Neonates frequently suffer from life threatening infections. Immaturity of the immune system increases the vulnerability to infection, and the preterm and term neonatal immune system has specific deficiencies relative to that of an older child or adult [1, 2]. During pregnancy, the physical barrier of the placenta and the maternal immune system protect the developing human fetus from infection. However, maternal infections such as rubella, almost eradicated in developed nations through vaccination [3], or the zika virus, an emerging pathogen [4, 5], can ravage the developing embryo and fetus, leading to life-long disabilities. Furthermore, immaturity of natural barrier systems such as skin, bronchial epithelium and the lining of the gastrointestinal tract compound the weaknesses of the immune system of the premature infant [6, 7]. The importance of interactions between the developing immune system, epithelial barriers, and the microbiome to protect the preterm neonate from infection and promote health is increasingly recognized [8, 9]. Ethical and political concerns limit our ability to study the embryological development of the human immune system to the same depth [10, 11].

The ‘classical’ Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), essential thrombocythaemia (ET), primary myelofibrosis (PMF) and polycythaemia vera (PV), are characterized by clonal myeloproliferation with effective maturation causing accumulation of terminally differentiated cells in the peripheral blood and/or splenomegaly. Although each disease has distinct clinical manifestations clonal haematopoiesis is driven, in most cases, by upregulation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway [1]. Polycythaemia vera and ET are relatively indolent, with most patients having nearly normal life expectancy, in contrast to PMF [2]. Thrombosis and haemorrhage are the main causes of morbidity and mortality in both PV and ET, and evolution to myelofibrosis (MF) and/or accelerated/blast phase (AP/BP) is estimated to occur in 10% of patients [3, 4]. Overt (classical) PMF is the most aggressive of the three diseases, with a median overall survival of five years. The most common causes of mortality are transformation to BP (20 to 25% of patients), thrombosis, cardiovascular complications and infections [5]. However, it is important to note that incidence figures, survival and also risk-factor determinations may be inaccurate and at times conflicting because of the inadvertent labelling in some studies of patients with prefibrotic/early PMF (prePMF) or ‘masked’(prodromal) PV as ET [6–8].

Disorders of histiocytic and dendritic cell origin, traditionally referred to as histiocytoses [1], form a group of extremely rare tumours, characterized by variable malignant potential and unpredictable clinical course, from spontaneously regressing to rapidly progressing. While the neoplastic character of some of these entities is still debated, the most commonly acknowledged predictors of malignant behaviour remain as morphological features, i.e. degree of cellular anaplasia. Some of these disorders show predilection for skeletal involvement (Langerhans cell histiocytosis, LCH; Erdheim–Chester disease, ECD) but bone marrow (BM) infiltration is infrequent. In turn, entities classified as frankly malignant (e.g. histiocytic sarcoma, HS) most often form tumoural masses in lymph nodes or at extranodal sites. Interestingly, many of the tumoural lesions in this category demonstrate ability to transdifferentiate to and from other malignancies, including lymphomas and leukaemias. Therefore although primary histiocytic or dendritic cell disorders are most commonly diagnosed in skeletal, soft tissue or lymph node biopsies, BM biopsies (BMB) and aspirates may be obtained for staging purposes or in cases when occurrence of secondary malignancy is suspected.

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.

Mastocytosis is a diverse group of rare diseases due to a clonal proliferation of neoplastic mast cells that can involve a wide variety of organ systems. The two main categories of mastocytosis are cutaneous mastocytosis (CM) showing only skin involvement, and systemic mastocytosis (SM) with at least one extracutaneous organ involved. In many cases of SM, the bone marrow (BM) shows varying degrees of infiltration. Most cases of CM develop during childhood, while adult patients in their fifth and sixth decades tend to present with SM [1]. The clinical course can vary from spontaneous regression in young children with CM to a highly aggressive course primarily seen in adult patients. Even within the category of SM, the presentation can range from indolent to aggressive, and it is thus divided into five subcategories as outlined in the most recent edition of the 2016 World Health Organization (WHO) classification of mastocytosis (Table 12.1) [2]. Of note, mastocytosis is now considered a distinct clinicopathologic entity that is separate from other myeloproliferative neoplasms.

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal myeloid neoplasms characterized at the time of their initial presentation by the simultaneous presence of myelodysplastic and myeloproliferative features, which prevent them from being classified as either myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). The incidence of MDS/MPN is estimated at 0.1 to 3/100,000 individuals. They are characterized by hypercellular bone marrow (BM) morphology due to proliferation in one or more of the myeloid lineages. Cytopaenias and dysplastic changes of any cell line may be seen in conjunction with elevated white blood cell (WBC) counts, thrombocytosis and organomegaly, features more commonly associated with MPN. Hepatosplenomegaly is frequently seen. The most common entities within the MDS/MPN group include chronic myelomonocytic leukaemia (CMML), atypical chronic myeloid leukaemia BCR-ABL1 negative (aCML) and juvenile myelomonocytic leukaemia (JMML), which is seen exclusively in paediatric patients. A less well-defined group of MDS/MPN-like diseases includes MDS/MPN unclassifiable (MDS/MPN-U) and a recently recognized entity of MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), previously known as refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T). It was considered a provisional entity within the group of MDS/MPN-U in the 2008 edition of the WHO, but has now been promoted to a true entry in the updated 2016 WHO edition. Since the publication of the last WHO Classification in 2008, multiple studies have examined the molecular pathogenetic features of the MDS/MPN entities (see Table 11.1). Many of these results have been incorporated into the updated 2016 WHO classification.

