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

Abstract

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.

Splenomegaly: Dare to think rare

“…However, in most instances, clinical and laboratory findings coupled with the molecular search for driver mutations and/or molecular or cytogenetic markers of clonality of hematopoiesis and BM biopsy examination prompt the diagnosis. 19 From the histopathologic perspective, mimickers of MPN include immune thrombocytopenia (ITP) treated with agonists of thrombopoietin receptor that impart a striking MPN-like histologic appearance to BM biopsy, and the rare instances of autoimmune myelofibrosis, a condition in which the coexistence of lymphoid infiltrate may further trigger a diagnosis of lymphoproliferative disorder. 20,21 Spleen histology is less frequently experienced in clinical practice.…”

How I manage myeloproliferative neoplasm‐unclassifiable: Practical approaches for 2022 and beyond

“…Diagnostic trephine biopsies showed age‐adjusted hypercellularity in the majority of cases (67%), increased (100%) and clustered (83%) MKC and a median (range) WHO fibrosis score of 1 (0–3). As highlighted by Pizzi et al, 6 this suggests that most new MPN‐U, diagnosed according to WHO 2016 criteria, fall within the early, non‐fibrotic and non‐advanced stage. Kim et al 12 characterised 199 MPN patients, eight of whom had MPN‐U, where CALR was the most frequent mutation, although it must be noted that this conclusion is limited by the small numbers of patients.…”

“…Perhaps representing an arbitrarily defined early/prodromal phase, 21 cases could be re-classified as ET or PV whereas within the advanced phase, the vast majority could be reclassified as overt MF (25) and PV (6). The authors reported that this was most likely reflective of refined definition of prefibrotic MF and overtly fibrotic MF and updated Hb/haematocrit values within the PV category.…”

“…From a practical stance, cases of MPN-U frequently tend to fall within specific phenotypic categories. 5,6 Firstly, there are those which represent a prodromal, pre-proliferative phase MPN and therefore may share some of the classical MPN clinical features, but do not yet meet the required diagnostic criteria for accurate subclassification. For example, it may be a prepolycythaemic presentation of polycythaemia vera (PV), or a masked phenotype, e.g.…”

“…Secondly, there are those which represent a very late presentation of a classical MPN, where advanced fibrosis or disrupted BM architecture obscures the underlying diagnosis, or those where co-existing neoplastic, or indeed inf lammatory, disorders obscure the diagnostic features. 6 Finally, there are those cases which meet the diagnostic criteria for more than two MPNs at presentation, or there is clinicopathological mismatch, and hence cannot be easily classified as one of the classical MPNs. There are a number of important differential diagnoses to consider when making a diagnosis of MPN-U, and a number of diagnostic pitfalls that must be avoided.…”