BLOOD-真红、原发性血小板增多、骨纤的WHO诊断标准地修正

doi:10.1182/blood-2007-12-128454 Prepublished online Apr 9, 2008; 2008 112: 231-239 Jerry L. Spivak and Richard T. Silver myelofibrosis: an alternative proposal polycythemia vera, essential thrombocytosis, and primary The revised World Health Organization diagnostic criteria for http://bloodjournal.hematologylibrary.org/cgi/content/full/112/2/231 Updated information and services can be found at: (4028 articles)Neoplasia • (2381 articles)Clinical Trials and Observations • (54 articles)Perspectives • (485 articles)Free Research Articles • collections: BloodArticles on similar topics may be found in the following http://bloodjournal.hematologylibrary.org/misc/rights.dtl#repub_requests Information about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/misc/rights.dtl#reprints Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/subscriptions/index.dtl Information about subscriptions and ASH membership may be found online at: . Hematology; all rights reservedCopyright 2007 by The American Society of 200, Washington DC 20036. semimonthly by the American Society of Hematology, 1900 M St, NW, Suite Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published For personal use only. by on July 22, 2008. www.bloodjournal.orgFrom Perspective The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal Jerry L. Spivak1 and Richard T. Silver2 1Johns Hopkins University School of Medicine, Baltimore, MD; and 2Weill Cornell Medical College, New York, NY Introduction In its August 15, 2007, issue, Blood published a proposal for revision of the World Health Organization (WHO) diagnostic criteria for the chronic myeloproliferative disorders (MPDs) poly- cythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF).1 Algorithms based on these diagnostic crite- ria were subsequently published in Leukemia.2 Ostensibly prompted by newly described MPD molecular abnormalities, the proposed revision was both timely and appropriate. The initial WHO diagnostic criteria for these disorders, published in 2001,3 were never prospectively evaluated and subsequently were invalidated.4 The discovery of JAK25-9 and MPL10-12 gene mutations not only provided new insights into the molecular basis of the MPD but also new molecular approaches to their diagnosis. Unfortunately, the proposed guideline revision and the attendant algorithms not only recapitulated all the faults of the initial WHO diagnostic criteria but also failed to capitalize on the biologic insights and opportunities offered by these newly discovered mutations to improve diagnostic accuracy. This was because the proposed revision eschewed the fundamental tenets of evidence-based medicine.13-15 The purpose of this review, therefore, is to offer an alternative perspective of the diagnostic approach to PV, ET, and PMF to enable clinicians to select the appropriate diagnostic tests for a particular MPD within the context of their own practices. The back story The MPDs are neither new nor rare diseases, but they continue to confound physicians diagnostically for reasons that are many and cogent. Although not rare, the MPDs are sufficiently uncommon that most physicians see few such patients; and because disease duration for the MPD is typically measured in decades, physicians rarely have the opportunity to observe their full natural history. Importantly in this regard, the initial clinical manifestations of the MPDs are highly variable and their clinical phenotypes are also subject to change with time. These disorders not only mimic each other phenotypically but many other benign and malignant blood disorders as well. For example, PV can present as isolated erythrocytosis,16 leukocytosis,17 thrombocytosis18,19 (Figure 1A), or even myelofibrosis,20,21 whereas isolated thrombocytosis is the presenting feature in approximately 20% of PMF patients.22 In addition, myelofibrosis is a well-recognized feature of PV23-25 and erythrocytosis can develop in PMF during the course of the illness26 (Figure 1B). William Osler was not the first to identify PV as a distinct clinical entity,27 but he was the first to recognize its capacity for phenotypic mimicry and devised diagnostic criteria that addressed the problem.28 The Polycythemia Vera Study Group (PVSG) subsequently expanded Osler’s diagnostic criteria29 and, as new knowledge was obtained, other groups formulated diagnostic criteria for PV,30,31 ET,32 and PMF,33 but to date there has been no uniformly agreed on set of diagnostic criteria, or at least not one, according to recent surveys,34,35 to which most clinicians strictly adhere. In 2001, the WHO attempted to fill this void with a new MPD classification, grouping PV, ET, and PMF together with chronic myelogenous leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, the hypereosinophilic syndrome, and unclas- sifiable MPDs under the rubric of “the chronic myeloproliferative diseases.”3,36 The rationale was to apply to the MPD the WHO Revised European-American Lymphoma (REAL) classification paradigm that had been successfully used for lymphoid and myeloid neoplasms. The REAL scheme combines morphology, genotype, immunophenotype, and clinical phenotype to define distinct clinical entities.3 The principles espoused by the WHO were both laudable and appropriate, but only to the extent that the REAL classification paradigm used for other hematologic neo- plasms was applicable to the MPD; unfortunately, this proved to be limited. The WHO also provided diagnostic criteria for the MPDs, and these soon proved to be problematic.4 The problem The WHO MPD diagnostic classification was based on the shared features of “myeloproliferation” with relatively normal maturation and a tendency to extramedullary hematopoiesis that characterize the various MPDs.3 The shared feature of myeloproliferation, however, was more apparent than real because, with respect to the involved stem cell, PV, ET, and PMF are actually disorders of myeloaccumulation, not myeloproliferation.37-39 In this regard, in contrast to the other “myeloproliferative” disorders, survival with PV, ET, or PMF, even with supportive therapy alone, is usually measured in decades, and transformation to acute leukemia is much less common and often treatment-related. Beyond these character- istics, PV, ET, and PMF share more in common genotypically and phenotypically with each other than they do with the other MPDs with which they have been classified36; and on this basis alone, they merited a separate classification. This contention was solidified recently by the discovery of JAK25-9 and MPL gene mutations10-12 in MPD patients. Indeed, considering their genotypic similarities and the tendency for each disorder to acquire the phenotypic Submitted December 20, 2007; accepted March 25, 2008. Prepublished online as Blood First Edition paper, April 9, 2008; DOI 10.1182/blood-2007-12-128454. © 2008 by The American Society of Hematology 231BLOOD, 15 JULY 2008 � VOLUME 112, NUMBER 2 For personal use only. by on July 22, 2008. www.bloodjournal.orgFrom characteristics of the others, it is worth asking whether PV, ET, and PMF are separate diseases, different manifestations of the same disease, or a combination of both, and current molecular evidence supports the last possibility.22,40,41 The REAL paradigm, although useful for distinguishing and classifying lymphoid and many myeloid neoplasms, was not appropriate for PV, ET, and PMF. These 3 disorders share in common the following features: origin in a multipotent hematopoi- etic progenitor cell, relatively normal cellular maturation, pheno- typic and genotypic mimicry, and a tendency to evolve into each other or develop myelofibrosis. They also do not have unique immunophenotypes. Therefore, none of the REAL paradigm tenets, alone or together, was diagnostically useful. Nevertheless, the WHO based their diagnostic criteria on morphology, and with respect to PV, as a surrogate for red cell mass and plasma volume studies, substituted hemoglobin values of more than 18.5 g/dL in men and more than 16.5 g/dL in women, or more than 99th percentile of the chosen method-specific reference range for age, sex, and altitude of residence.3 However, no data were offered to support the substitution of specific hemoglobin values as a surrogate for direct measurement of the red cell mass. Ostensibly, the hemoglobin reference standards were for those physicians who lacked access to a nuclear medicine facility, but proof that such values were clinically meaningful was not provided. Considering the many phenotypic similarities between PV, ET, and PMF, what should have been most important was defining their differences. With respect to laboratory characteristics, only erythro- cytosis sets PV apart from its companion MPD, whereas during the early stages of the disease, an increase in circulating CD34� cells is characteristic for PMF, although this is not uniformly so.42,43 Importantly, ET has no specific clinical or laboratory characteris- tics that distinguish it from PV. Therefore, considering that trilineage involvement is the ultimate possible phenotype for an MPD arising in a multipotent hematopoietic stem cell, recommen- dation of an accurate method for detecting absolute erythrocytosis should have been mandatory. Unfortunately, the WHO alternatives to direct measurement of the red cell mass proved to be inadequate because of the erroneous assumption that, in an MPD patient, a normal hemoglobin or hematocrit level signified that the red cell mass was normal. In 2005, Johansson et al4 challenged the WHO assertion that only hemoglobin levels greater than 18.5 g/dL (hematocrit� 55.5%) in a man or greater than 16.5 g/dL (hematocrit � 49.5%) in a woman (or the equivalent� 99th percentile of the method-specific reference value) established the presence of absolute erythrocyto- sis. They applied the WHO criteria to 77 PV patients and 66 patients with apparent erythrocytosis, all of whom had direct red cell mass and plasma volume measurements.4 They found that the WHO criteria identified absolute erythrocytosis in only 35% of the male PV patients and 63% of the women, whereas 14% of the men and 35% of the women without erythrocytosis were noted as having it (Figure 2). Moreover, the degree to which the WHO hemoglobin criteria failed was actually worse than it appeared because, by direct measurement, the red cell mass is not considered elevated unless it is 125% of normal.44 This not only enhances the specificity of the test, it also indicated that the WHO recommendations lacked sensitivity. Surprisingly, these objective data were omitted in the revised WHO diagnostic recommendations, which remain un- changed.1 The specificity of the WHO PV diagnostic criteria was Figure 1. Evolution of essential thrombocytosis and primary myelofibrosis into polycythemia vera. (A) Erythrocytosis developing in a 60-year-old man with essential thrombocytosis 6 years after diagnosis. The increase in the JAK2 V617F neutrophil allelic burden with time is also shown. The hemoglobin (Hgb) level was reduced by phlebotomy. (B) Erythrocytosis developing in a 70-year-old woman with classic PMF of 17 years’ duration, while taking hydroxyurea to control splenic enlargement (bracketed line). The hemoglobin (Hgb) level was reduced by phle- botomy. Figure 2. Correlation of the WHO hemoglobin guidelines for the diagnosis of PV with actual red cell mass and plasma volume measurements. (A) Men. (B) Women. Similar results were obtained if the corresponding hematocrit values were used. The data are recalculated from Johansson et al.4 232 SPIVAK and SILVER BLOOD, 15 JULY 2008 � VOLUME 112, NUMBER 2 For personal use only. by on July 22, 2008. www.bloodjournal.orgFrom also challenged by the British Committee for Standards in Haematology.45 Blood volume physiology Most discussions of the blood volume emphasize the important direct and exponential relationship between hematocrit and blood viscosity as it occurs in large vessels.46,47 However, the emphasis should really be on the behavior of blood flow in arterioles, capillaries, and venules. In these small vessels, the ratio of vessel surface area to its volume is greatest and the exposure of the blood to the frictional drag of the vessel wall is maximal. Thus, the flow of plasma nearest the vessel wall is retarded compared with the flow of red cells at the vessel center.48 Because of this, there are always fewer red cells in these small vessels; and as a consequence, the volume of distribution of red cells in the circulation differs from that of plasma. Because the microvasculature composes almost 20% of the circulatory system,49 the hematocrit of blood taken from a peripheral artery or vein will not accurately reflect the total body hematocrit.50 From a practical perspective, this has important ramifications with respect to the potential for organ-specific thrombosis when the red cell mass is increased. First, the hematocrit is not uniform in all organs, being highest in the spleen and liver and lowest in the brain, bowel, and kidneys.49 Second, normally, whenever there is a hypoxia-induced increase in erythropoiesis, there is a reciprocal decrease in the plasma volume.51-54 This is also true when red cell transfusions are given55 and has the effect of maintaining a normal blood volume at the expense of an increase in peripheral vascular resistance (Table 1). In PV, however, the plasma volume usually does not shrink with the development of erythrocytosis and may even expand, particularly in women (Table 1), masking the absolute increase in red cell mass.39,56-58 Thus, it is not surprising that the WHO hemoglobin or hematocrit guidelines were invalid. There are also other important implications of red cell mass and plasma volume determinations not addressed by the latest WHO recommendations. First, a high hematocrit is not synonymous with erythrocytosis any more than a normal hematocrit is synonymous with the absence of erythrocytosis when PV is a diagnostic consideration.39 A high hematocrit can be simply the result of plasma volume contraction (Table 1). Indeed, unless the hematocrit is more than or equal to 60% in a man or woman, it is not possible to distinguish plasma volume contraction from absolute erythrocy- tosis.59 It was for this reason that the PVSG stipulated that direct determination of the red cell mass and plasma volume should be an integral part of the evaluation of a high hematocrit.29 The clinical problem of plasma volume contraction is not trivial,60-63 and there is no excuse for ignoring this group of patients. We recognize the WHO concern that some physicians may not have access to red cell mass and plasma volume