The term “acute leukemia” actually covers a large number of different diseases. This is mostly related to the lineage involved, yet, even in a single lineage, differences exist according to the differentiation stage where maturation blockade occurred or to the type of chromosomal/molecular anomalies associated with the disease. This chapter provides a guide of how immunophenotypic anomalies, typically identified very early in the diagnosis process, can orient further cytogenetic or molecular investigations, allowing for a faster integrated diagnosis and better focused patient management.

Bone marrow (BM) hyperplasia, a non-neoplastic expansion of one or more of the haematopoietic cell lineages due to an increased number of cells, can manifest in a range of morphological appearances depending on the underlying cause. Similarly to other tissue types, hyperplasia is often associated with an increase in the number of cells with less mature morphology. It is this reactive atypia/dyshaemopoietic morphology that needs careful assessment and correlation/integration with clinical, biochemical, radiological and often molecular findings to correctly interpret the underlying process and avoid misdiagnosis as a neoplastic proliferation. This chapter will consider erythroid, myeloid and megakaryocytic hyperplasia. Reactive conditions of histiocytes are covered in Chapter 6.

Acute myeloid leukaemia (AML) is a highly complex and heterogeneous disease. Proper classification according to the 2016 World Health Organization (WHO) classification requires a systematic approach and integration of key clinical, laboratory, pathologic and genetic information [1, 2]. Great advances in our understanding of the pathogenesis and molecular underpinnings of AML have been realized since the original AML classification using the French–American–British (FAB) system (1976). This genetic revolution not only contributes to enhanced disease diagnosis and prognostication but also to ongoing improvements in therapeutic strategies.

Myeloid and lymphoid neoplasms with eosinophilia (MLNE) and rearrangements of PDGFRA, PDGFRB and FGFR1 were recognized as a standalone category in the 2008 WHO classification. PCM1-JAK2 was added to this family as a new provisional entity in the 2016 WHO classification [1, 2]. The features shared by neoplasms in this category include a common presentation with eosinophilia or hypereosinophilia in peripheral blood and an increased number of eosinophilic forms in bone marrow (BM). Some cases present as acute leukaemia. Some cases may lack hypereosinophilia. The underlying mechanism is the overexpression of an aberrant tyrosine kinase as a result of a fusion gene, or rarely of a mutation, and a diagnosis and classification requires the demonstration of the specific gene fusions. The cell of origin is a mutated pluripotent stem cell that has the potential to involve myeloid, lymphoid or both lineages, concomitantly or sequentially, leading to clinically complex and heterogeneous manifestations. A common scenario is the presentation as a chronic myeloproliferative neoplasm (MPN), usually with eosinophilia followed within a variable time period and depending on the gene fusion involved, by a progression to acute myeloid leukaemia (AML) or mixed phenotype acute leukaemia (usually in the BM), and B- or T-lymphoblastic leukaemia/lymphoma (B-/T-ALL) in BM or in an extramedullary site. Thus it is critical to recognize the clinicopathologic features of these neoplasms, identify the molecular genetic lesions and classify them accordingly. An accurate diagnosis and classification have important therapeutic and prognostic implications.