Time for revival of the red blood cell count and red cell mass in the differential diagnosis between essential thrombocythemia and polycythemia vera?

摘要

The correct diagnostic classification of the Philadelphia-negative chronic myeloproliferative neoplasms (MPN) in the three subcategories, essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF), relies upon diagnostic criteria that aim at minimizing misclassification.1 Several reports have addressed the issue that JAK2V617F positive “ET” patients are frequently misclassified since they actually have a diagnosis of PV.2–8 This misclassification is partly based upon the use of the hemoglobin (Hb) concentration as a surrogate marker for the red cell mass (RCM), irrespective of the fact that the Hb concentration is influenced by iron deficiency, which is prevalent in PV patients. Indeed, these concerns have been addressed and confirmed in several studies showing that a high proportion of ET patients (approx. 45-65%) did not meet the World Health Organization (WHO) diagnostic criterion of an elevated Hb, despite an increased Cr-51 RCM.5–7 However, despite the convincing data published in 2005 by Johansson et al.,5 these concerns were not translated into the revised 2007 WHO diagnostic recommendations. These recommendations, therefore, remained unchanged9 and were addressed and met by alternative diagnostic approaches in ET, PV and PMF patients.2 In their 2013 study,3 Silver et al. for the first time prospectively evaluated the accuracy of the 2007 WHO criteria for diagnosing PV, especially in “early-stage” patients. This and other studies support the latest updated WHO criteria (2016) for diagnosing MPN,1,9 which included these novel data with regard to the inaccuracy of the Hb-concentration, and even the hematocrit (HCT), in the differential diagnosis between ET and PV patients by lowering the Hb/HCT thresholds (> 16.5 g/dL/0.49 in men and > 16 g/dL/0.48 in women).1 Thus, the 2013 Silver study in a prospective setting and with a median 5-year follow up time convincingly demonstrated that the surrogate markers Hb and HCT are inadequate in the assessment of an increased RCM for early PV cases, since 64.3%, 28.5%, and 28.5% of their patients would not have been diagnosed as PV using Hb, HCT, and either Hb or HCT values, respectively.3 Importantly, of the 28 patients with an increased RCM in their study, 18 did not meet the WHO 2007 criteria for an increased Hb value. For the four women, the median Hb count was 15.2 g/dL (range: 14.4-16.4 g/dL) and for the 14 men 17.2 g/dL (range: 15.6-18.1 g/dL), respectively. Similarly, eight patients (1 woman and 7 men) did not meet the WHO criteria for an increased HCT value, being 44.3% for the woman, and for the seven men the median HCT was 48.5% (range: 45.7-49.4 %).3 Silver et al. also highlighted the value of bone marrow (BM) morphology3 as emphasized in the WHO classification. Accordingly, this study supported previous reports by Johansson et al.,5 Cassinat et al.,6 and Alvarez-Larran et al.7 which all revived ancient knowledge, written by the Polycythemia Vera Study Group (PVSG), and underscoring the inaccuracy of the Hb and the HCT values for diagnosing PV and the need for RCM measurement instead.10 This has since fostered intense debate in several reviews and perspective papers expressing conflicting opinions. On the one hand, some authors believe that only RCM measurements can reliably distinguish PV from other MPN,2–4,11 while others would disregard RCM measurements,12–15 arguing that Hb/HCT thresholds should be used as surrogate markers for RCM measurements. This lively debate has recently been further fueled by a comprehensive and scholarly review on MPN, emphasizing the urgent need for RCM investigations to distinguish PV from other MPN,16 adding that BM morphology has no place in the distinction of PV from other MPN subtypes.16 Others have highlighted the importance of BM morphology in PV and its usefulness in distinguishing between ET and PV.3,17–21 A very recent study has established a clear-cut distinction between ET and PV, and, therefore, also the reproducibility of BM morphology in so-called masked polycythemia vera (mPV) and its differentiation from ET.21 The disease entity mPV will be further addressed below.