Leukemia (2014) 28, 1191–1195 & 2014 Macmillan Publishers Limited All rights reserved 0887-6924/14 www.nature.com/leu REVIEW Rethinking the diagnostic criteria of polycythemia vera T Barbui1, J Thiele2, AM Vannucchi3 and A Tefferi4 The aim of this review is to critically address the validity and clinical applicability of three major diagnostic classification systems for polycythemia vera (PV), that is, those proposed by the Polycythemia Vera Study Group (PVSG), the British Committee for Standards in Haematology (BCSH) and the World Health Organization (WHO). Special focus is on which one of the three red cell parameters (hemoglobin—HB, hematocrit—HCT and red cell mass—RCM) should be used as the diagnostic hallmark of PV. The revised BCSH employed a persistently raised HCT level as the first diagnostic criterion in combination with the presence of a JAK2V617F mutation. On the other hand, the WHO classification used a raised HB value as a surrogate for increased RCM in association with molecular markers and for the first time, the bone marrow (BM) morphology was included as a minor criterion. Ongoing controversy and discussion regards the use of certain threshold values for HCT and HB as surrogates for RCM as well as the existence of prodromal- latent disease, so-called masked PV (mPV). It has been shown that mPV can be recognized in patients not meeting the required HB or HCT threshold levels by both the WHO and BCSH criteria. These cases present with the same baseline clinical features as overt PV but present worsened survival. A critical reappraisal of the WHO criteria may suggest either to reduce the thresholds for HB or to consider HCT values as major diagnostic criterion, as in the BCSH, in association with JAK2V617F mutation. The clinical utility of using HCT as reference variable is supported also by results of clinical trials which explicitly recommend to use the HCT threshold for monitoring treatment. In questionable cases as in mPV, BM biopsy examinations should be mandated together with mutation analysis. Leukemia (2014) 28, 1191–1195; doi:10.1038/leu.2013.380 Keywords: polycythemia vera; diagnostic criteria; masked polycythemia; bone marrow histology; risk factors for survival INTRODUCTION CLASSIFICATION SYSTEMS The Polycythemia Vera Study Group (PVSG) was the first Polycythemia Vera Study Group to establish consensus diagnostic guidelines in polycythemia As it has been amply emphasized12,14,16,17 the PVSG criteria24,25,26 vera (PV) as an instrument for conducting a number of clinical stipulate an elevation of the RCM as the most important feature trials.1 Since then, those criteria have undergone significant for the diagnosis of PV (Table 1), irrespective of the HCT or HB modifications by two other classification systems2–4 that value. A fierce debate is still going as regards surrogate markers of included the JAK2V617F or other functionally similar mutations RCM that could constitute a reliable indicator of the body’s red cell which were found to be present in virtually all patients with content. As shown by two groups, in both males and females a overtorinapparent(masked)PV.5–11 However, controversies raised HB is not always equal to an absolute erythrocytosis and and an intense debate still persist on which one of the three red conversely, an HB concentration below the required cutoff level cell parameters (that is, hemoglobin (HB) level, hematocrit (HCT) could be associated with an increased RCM.13,16 However, there is value and red cell mass (RCM) measurement) should be used a consensus that males and females presenting with sustained as the most reliable indicator of an increased RCM for the HCT values 460% and 456% respectively can be assumed to diagnosis of PV.12–17 Moreover, a conflict of opinion has have an absolute erythrocytosis and therefore do not require frequently been expressed concerning the usefulness and confirmatory studies like RCM.30,31 Prompted by these findings, validity of bone marrow (BM) examinations in this disorder.12,14 the procedure for RCM determination has been abandoned in While overt disease usually presents no diagnostic challenges, daily clinical practice since it is a cumbersome and costly test that prodromal-early stage18–20 or masked PV (mPV)21 and terminal is also suboptimal in its diagnostic accuracy.32,33 In clinical (so-called) spent phases or post-PV myelofibrosis22 may be practice, clinicians are well aware that this key issue will not be difficult to establish.23 resolved any time soon and for this reason the majority of them Aim of this paper is to highlight some of the problems would recommend individual choice on this crucial matter.3 and pitfalls associated with the three major classification Although BM examinations were not part of the diagnostic