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Editorials
in the diagnostic setting of JAK2V617F positive ET and PV, the transitional stage between ET and PV may be wrongly described as a new disease entity within MPN.22 Thus, it is tempting to speculate whether the “novel” dis- ease entity (mPV) would ever have been born, if arguing that a large proportion of these mPV patients are only “masked” as long as RCM is not being estimated. As dis- cussed above, reports on masked PV22,23 were influential in lowering the Hb/HCT thresholds in the 2016 WHO clas- sification of MPN.1,27 This was defined as a new JAK2V617F-positive entity with a phenotype mimicking ET (isolated thrombocytosis) but, as in PV, associated to endogenous erythroid colony formation (EEC) or the BM features of PV, which had previously been described as latent or inapparent PV.41,42 The revised WHO 2016 classi- fication was, among others, based upon the mPV studies, which defined threshold values as optimal cut-off levels for distinguishing JAK2V617F ET from mPV (Hb 16.5 g/dL/HCT 0.49 in men and 16 g/dL/HCT 48 % in women, respectively)43 and were subsequently validated in larger cohort studies.15,44
Very recently, the notion that mPV may not be a novel disease entity but has emerged consequent to the inaccu- racy of diagnosing PV in the absence of an estimation of RCM has been supported by a large French single center study of 2,480 RCM estimations in patients with JAK2V617F positive ET, “masked PV”, and PV.45 This study showed that patients with mPV actually have an increased RCM and are, therefore, easily "unmasked " and revealed to be true PV once RCM is estimated.45 Thus, these mPV patients share clinical and biological fea- tures with both ET and PV, with a median age, platelet, Hb and leukocyte levels comparable to those of ET patients, and at the same time classic PV features, (which, in addition to the increased RCM, also include lower Epo level and lower MCV), and have splenomegaly more fre- quently than ET patients.45 Accordingly, patients being described as mPV nicely present a picture of a diagnosis of MPN as a moving target that is highly dependent on the time point for diagnosis in the biological continuum from early JAK2V617F positive ET to overt PV.
The mPV story underscores the urgent need for a ren- aissance of the RCM and plasma volume assessment in these patients, since otherwise JAK2V617F positive “ET” patients and mPV patients will not receive adequate treat- ment by phlebotomies and so will obviously also have an increased risk of thrombosis.38,39 The French and other studies, including those pioneered by Silver and Spivak, also put into perspective the view that it is indeed possi- ble to incorporate RCM estimations into 'good clinical practice' in the differential diagnosis between JAK2V617F positive ET and PV.2-8,16,45 However, as noted above, there are still conflicting opinions as to the need for RCM measurements in distinguishing between patients with JAK2V617F positive ET, mPV and overt PV.2-4,11-15 Of note, a very recent study showed that when applying the 2016 WHO criteria, increased RCM was significantly associat- ed with increased Hb/HCT ( 93.8%/94.6%),15 thus sup- porting the 2016 WHO criteria for PV, implying Hb/HCT values should be used as surrogate markers for RCM measurements.15 In this study, the importance of BM mor- phology for a diagnosis of PV was also highlighted.15
Red blood cell count as a surrogate marker for red cell mass?
Recently, Michiels et al. underscored the importance of RBC count in addition to a BM biopsy as a powerful tool to differentiate between ET and PV.8 In their study, the diagnostic value of RCM in relation to RBC count, Hb and HCT in discriminating between JAK2V617F ET and PV was assessed. The best correlation was found between RBC count and RCM. Thus, at RCM above 30 mL/kg the RBC count was above 5.8x1012/L, and this diagnosed PV in all their patients. All JAK2V617F ET patients had a normal RCM and a RBC count below 5.8x1012/L. It was concluded that a RBC count within the normal range (< 5.8x1012/L in males and < 5.6x1012/L in females) enables JAK2V617F ET to be distinguished from prodromal PV and overt PV. Thus, they also concluded that the RBC count and a BM biopsy might obviate the need for RCM measurement.8
Are hemoglobin and hematocrit values imperfect surrogate markers for red cell mass?
In this issue of Haematologica, Silver et al. convincingly confirm the urgent need to investigate JAK2V617F posi- tive ET patients using RCM estimations,46 repeating the important message that a normal Hb or HCT value does not signify a normal RCM in MPN.2-8,10,11,16 Based upon JAK2V617F positivity, chromium-51 RCM, and BM biop- sy morphology, 83 and 39 patients were diagnosed with PV and ET, respectively. Chromium-51 RCM separated PV from ET JAK2V617F, whereas red cell values (Hb, HCT, RBC count) overlapped in 25.0-54.7%. The authors concluded that a significant proportion of PV patients may be underdiagnosed by using only red cell values. Of note, using ROC analyses, the authors found threshold values for the Hb / HCT coincidentally similar to the WHO 2016 criteria. Furthermore, it was concluded that (without isotope studies) BM biopsies and serum erythro- poietin values should become mandatory since they improve diagnostic accuracy. In this perspective, the paper by Silver et al. is highly relevant and timely. It car- ries a novel approach into the future and will hopefully promote an optimal classification of MPN by a renais- sance of the use of RCM estimations (the “gold standard” for discriminating JAK2V617F ET from PV) as a highly important tool to ensure a correct diagnostic classification of MPN. This will be a major scientific step forward in improving good clinical practice in MPN patients. It will reintroduce RCM and plasma volume estimations as essential for correct diagnostic classification of MPN, at least in JAK2V617F positive "ET" patients. In patients with huge splenomegaly but still a low normal or even lowered HCT, in the transitional stages between PV and post-polycythemic myelofibrosis, a RCM estimation may reveal the true nature of the disease as PV and accordingly a need for phlebotomies due to an expanded RCM in patients who still present a normal Hb-concentration and normal HCT consequent to hemodilution due to an expanded plasma volume. As previously noted, RCM estimation in JAK2V617F positive ET patients will likely reduce the risk of thrombosis in a substantial proportion of “ET” patients since they will be correctly classified as PV and will, therefore, receive treatment with phle-
haematologica | 2019; 104(11)


































































































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