doi:10.1038/sj.leu.2403804 hypereosinophilic syndrome as being composed largely of cases Published online 19 May 2005 of chronic eosinophilic leukemia and of T-cell lymphoma with The designations given to the clonal (neoplastic) lymphohema- reactive eosinophilia, probably IL-5 mediated in most cases. The topoietic disorders undergo periodic revision. The World Health chronic myelogenous leukemias are shown in Table 1. Organization (WHO) draws together experts to consider Another shortcoming of the classification of the clonal myeloid diseases is the failure to stratify them by degree of reclassification of these diseases as knowledge of their 2–4 pathobiology advances.1 The clonal lymphoid diseases have malignant change, a critical feature of these neoplasms. For had notable attention. These neoplasms arise from transforming example, oligoblastic myelogenous leukemia (‘refractory ane- mutations in lymphocytes that have been defined with increas- mia with excess blasts’ in the WHO classification) is more ing precision. They have been related to their presumptive closely related to the other oligoblastic myelogenous leukemias, normal homologue in the lymphocyte maturation sequence and such as myelomonocytic leukemia, based on the frequency of to the localization of their normal homologue in a relevant leukemic blast cells (its degree of leukemicness) and, therefore, lymphoid structure (eg, skin, gut region, lymph node region, its course, than to clonal sideroblastic anemia (‘refractory spleen, etc). The application of gene expression analysis will sideroblastic anemia in the WHO classification’) with which it result in further refinements of the classification. The next usually is paired. In part, this disassembly is a reflection of the iteration of the classification of the clonal lymphoid diseases failure to accept that the ‘myelodysplastic’ disorders are part of will include at least two and, perhaps, three subtypes of diffuse the spectrum of aberrancy resulting from mutations in multi- large B-cell lymphoma. It is likely that other refinements in potential hematopoietic cells that are limitless in morphological classification based on gene expression profiles will be made. expression. Three cheers for the lymphologists! The retention of arbitrary ‘breakpoints’, such as calling a disorder refractory nonsideroblastic anemia if it has less than 15% pathological sideroblasts and calling it sideroblastic Classifying clonal myeloid diseases anemia if it has 15% or more pathological sideroblasts, and calling a case refractory anemia with excess blasts if it has less The re-evaluation of the classification of the clonal myeloid than 21% blasts in a marrow examination, but acute myelo- diseases has not been as frequent as that of the clonal lymphoid genous leukemia if it has 21% or more blasts in a marrow diseases, although a revision was published in 2001.1 In general, examination,2–4 is reminiscent of the arbitrary rules established the changes were minimal in that obsolescent terminology such by the tsars, and our acceptance of these rules is reminiscent of as ‘refractory anemia’ was left in place and the phrase ‘excess the behavior of the 19th century Russian peasantry. blasts’, which is a reflection of fuzzy thinking, was perpetuated. This polemic is not intended to revisit the shortcomings of the Also, the classification was made redundant by listing morpho- classification of clonal myeloid diseases in general; it has been logic and genetic alterations that are not mutually exclusive. dealt with elsewhere.2–4 Rather, I wish to raise the issue of the A practical and comprehensive subclassification of the clonal designation of another syndrome that is a singular clonal myeloid diseases by genotype is unlikely to replace completely myeloid disease, chronic idiopathic myelofibrosis. The disease the morphologic classification because of the large number of is a chronic clonal myeloid disorder characterized by (a) apparent primary genetic mutations associated with myeloid anemia, (b) splenomegaly, (c) immature granulocytes, erythro- diseases. For example, there have been over 100 primary blasts, teardrop-shaped red cells and an increase in CD34 þ genetic alterations associated with AML alone, although three cells in the blood, (d) marrow fibrosis, (e) osteosclerosis, and major translocations, (t(8;21), t(15;17), Inv16 or t(16;16)), (f) fibrohematopoietic tumors that can occur in virtually any account for about 20% of cases, if one includes all age groups. tissue.5 Genotype can be very useful as a supplement to phenotype as is the case in ‘the chronic myelogenous leukemias’, in which Chronic megakaryocytic leukemia group the explicit definition of chronic myelogenous leukemia with BCR rearrangement has helped stratify these disorders. Heuck originally described the disorder in 1879 under the title Identification of other mutations have also clarified the ‘Two Cases of Leukemia and Peculiar Blood and Bone Marrow Findings’.6 Of course, he was correct that it is leukemia. Since Correspondence: Professor MA Lichtman, University of Rochester that description about 125 years ago, over two dozen designa- Medical Center, 610 Elmwood Avenue, Rochester, NY 14642-0001, USA; Fax: þ 1 585 271 1876; E-mail: [email protected] tions for the disease have been proposed or used, and different Received 11 April 2005; accepted 12 April 2005; Published online 19 ones have been preferred in different countries. Indeed, one May 2005 group, expert in the field, used two different designations in the Commentary 1140 Table 1 The chronic myelogenous leukemias13 megakaryocytopoiesis, megakaryocyte clusters, often around marrow sinuses, loss of anchoring to the abluminal aspect of the BCR-rearrangement-positive CML marrow sinus with entry of whole megakaryocytes into the sinus BCR-rearrangement-negative CML14 lumen, pleomorphic changes of megakaryocytic nuclei, sometimes described as cloud-like, as a result of nuclear ballooning Chronic myelomonocytic leukemia and hypochromasia, and variability of nuclear and cytoplasmic PDGFRb positive15 Other genetic abnormalities size are striking. The dominance of neoplastic megakaryocytopoiesis is evident also in cases with intense marrow fibrosis and Juvenile myelomonocytic leukemia reductions in erythropoiesis and