Impact of the 2016 revised WHO criteria for myeloproliferative neoplasms, unclassifiable: Comparison with the 2008 version
Authors: Alessandra Iurlo, Umberto Gianelli, Daniele Cattaneo, Juergen Thiele, Attilio Orazi
Journal: American Journal of Hematology (2017)

The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia has been recently published.1 The major changes for the BCR-ABL1-negative myeloproliferative neoplasms (MPNs) include improved standardization of morphologic features, a more precise definition of clinical and laboratory findings (eg, definition of early stage diseases) and the integration of recently identified molecular features (ie, CALR and MPL mutations) among the diagnostic criteria characterizing these entities. More specifically, for diagnosing polycythemia vera (PV) the hemoglobin (Hb) and hematocrit (Hct) thresholds had been lowered to capture a non-negligible number of so-called "masked/prodromal phase" PV2 where the utility of bone marrow (BM) morphology as one of the major criteria for this diagnosis has now been recognized.3 In primary myelofibrosis (PMF), the distinction between early/prefibrotic primary myelofibrosis (pre-PMF) and overtly fibrotic PMF has been formalized including specific morphologic criteria. In addition, the minor criteria necessary to support these two diagnoses have been decreased from at least two to at least one.1 Moreover, morphologic features for the differential diagnosis between pre-PMF and essential thrombocythemia (ET) has been better clarified.4 Finally, in ET the importance of BM morphology has been confirmed with particular attention to the grade of BM fibrosis which only very rarely can be slightly increased (up to grade 1).4 The major aim of the revised BCR-ABL1-negative MPNs diagnostic criteria was to allow a more precise MPN diagnosis in most of the cases, reducing the percentage of patients in the MPN, unclassifiable (MPN-U) category. According to the WHO classification, the designation of MPN-U should be used for cases with clinical, morphologic, and molecular features of MPN but failing to meet the diagnostic criteria of a specific entity or for cases presenting with overlapping features. Schematically, this setting includes patients: (1) in the prodromal/early stages of MPN in which the characteristic features are not yet fully developed; (2) with advanced stages of MPN, in which pronounced myelofibrosis and/or osteosclerosis or transformation to a more aggressive stage produce changes in the primary disorder-associated histologic features; (3) in whom the coexistence of another neoplastic or inflammatory disorder obscures the MPN-associated histologic features. The exact incidence of MPN-U is unknown, but some reports indicate that in largest series, the prevalence of MPN-U range from 10 to 15% of all the cases.3 In one study addressing clinical diagnosis of ET versus PV, a more than 30% incidence rate of MPN-U was reported.5 It is clearly evident that frequency varies significantly according to the experience of the diagnostician and the specific classification system and criteria used.6 Careful evaluation of clinical, morphologic, and molecular features reduced the frequency of MPN-U at presentation to less than 5%, in other studies.4 Recently, some of the authors of the present letter reported the clinical, morphologic, and molecular features of 71 MPN-U patients seen at two academic centers.6 In this case series, we did not find cases of MPN-U in which the MPN coexists with a neoplastic or inflammatory disorder. In detail, based on the grade of BM fibrosis we were able to distinguish 29 (41%) cases in the prodromal/early phase and 42 (59%) in the advanced fibrotic phase of MPN. Their morphologic profiles were then compared to those of a reference group composed of 103 WHO-diagnosed BCR-ABL1-negative MPNs by performing a multiple correspondence analysis (MCA). We found that all but four of the cases could be grouped in three morphologic clusters with some similarities with those of the classic BCR-ABL1-negative MPNs. In the present study, we applied the 2016 revised diagnostic criteria to this previously published series of MPN-U, to see whether the use of the modified criteria would allow a more precise MPN subtype diagnosis by decreasing the number of cases classified as MPN-U. The analysis focused mainly on two groups of MPN-U patients, those in the prodromal/early phase and those with advanced fibrotic phase disease. The results are found summarized in Table 1. Within the first group by using the 2016 revised criteria, we were able to re-classify 21 (72%) out of 29 cases (20 ET and one PV). Of the remaining eight cases, three of them displayed morphologic features of ET but lacked the required threshold values for the platelet count, three were consistent with pre-PMF but without the required clinical criteria and two showed a PV-like morphology but without definite clinical correlates. In the advanced fibrotic group, we were able to re-classify 31 (74%) out of 42 cases (25 advanced PMF and 6 PV). Of the remaining 11 cases, seven displayed a PMF-like morphologic phenotype but lacked any of the minor diagnostic criteria and four were morphologically consistent with PV, but failed to meet the required Hb threshold values (three cases) or were not associated with a JAK2 mutations (carried mutation of the CALR gene). In summary, by means of the revised WHO 2016 diagnostic criteria, we were able to reclassify 52 (73%) out of 71 cases, so reducing in our series the rate of discrepancy between clinical parameters and the morphologic profile from 55% (2008 WHO classification criteria) to 27% by using the revised WHO 2016 diagnostic criteria. This result is most likely a consequence of the improved definition of the morphologic features associated with pre-PMF and overtly fibrotic PMF, the reduction of the number of minor criteria required for diagnosing of PMF and also of the newer Hb/Hct parameters required for PV diagnosis. Overall this new approach improves our diagnostic capability by reducing of about 30% the size of the MPN-U category. In conclusion, our results reinforce the postulate that the MPN-U category is heterogeneous but identification of different subgroups of patients is possible and much desirable to achieve a better decision making and management of these patients with evident clinical consequences. We expect that the use of the WHO 2016 revised diagnostic criteria will allow a reduction in the number of cases classified as MPN-U, particularly in centers with a high rate of unclassifiable cases. The authors declare they have no potential conflicts of interest.