criteria systems that comprise the original24–26 and slightly revised27–29 established by the PVSG (Table 1), a number of interesting criteria proposed by the PVSG, the original30 and revised findings were reported by this group.23,34,35 In particular, it was guidelines2 reported by the British Committee for Standards reported that 36 (13%) of the 281 pretreatment biopsies carried in Haematology (BCSH) and the revised consensus classifi- out in overt PV cases demonstrated a BM hematopoietic cellularity cation promoted by the World Health Organization (WHO) of o60% and therefore appeared relatively normal.23 However, in 2008.4 this unusual rate of normal BM features in PV patients requires 1Papa Giovanni XXIII Hospital, Research Foundation, Bergamo, Italy; 2Institute of Pathology, University of Cologne, Cologne, Germany; 3Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy and 4Division of Hematology, Mayo Clinic, Rochester, MN, USA. Correspondence: Dr T Barbui, Scientific Director Research Foundation, Ospedale Papa Giovanni XXIII, Piazza O.M.S., 1, Bergamo (Bg) 24127, Italy. E-mail: [email protected] Received 28 November 2013; accepted 4 December 2013; accepted article preview online 19 Decenber 2013; advance online publication, 17 January 2014 Polycythemia vera T Barbui et al 1192 careful assessment since some morphological criteria employed using these criteria for conducting a number of important clinical for BM examinations were not explicitated. In fact, one should be trials that included the assessment of the value of phlebotomy aware that in the elderly population comprising PV patients and the description of the fatal leukemogenicity associated with (median age about 61 years),36 the subcortical BM spaces are chlorambucil and P32.1,25 It has to be acknowledged that the regularly occupied by fat cells and the sole expansion of PVSG clinical studies have significantly influenced clinical practice hematopoietic tissue towards this area implies hypercellularity.37 in PV for the last several decades. Only the discovery of JAK2V617F A second aspect to be considered, in addition to the expansion of and related mutations as a molecular marker in MPN has the granulo- and erythropoiesis compartment, concerns the undermined the utility of the PVSG criteria. features of the numerically expanded megakaryocyte lineages.34,37 The distinct features that characterize the megakaryocyte compartment in PV include changes in megakaryopoiesis with British Committee for Standards in Haematology pleomorphous aspect, that is, small, medium-sized, large and Shortly after the seminal discovery of JAK2V617F and related giant megakaryocytes that are either dispersed or loosely mutations ushering new insights for the understanding of the clustered and show no significant abnormalities of differentiation pathophysiology of MPN, the formerly proposed diagnostic PV (no dysplastic features).38–41 These characteristics enable a guidelines by the BCSH30 were amended.2 These modifications differentiation between a reactive state (secondary erythrocytosis- focused on a high HCT level (452% in men and 448% in women) polycythemia) and other entities of chronic myeloproliferative maintained for more than 2 months, as the first diagnostic neoplasia (MPN),23,42 particularly if a proper standardization of criterion in patients harboring the JAK2V617F mutation (Table 2). relevant BM parameters is employed for routine evaluation.43,44 In these cases, the measurement of RCM is not required for Moreover, a rate ranging between 10 and 20% of BM reticulin diagnosis when the other two criteria are both met.48 On the fibrosis has been reported in samples at diagnosis of PV, and is other hand, the problem of mutation-positive patients not predominantly of minor degree.37,40,41,45,46 The corresponding meeting the postulated threshold level of HCT cannot be data provided by the PVSG showed a moderate-to-marked undermined. In an international study on 1545 PV patients of increase of reticulin fibrosis in 11% and a slight one in 25% of which 98% presented with JAK2V617F or related mutations and the patients. It should be mentioned that fibrosis greater than 81% with a subnormal erythropoietin level, the median HCT grade 147 is a relatively rare finding in initial BM biopsies of PV level was 57% in men and 54% in women but ranged from 42 to patients and accounts for only 3–5% of samples.40,45,46 78% and 36 to 76%, respectively.36 It is tempting to assume that Noteworthy is that patients presenting with fibrosis were less patients who do not conform with the HCT threshold values may prone to experience thrombotic complications during their clinical represent cases described formerly as idiopathic erythrocytosis course and conversely more prone to develop