granulopoiesis. In this setting, Chronic megakaryocytic leukemia (ie idiopathic myelofibrosis) the bundles of collagen and reticulin are heavily interspersed Chronic neutrophilic leukemiaa a with clumps of dysmorphic megakaryocytes. Abnormal mega- Chronic eosinophilic leukemia (ie hypereosinophilic syndrome) karyocytopoiesis, also, is the hallmark of patients in the PDGFRa positive16 Other genetic abnormalities prefibrotic phase of the disease. Thus, neoplastic megakaryocytopoiesis is the dominant feature of incipient or advanced Chronic mastocytic leukemiaa,b idiopathic myelofibrosis and supports the designation chronic Chronic basophilic leukemiac,17 megakaryocytic leukemia. c,18 Chronic monocytic leukemia One could ask whether essential (primary) thrombocythemia is The categorization of each of chronic eosinophilic and myelomonocytic not, also, a chronic megakaryocytic leukemia. It is one in the leukemias into PDGFR mutation-positive and -negative groups is sense that it is clonal disorder originating in a primitive important because of the response of the former to imatinib mesylate multipotential hematopoietic cell from which the principal or its congeners. a disturbance is exaggerated megakaryocytopoiesis and elevated Uncommon disorders. platelet counts, but the term thrombocythemia does capture the bSystemic mastocytosis in the WHO classification.1 cRare disorders. central issue. It is, in effect, a ‘benign’ leukemia if one uses the term ‘leukemia’ to designate benign and malignant neoplasms of a primitive, usually multipotential hematopoietic cell. The use of the term benign is a counterpoint to acute (polyblastic) and title of two papers on the subject in the same year of publication: subacute (oligoblastic) myelogenous leukemias and not meant to primary osteomyelofibrosis/-sclerosis in one and agnogenic imply the absence of morbidity, as discussed previously.2 myeloid metaplasia in the other. In a third paper published Importantly, thrombocythemia is never associated with leukemic later, they used idiopathic (primary) myelofibrosis. Agnogenic blast cells in blood or marrow. Idiopathic myelofibrosis behaves myeloid metaplasia had been the most frequent designation in more like the chronic myelogenous leukemias and like them has the United States, but has been superseded by myelofibrosis overt morphological leukemic hematopoiesis, quite different with myeloid metaplasia or idiopathic myelofibrosis, the two from thrombocythemia. This distinction from chronic mega- most frequently used terms for the disease, currently. The WHO karyocytic leukemia (idiopathic myelofibrosis in the WHO classification refers to the disease as chronic idiopathic classification) is a profound one as noted by the markedly longer myelofibrosis. life expectancy on average of a patient with thrombocythemia at No designation has been formulated that accommodates the the time of diagnosis (virtually the same as an unaffected six key phenotypic features of (a) a clonal (neoplastic) comparison population)19–21 as compared to a patient with hematopoietic multipotential cell abnormality, (b) variable chronic megakaryocytic leukemia who lives on average about alterations in the steady-state level of blood cells, (c) dominant 3–4 years after diagnosis.19–21 Thus, the nosologic grouping of neoplastic megakaryocytopoiesis, (d) a propensity to extrame- polycythemia vera, thrombocythemia and idiopathic myelofibro- dullary fibrohematopoietic tumors, (e) an intense reactive sis has historical roots, but today is pathobiologically inaccurate. (polyclonal) marrow fibrosis, and (f) a propensity to osteo- Of the numerous prior designations for idiopathic myelo- sclerosis.5 This disconnect is not a surprise since no practical fibrosis, ‘megakaryocytic myelosis’ may have been the most apt. designation could accommodate the principal manifestations of It highlighted the primary phenomenon. Indeed, the choice of most leukemias. These characteristics are implied by the chronic idiopathic myelofibrosis by the WHO panel was designations, for example, acute promyelocytic leukemia contentious because of the relatively high frequency of a (dominant leukemic promyelocytic cell type, Auer rods, prefibrotic phase of the disease. Thus, some preferred the term, hemorrhage resulting from intravascular coagulation and/or chronic megakaryocytic–granulocytic myelosis. Granulocytic fibrinolysis), chronic eosinophilic leukemia (dominant leukemic hyperplasia with mild neutrophilia is a frequent early event in eosinophilic cell type, cardiac and neurological tissue damage), this disease, but like most other clonal myeloid disorders, this acute monocytic leukemia (dominant leukemic monocytic cell reflects its origin in a primitive multipotential cell; the major type, striking tissue infiltrates, tendency to hyperleukocytosis, myeloid lineages are usually involved to some extent in clonal disseminated intravascular coagulation and meningeal involve- myeloid diseases. For example, increased neutropoiesis and ment) and so forth. mild neutrophilia is a feature of thrombocythemia. The term The most constant feature of idiopathic myelofibrosis is the ‘myelosis’, although euphonious, is a euphemism for myelo- expansion of neoplastic megakaryocytes. It, thus, could be genous leukemia. designated chronic megakaryocytic leukemia, expanding The term chronic megakaryocytic leukemia (a) reflects the Heuck’s designation of leukemia. The presence of blood principal and most constant neoplastic alteration in the disease, leukemic blast cells at diagnosis, although not invariable using (b) corresponds to the nomenclature for most other clonal customary analyses, is similar to that of chronic myelogenous myeloid disease, (c) assists in decreasing (all too gradually) leukemia (0–9%, with a mean of about 0.5–1.0%).7 Both anachronistic terminology, (d) implies multilineage involvement diseases are types of oligoblastic myelogenous leukemia. In (leukemia), (e) implies the epiphenomena of marrow fibrosis, idiopathic myelofibrosis, the megakaryocytic alterations are the osteosclerosis, and fibrohematopoietic extramedullary tumors, most striking and the most constant.7–12 Neoplastic expansion of and (f) indicates the propensity to terminate in an acute

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