Abstract
Simple SummaryMyeloproliferative neoplasms (MPNs) are clonal hematological disorders, characterized by increased proliferation of the myeloid lineages in the bone marrow. Since their original recognition by William Damashek in 1951, MPNs have been extensively investigated at a clinical-pathological and molecular level. This prompted a progressive refinement of their classification and diagnostic criteria. Uncertainties nonetheless remain in a small (yet consistent) subset of cases, characterized by unconventional and/or overlapping clinical-pathological features. Such cases (referred to as MPN, unclassifiable [MPN-U]) encompass a broad spectrum of entities, including early phase MPNs, terminal (i.e., fibrotic) MPNs, MPNs associated with inflammatory or neoplastic disorders, and poorly characterized MPNs with clinical-pathological mismatch or atypical molecular features. In this review, we discuss the rationale behind the classification and diagnostic criteria of MPNs, focusing on the still open issues concerning MPN-U.Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by increased proliferation of one or more myeloid lineages in the bone marrow. The classification and diagnostic criteria of MPNs have undergone relevant changes over the years, reflecting the increased awareness on these conditions and a better understanding of their biological and clinical-pathological features. The current World Health Organization (WHO) Classification acknowledges four main sub-groups of MPNs: (i) Chronic Myeloid Leukemia; (ii) classical Philadelphia-negative MPNs (Polycythemia Vera; Essential Thrombocythemia; Primary Myelofibrosis); (iii) non-classical Philadelphia-negative MPNs (Chronic Neutrophilic Leukemia; Chronic Eosinophilic Leukemia); and (iv) MPNs, unclassifiable (MPN-U). The latter are currently defined as MPNs with clinical-pathological findings not fulfilling the diagnostic criteria for any other entity. The MPN-U spectrum traditionally encompasses early phase MPNs, terminal (i.e., advanced fibrotic) MPNs, and cases associated with inflammatory or neoplastic disorders that obscure the clinical-histological picture. Several lines of evidence and clinical practice suggest the existence of additional myeloid neoplasms that may expand the spectrum of MPN-U. To gain insight into such disorders, this review addresses the history of MPN classification, the evolution of their diagnostic criteria and the complex clinical-pathological and biological features of MPN-U.
Highlights
The Myeloproliferative Neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by increased proliferation of the myeloid lineages in the bone marrow (BM) [1]
Following the 2001 World Health Organization (WHO) Classification, the molecular bases of myeloid tumors were deeply investigated with the discovery of JAK2 and MPL mutations in Philadelphianegative chronic myeloproliferative diseases (CMPDs) [18], KIT mutations in Mastocytosis [19], and PDGFRA, PDGFRB, and
FGFR1 rearrangements in subsets of myeloid/lymphoid neoplasms with eosinophilia [20]. All of this was included in the 2008 WHO Classification (Table 1; panel C), which definitively recognized the neoplastic nature of such conditions and abandoned the term CMPD
Summary
The Myeloproliferative Neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by increased proliferation of the myeloid lineages in the bone marrow (BM) [1] These disorders primarily affect adult to elderly patients with a cumulative annual incidence of 1–5 cases/100,000 [2]. MPNs (Polycythemia Vera, PV; Essential Thrombocythemia, ET; Primary Myelofibrosis, PMF); (iii) non-classical Philadelphia-negative MPNs (Chronic Neutrophilic Leukemia, CNL; Chronic Eosinophilic Leukemia, CEL); and (iv) MPN, unclassifiable (MPN-U) [1] This classification stems from the decades-long cooperation of hematologists, pathologists, and molecular biologists, which aimed at a better understanding of the pathophysiology, diagnostic criteria, and management of such disorders. Far from being solely academically relevant, the rationale of MPN classification is instrumental to address the open issues on these tumors It supports everyday clinical practice, providing theoretical and practical clues for the diagnosis of difficult cases. Philadelphia-negative MPNs and MPN-U, which are the most heterogeneous and challenging of all MPNs
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