The Classification of Myeloproliferative Neoplasms: Rationale, Historical Background and Future Perspectives with Focus on Unclassifiable Cases

Simple Summary: Myeloproliferative 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.

Automated summary

Myeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic stem cell disorders, characterized by increased proliferation of the myeloid lineages in the bone marrow. The classification and diagnostic criteria of MPNs have evolved over time to include a subset of cases that cannot be clearly classified, such as early phase MPNs, terminal fibrotic MPNs, and those associated with other disorders. Further research is needed to fully understand and classify these unclassifiable MPNs.