The bone marrow (BM) is a frequent site of haematogenous spread for all types of cancer. Metastatic spread of disseminated tumour cells (DTCs) to the BM is detected in 0.2 to 12% of patients with solid tumours [1]. The variability in incidence is related to the incidence of the primary tumour and its homing behaviour [2]. Common primary tumours affecting the BM are listed below (Table 17.1).

Immunophenotyping is an important part of the integrated haematopathologic diagnostics of bone marrow (BM) samples. Integrated diagnosis should include clinical information, peripheral blood (PB) and BM smear cytology, flow cytometry (FCM) of BM aspirate, BM trephine biopsy (BMB) morphology, BMB immunohistochemistry (IHC) and cytogenetic/molecular genetic data if appropriate. Flow cytometry and IHC provide complementary information [1]. Immunophenotyping by FCM has the advantage of measuring high numbers of cells and the possibility to evaluate co-expression of several markers in various cell populations in a multicolour setting. Immunohistochemistry provides a possibility of in situ interpretation of morphology and immunophenotype simultaneously. Double IHC stains are possible but not widely used as of yet.

Bone marrow (BM) trephine biopsy (BMB) is a frequent and routine diagnostic investigation, as nicely described in the previous chapters, and is also widely used for follow-up of haematological disorders to judge the effectiveness of therapeutic interventions [1]. In addition, several drugs applied primarily for the treatment of non-haematological disorders may cause serious haematological side effects, such as pancytopaenia, agranulocytosis or anaemia. On occasion, the causative link between the haematological symptoms and the previous drug exposure is not perceived and it is not uncommon for BMB to be obtained in such circumstances without any information of a history of previous drug exposure being made available to the haematopathologist [2].

Neoplasms arising from precursor lymphoid cells committed to the B-cell or T-cell lineage can present primarily in the bone marrow (BM), blood (i.e. leukaemic presentation) or at extramedullary tissue sites (i.e. lymphomatous presentation) (Table 14.1). Hence, these neoplasms are appropriately termed as B- or T-lymphoblastic leukaemia/lymphoma [1, 2].

Knowledge and understanding of the appearance of normal bone marrow (BM) and therefore normal haematopoiesis is essential for both general pathologists and specialist haematopathologists. It is only once normal cytology and histology is understood that abnormalities can be identified and defined, leading to the accurate diagnosis of pathologies seen in the BM.

Infective, granulomatous and benign histiocytic disorders are only rarely an indication for bone marrow (BM) examination and therefore often represent unexpected or incidental findings. Yet since they are frequently linked to a variety of life-threatening underlying conditions, diagnosing such disorders in the BM is almost always significant for the affected patient. This chapter summarizes and illustrates the most common disorders of this type in the BM with a special emphasis on diagnostic and differential diagnostic clues.

The classification of mature neoplasms has evolved over the years, with the current WHO classification based largely on the genetics and cellular origin of lymphoid neoplasms [1]. Clinical behaviour of lymphoid neoplasms, however, continues to play an important role in defining disease entities. Mature lymphoid neoplasms in the case of leukaemias primarily involve blood and bone marrow (BM), while in lymphomas, most entities, with an occasional exception (e.g. Waldenström macroglobulinaemia/lymphoplasmacytic lymphoma) show predominant involvement of extramedullary sites/site with secondary involvement of the bone marrow (BM). In patients with lymphomas, the BM may be biopsied as part of staging (e.g. follicular lymphoma) or when the primary site of involvement is not amenable to biopsy (e.g. primary splenic lymphomas such as splenic marginal zone lymphoma or hepatosplenic T-cell lymphoma). Less commonly, a mature lymphoid neoplasm may be an unexpected or suspected diagnosis initially made on BM biopsy (BMB) performed during investigation of B-symptoms or unexplained cytopaenias.

Trepanning of the bone is one of the oldest known procedures carried out by man and the use of the modern trephine biopsy has a venerable history. Parapia has published an admirable summary of the history of the topic and this should be consulted for the excellent illustrations of historical instruments [1]. The history is briefly summarized here [1]. Trepanning of the skull is the oldest known surgical procedure in humans and evidence of this practice has been found in Europe, North Africa, South America, Asia and New Zealand. In Peru, where the procedure is likely to have been carried out to treat headache, mental illness and to relieve intracranial pressure, sharp knives of obsidian, stone and bronze were used for trephination. Celsus, the Roman physician, described a modiolus – an iron instrument with a serrated cylinder that was rotated over a central pin by means of a strap. The early interventions were therapeutic and the first diagnostic biopsy was undertaken in Pianese in Italy in 1903. In 1922, Morris and Falconer used a drill-like instrument to biopsy the tibia, producing similar specimens to modern biopsies and, in the same year, Seyfarth developed a puncture needle for open biopsy of the sternum, producing smears, touch preparations and blocks for sectioning. The modern era probably began in 1958 when McFarland and Dameshek described a technique for biopsy of the right posterior iliac crest using a Silverman needle, which had been described in 1938. Further improvements followed, with modified instruments described by Jamshidi in 1971 and an electric drill technique by Burkhardt in 1971. Recent developments are described later in the chapter.

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.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid neoplasms defined by peripheral cytopaenia, morphologic dysplasia in one or more haematopoietic lineages, and genetic instability with risk of transformation to acute myeloid leukaemia (AML). A diagnosis of MDS requires the presence of cytopaenia, plus one or more of the following diagnostic features: morphologic evidence of dysplasia in >10% of cells involving at least one haematopoietic lineage, increased blasts, and/or an MDS-defining cytogenetic abnormality. Modern diagnosis of MDS was standardized by the French–American–British (FAB) cooperative group in 1982, which included the first standard descriptions of myelodysplasia [1], and was further refined in the World Health Organization (WHO) classification of 2001, which more specifically quantified dysplasia (Table 8.1) [2].