measurements because of economic or geographic considerations. In this regard, the assumption that JAK2 mutation assays are not currently subject to the same constraints is also erroneous. From our perspective, in developed countries, it is a deviation from standard of care if these tests are not available, at the very least, in major academic centers. For other circumstances, we offer some alternatives. First, micro- cytic erythrocytosis is an important clue to the presence of an increased red cell mass (Figure 3).64 Second, because it is necessary for the red cell mass to be greater than 125% of normal to qualify for absolute erythrocytosis, phlebotomy can be diagnostic as well as therapeutic. If absolute erythrocytosis is suspected, there should be a minimum excess of approximately 700 mL of red cells in either a man or woman. If reduction of the hematocrit to less than 45% in a man or less than 42% in a woman requires 2 or more phlebotomies, absolute erythrocytosis can be assumed. A further important PVSG stipulation was that, after such a phlebotomy trial, the hematocrit should increase by at least 10% within 3 months in the absence of iron deficiency.65 These criteria should ensure that physicians without access to a nuclear medicine facility can achieve diagnostic accuracy; they should not, however, be used as surrogates for direct red cell mass and plasma volume measurements when available because not all patients with a high hemoglobin or hematocrit have an elevated red cell mass, whereas many MPD patients with a supposedly normal hematocrit or hemoglobin level do.56,57 Finally, it should be emphasized that red cell mass and plasma volume determinations only establish the presence of erythrocytosis, not its cause. JAK2 V617F The discovery of the JAK2 V617F mutation5-9 was the most important advance in the study of the MPD since the demonstration Table 1. Examples of the diagnostic value of red cell mass (RCM) and plasma volume (PV) determinations Initial diagnosis Secondary erythrocytosis Essential thrombocytosis Budd-Chiari syndrome Final diagnosis Renal disease with renal cysts and plasma volume contraction Polycythemia vera with plasma volume expansion Polycythemia vera with plasma volume expansion Age, y 37 61 30 BSA 2.01 1.64 1.57 Hemoglobin, g/dL 17.1 14.9 13.5 Hematocrit, % 54.4 45.9 40.3 Expected*/observed Expected* Observed Expected* Observed Expected* Observed RCM, mL 1724 1956 1240 2010 1323 2845 PV, mL 2818 2250 1984 2459 2190 3507 TBV, mL 4542 4206 3224 4469 3513 6352 All 3 patients were female. These examples illustrate the utility of RCM and PV determinations in establishing the presence of true erythrocytosis or plasma volume contraction in clinical situations in which this information could not be obtained in any other way. The ET patient was a JAK2 V617F heterozygote with stainable marrow iron, a normal serum ferritin and red cell MCV, and no splenomegaly. The PV patient was having recurrent intra-abdominal venous thrombosis despite therapeutic anticoagulation. BSA indicates body surface area; and TBV, total blood volume. *The expected values were derived from the tables in Pearson et al.44 DIAGNOSIS AND MYELOPROLIFERATIVE DISORDERS 233BLOOD, 15 JULY 2008 � VOLUME 112, NUMBER 2 For personal use only. by on July 22, 2008. www.bloodjournal.orgFrom 30 years earlier that these were clonal disorders involving a multipotent hematopoietic stem cell.66,67 JAK2 is the cognate tyrosine kinase of the erythropoietin and thrombopoietin receptors and also the obligate chaperone responsible for their cell surface expression.68,69 The substitution of phenylalanine for valine (V617) in the regulatory JH2 domain of JAK2 leading to constitutive kinase activation occurs in approximately 95% of PV patients and in approximately 50% of PMF and ET patients.41,70,71 Indeed, this mutation explains many of the clinical and laboratory features shared by these 3 disorders, although it does not appear to be the initiating mutation.40,72-74 How one mutation could be responsible for 3 different clinical phenotypes is still unresolved, but in vitro clonal assays,38 animal models,75 and studies quantifying the JAK2 V617F neutrophil allele burden in MPD patients41,76,77 indicate that both gene dosage and sex of the patient have roles. In ET, in which females predominate, the JAK2 V617F neutrophil allele burden is usually low41 and isolated thrombocytosis is the rule, whereas in PV, the higher neutrophil allele burden was associated with higher hemato- crit and leukocyte counts, a lower platelet count, splenomegaly, and pruritus.78 As a corollary, some ET patients with a rising neutrophil allele burden transform over time to PV (Figure 1A) or PMF, although JAK2 V617F expression is not mandatory for this to occur.77 Importantly, ET patients expressing JAK2 V617F also appear to have a “PV-like” phenotype compared with their JAK