Diagnostic impact of the 2016 revised who criteria for polycythemia vera
Authors: Tiziano Barbui, Juergen Thiele, Heinz Gisslinger, Alessandra Carobbio, Alessandro M. Vannucchi, Ayalew Tefferi
Journal: American Journal of Hematology (2017)

Two recent publications present conflict opinions regarding the impact of the lowered hemoglobin (Hb) threshold values (≥16.5 g/dL for men ≥16.0 g/dL for women) proposed in 2016 by the World Health Organization (WHO) for the diagnosis of polycythemia vera (PV).1-3 We welcome particularly the comments expressed by Ethier et al.2 as they provide an opportunity to address the impact of the lowered Hb threshold values proposed by the 2016 revised WHO criteria for the diagnosis of prodromal, so-called masked polycythemia vera (mPV).4 We also share the opinion of the authors that recognition of prodromal stage PV constitutes an important advancement in this field and will certainly avoid underdiagnosis thereby contributing to prevention of thrombotic events by means of earlier diagnosis.2, 4, 5 Misdiagnosing of mPV for essential thrombocythemia (ET) is an important issue,6 since a diagnosis of ET means that phlebotomies will erroneously not be considered.2 In this context, it should be emphasized that PV patients require phlebotomies to a therapeutic hematocrit target of less than 45%, as shown by results of the controlled Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial.7 Ethier et al.,2 by strict application of the low Hb thresholds as reported by the WHO criteria in the Canadian population, found in about 4.1% of all complete blood counts (CBC) from unselected male subjects and in 0.35% of female subjects an Hb value at or above that threshold. This would have increased the incidence "of potential PV patients by up to 12-fold in males and 3-fold in females from current standards."2, 8 In this context, the authors concluded that "the use of the lowered Hb levels as a screening method has the potential to lead to unnecessary investigations"; therefore, they expressed concern regarding "financial and psychological burden."2 Moreover, the authors tested whether other CBC parameters may impact on the incidence of suspected PV cases following the revised WHO criteria.1 According to an exploratory analysis of all CBC results from unselected adults, neutrophilia and thrombocytosis were included but confirmed the previous findings, ie up to 60 times more males and 3 times more women would require an investigation.2 Finally, they suggested that patients with Hb values over the new threshold could be investigated only if they have symptoms of MPN, a history of thrombosis, if they show persistent neutrophilia or thrombocytosis, or if they are already known to have a JAK2 mutation.2 The challenges of a low Hb threshold for PV diagnosis have been also recognized and addressed by Rumi and Cazzola, who described their screening procedure in clinical practice.3 According to their data, the best compromise between the need of diagnosing PV early and the risk of considerably expanding the number of potential PV patients would be a Hb threshold of 17.0 g/dL (upper normal limit) in men, and taking into consideration thrombocytosis and/or leukocytosis in patients with Hb levels between 16.5 and 17.0 g/dL.3 To untackle this point, we compared the 2008 updated classification and the 2016 revised diagnostic criteria1 in 375 patients presenting with WHO-defined PV from our database (Table 1). All these cases showed bone marrow (BM) biopsy features at diagnosis, characteristic for PV.4 Table 1 reveals no difference in comparison with the mPV patients already published, in terms of presentation, and thrombosis in follow-up.4 By using CBC parameters according to Ethier et al.2 many patients with PV as defined by the WHO 2016 criteria were actually missed including those with history of previous thrombosis (Table 2). Of the applied CBC parameters thrombocytosis was the most frequent finding covering greater than two-thirds of the mPV cases while a combination of neutrophilia and thrombocytosis was found in only one-third of the patients. Thus, in this cohort, the Canadian proposal failed to screen as PV a percentage of patients ranging from 19% to 64%. Applying in men the Hb cut-off value proposed by Rumi and Cazzola3 lead to 14% of patients not meeting the WHO 2016 criteria (Table 2). This is not surprising since a 17 g/dL threshold level of Hb is not so different from the WHO threshold of 16.5 g/dL in males.1 Differentiation between JAK2- mutated ET and PV persists to be a matter of controversy, particularly in patients who present with increased Hb levels accompanied by thrombocytosis. As previously reported, the best cut-off for Hb to discriminate JAK2-mutated ET from PV was ≥ 16.5 g/dL for males and ≥ 16.0 g/dL for females, ie the lower threshold for mPV. The proportion of patients correctly classified as ET or PV when regarding Hb levels was 95% in males and 93% in females and 94% in both males and females, respectively.6 Altogether the diagnostic criteria proposed by the two groups2, 3 fall short to validate patients with presenting prodromal PV (false negative cases ranging between 14% and 64%) according to the 2016 revised WHO classification.1 Furthermore, an accurate differentiation from ET in patients with thrombocytosis is not possible, which carries therapeutic relevance concerning phlebotomies and the association between increased thrombotic complications and borderline increased hematocrit (45-50%) in PV and JAK2 mutation in ET. A practical algorithm has been recently proposed for these patients7 including blood mutation screening for JAK2V617F and if negative for JAK2 exon 12, followed by a serum erythropoietin (EPO) determination with a BM biopsy recommended to confirm diagnosis. ET is discriminated in this context by positive blood mutation analysis (JAK2V617F, CARL, MPL) and a BM biopsy examination will confirm diagnosis and distinguish it from prefibrotic/early primary myelofibrosis (pre-PMF).7 Distinction between these three MPN subtypes is not trivial and based on an integrated approach including clinico-pathological and molecular findings. In this context, the reported high rates of transformation from JAK2V617F mutated ET to PV9 are significantly influenced by an accurate WHO-defined clinico-morphological diagnosis.10 This explicit focus on the Hb threshold values and/or CBC data for screening is an improper simplification of the 2016 WHO diagnostic guidelines for PV1 that requires at least three major (Hb, BM morphology, JAK2 mutation) or two major criteria and the minor (subnormal EPO level) criterion. T.B. and A.M.V. were supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano) "Special Program Molecular Clinical Oncology 5x1000" to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative).