The 2016 WHO diagnostic criteria for polycythemia vera renders an accurate diagnosis to a broader range of patients including masked polycythemia vera: Comparison with the 2008 WHO diagnostic criteria
Authors: Kyohei Misawa, Hajime Yasuda, Marito Araki, Tomonori Ochiai, Soji Morishita, Mai Nudejima, Yumi Hironaka, Shuichi Shirane, Yoko Edahiro, Akihiko Gotoh, Akimichi Ohsaka, Norio Komatsu
Journal: American Journal of Hematology (2017)

In the 2008 World Health Organization (WHO) criteria for polycythemia vera (PV), arbitrary hemoglobin (Hb) thresholds of more than 18.5 g/dL in males and 16.5 g/dL in females were used as a surrogate marker for increased red cell mass (RCM). Although specificity for predicting increased RCM was high, sensitivity was reported to be low with 46% false negatives.1 Thus, a significant number of patients with highly suspected PV did not fulfill the 2008 WHO criteria mainly due to relatively highly set Hb levels. These patients fell under the category of myeloproliferative neoplasms unclassified (MPN-U) in the 2008 WHO criteria, and were often referred to as "masked PV (mPV)." 2 Masked PV is defined by patients with JAK2 mutations, bone marrow pathology consistent with PV, and Hb levels ranging from 16.0 to 18.4 g/dL in males and from 15.0 to 16.4 g/dL in females. Patients with mPV are reported to have higher rates of thrombotic events compared to PV patients diagnosed by the 2008 WHO criteria (PV-08), and speculations have been made that suboptimal treatment due to an absent diagnosis of PV was probably the cause. In order to distinguish mPV from essential thrombocythemia (ET), Barbui et al. performed ROC analysis and newly determined optimal Hb and hematocrit (Hct) cutoff levels of 16.5 g/dL and 49% in males, and 16.0g/dL and 48% in females, respectively,3 and these results were adopted in the revised 2016 WHO criteria for PV. Besides lowering of required hemoglobin levels, hematocrit cutoff levels were added, bone marrow pathology was upgraded from a minor to major criterion, and endogenous in vitro erythroid colony formation was removed in the 2016 WHO criteria. We validated the 2016 WHO criteria by applying this and the 2008 WHO criteria to our cohort consisting of 2056 patients with suspected myeloproliferative neoplasms (MPNs). As a result, 154 patients were diagnosed as PV according to the 2016 WHO criteria (PV-16) and 132 patients were diagnosed as PV by the 2008 WHO criteria (PV-08). All of the PV-08 patients were also diagnosed as PV-16. Twenty-two patients who were originally diagnosed as MPN-U by the 2008 WHO criteria were newly diagnosed as PV (PV-N) by the 2016 WHO criteria. Of the 154 PV-16 patients, 140 patients (90.9%) harbored JAK2V617F, 9 patients (5.8%) harbored JAK2 exon 12 mutations, and 5 patients (3.2%) were negative for either mutations. All PV-16 patients were negative for MPL and CALR mutations. Baseline characteristics of PV-08, PV-16, and PV-N are shown in Table 1. Patient characteristics did not differ between PV-08 and PV-16. Among all 22 PV-N patients, the reason for an unsuccessful diagnosis of PV-08 was not reaching the Hb levels required by the 2008 WHO criteria for PV. All PV-N patients harbored JAK2 mutations, which is supportive evidence that these patients were bona fide PV, and not patients with reactive erythrocytosis. Compared to PV-08, PV-N patients were predominantly male, presented with higher frequency of splenomegaly and higher platelet (Plt) counts. There was also a trend toward lower JAK2V617F allele burdens, a higher rate of thrombotic events, and lower treatment frequency in the PV-N patients. All of these features of PV-N closely resemble that of previously reported mPV patients. In fact, all 18 patients who met the definition of mPV in our cohort were also diagnosed as PV-N. Conversely, PV-N basically represented patients with mPV. A previous report pointed out that thrombotic events were more frequent in mPV than PV-08 patients, and the authors speculated that this was because optimal treatment was often not administered in mPV patients due to an absent diagnosis of PV.4 Therefore, it is extremely important that all 18 mPV patients in our cohort were diagnostically included as PV by the 2016 WHO criteria, and as a result, treatment outcomes in mPV patients can be expected to improve. The reason for lower Hb levels in mPV has not been elucidated, although one postulated theory is iron deficiency. However, there were no differences in ferritin levels between PV-N and PV-08 patients in our study. The CYTO-PV randomized trial reported that Hct levels below 45% was the optimal threshold to reduce cardiovascular complications in PV patients.5 Therefore, under-diagnosed PV patients with Hct over 45% could potentially be at risk for cardiovascular complications, and we searched our cohort for such a population. Importantly, even after application of the 2016 WHO criteria for PV, we still found 17 JAK2V617F-positive MPN patients showing relatively high Hct levels (45-49% in males and 45-48% in females) (high hematocrit MPN: HH-MPN) who could not be diagnosed as any of the defined PV criteria (PV-08, PV-16, or mPV). Of these 17 patients, median Plt counts and JAK2V617F allele burdens were 748 × 109/L and 35.2%, respectively. We previously reported that median Plt counts and JAK2V617F allele burdens in JAK2V617F-positive PV and JAK2V617F-positive ET were 504.6 × 109/L and 889.7 × 109/L, 71.7% and 35.5%, respectively.6 Thus, Plt counts and JAK2V617F allele burdens in HH-MPN patients resembled that of ET and not PV. Moreover, when the British Committee of Standards in Haematology (BCSH) criteria was applied to these 17 HH-MPN patients, 13 patients were diagnosed with ET and four patients did not meet the criteria for any of the MPNs. On top of this, only two of the HH-MPN patients showed BM pathology in line with PV. Therefore, it can be concluded that as a whole, HH-MPN represented ET patients, and the 2016 WHO criteria correctly excluded these patients from a diagnosis of PV. Distinguishing PV from ET is important because life expectancy is lower in PV, thrombotic events and transformation to myelofibrosis are more frequent in PV, and most of all, management recommendations differ between PV and ET. In conclusion, the 2016 WHO criteria rendered a diagnosis of PV to a wider range of patients including all masked PV patients while maintaining diagnostic accuracy. As a result, the 2016 WHO criteria can be expected to raise treatment rates and bring about better outcomes in PV patients. Authors thank Kazuhiko Ikeda (Fukushima Medical University), Nobuyoshi Hanaoka (Wakayama Medical University), Toshiro Kurokawa (Toyama Red Cross Hospital), Hideo Harigae (Tohoku University), Takayuki Ikezoe (Kochi University), Jun Murakami (University of Toyama), Kensuke Usuki (NTT Kanto Medical Center), Keita Kirito (University of Yamanashi), Masaaki Noguchi (Juntendo Urayasu Hospital), Michiaki Koike(Juntendo shizuoka Hospital), and Takao Hirano (Juntendo Nerima Hospital) for providing patient specimens and clinical data; Satoshi Tsuneda and Yuji Sekiguchi for their generous support and encouragement; Kyoko Kubo, Kazuko Kawamura, Junko Enomoto, and Megumi Hasegawa for providing secretarial assistance. Nothing to report. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.