Synoptic Diagnostics of Myeloproliferative Neoplasms: Morphology and Molecular Genetics

SIMPLE SUMMARY: The diagnosis of myeloproliferative neoplasms requires assessment of a combination of clinical, morphological, immunophenotypic and genetic features, and this integrated, multimodal approach forms the basis for precise classification. Evaluation includes cell counts and morphology in the peripheral blood, bone marrow aspiration and trephine biopsy, and may encompass flow cytometry for specific questions. Diagnosis nowadays is completed by targeted molecular analysis for the detection of recurrent driver and, optionally, disease-modifying mutations. According to the current World Health Organization classification, all myeloproliferative disorders require assessment of molecular features to support the diagnosis or confirm a molecularly defined entity. This requires a structured molecular analysis workflow tailored for a rapid and cost-effective diagnosis. The review focuses on the morphological and molecular features of Ph-negative myeloproliferative neoplasms and their differential diagnoses, addresses open questions of classification, and emphasizes the enduring role of histopathological assessment in the molecular era. ABSTRACT: The diagnosis of a myeloid neoplasm relies on a combination of clinical, morphological, immunophenotypic and genetic features, and an integrated, multimodality approach is needed for precise classification. The basic diagnostics of myeloid neoplasms still rely on cell counts and morphology of peripheral blood and bone marrow aspirate, flow cytometry, cytogenetics and bone marrow trephine biopsy, but particularly in the setting of Ph− myeloproliferative neoplasms (MPN), the trephine biopsy has a crucial role. Nowadays, molecular studies are of great importance in confirming or refining a diagnosis and providing prognostic information. All myeloid neoplasms of chronic evolution included in this review, nowadays feature the presence or absence of specific genetic markers in their diagnostic criteria according to the current WHO classification, underlining the importance of molecular studies. Crucial differential diagnoses of Ph− MPN are the category of myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement of PDGFRA, PDGFRB or FGFR1, or with PCM1-JAK2, and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). This review focuses on morphological, immunophenotypical and molecular features of BCR-ABL1-negative MPN and their differential diagnoses. Furthermore, areas of difficulties and open questions in their classification are addressed, and the persistent role of morphology in the area of molecular medicine is discussed.