Hemophagocytic lymphohistiocytosis (HLH) is a complex, life-threatening clinical syndrome of systemic hyperinflammation. The syndrome is often diagnosed based on the presence of clinical signs and symptoms that were included as diagnostic criteria for HLH by the Histiocyte Society in clinical treatment trials (1, 2). The criteria include fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, observation of hemophagocytosis, decreased function of natural killer (NK) cells, elevated ferritin, and elevated soluble interleukin-2 (IL-2) receptor levels (Table 27.1). Other complications of HLH that are not part of the criteria include central nervous system (CNS) involvement in 30–70% of patients (3, 4), as well as hepatitis or acute liver failure. Rarely, isolated CNS disease can also occur (5). The syndrome of HLH can be caused by a wide variety of etiologies, and it is imperative that clinicians bear this in mind when the clinical diagnosis is suspected (6).

Hematopoiesis is a complex process encompassing the continuous generation of specialized, mature blood cells from pluripotent hematopoietic stem cells (HSCs). The hematopoietic system is not fully developed at birth. The proportion of bone marrow (BM) components and normal hematologic values for neonates, infants, older children, and adults are different as a result of the unique characteristics of embryonal and fetal development of the hematopoietic system, which continues to evolve after birth [1]. Knowledge of these differences is essential to distinguish normal development from a pathologic process when evaluating blood and BM in pediatric patients.

Precursor lymphoid neoplasms comprise lymphoblastic leukemias (ALLs) and lymphoblastic lymphomas (LBLs), of either B- or T-cell origin. As a general rule, ALLs and LBLs are considered biologically equivalent. The distinction between ALLs and LBLs is arbitrary. Bone marrow or peripheral blood blasts ≥ 25% are defined as ALL. Neoplasms with predominant extramedullary involvement, bone marrow, or peripheral blood blasts < 25% are classified as LBL.

Non-Hodgkin lymphomas (NHLs) comprise about 10% of all childhood cancers [1]. They include a diverse collection of malignant neoplasms that arise from mature and immature lymphoid cells of B-cell and T-cell origin [1]. Adult and pediatric NHLs have a number of differences, including subtypes, tumor locations, and biologic behaviors, which are summarized in[1]. Morphologic evaluation of adequate tissue, immunophenotyping, and cytogenetic and molecular analysis are essential approaches in the diagnosis of NHLs. This chapter focuses on mature B-cell NHLs in children. Mature T-cell NHLs and immature lymphoid neoplasms are discussed in Chapters 9 and 13.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by a proliferation of one or more of the myeloid lineages [1]. These components include erythroid cells, megakaryocytes, and granulocytes, the latter of which include eosinophils. In many cases, these MPNs are associated with acquired clonal genetic abnormalities involving cytoplasmic or receptor protein tyrosine kinases.

Lymphadenopathy (LAD) is a common presentation in the pediatric population. Cervical LAD with neck mass is the most common manifestation [1]. The etiology of LAD is diverse, including various benign nonspecific reactive conditions, infections, neoplasms, and immune disorders, among others. In spite of the initial concern of lymphoma or infectious conditions, most cases of LAD turn out to be benign and nonspecific reactive. The morphologic features of nonspecific reactive LAD can overlap with those of specific infective LAD or lymphoma. Although some features are more associated with certain etiologies, they are not pathognomonic. Clinical correlation would be essential on this ground. The goal of this chapter is to use case-based illustration to thoroughly demonstrate the morphological features of reactive lymph node and specific entities of non-neoplastic/noninfective LAD.

Mastocytosis is defined as a clonal proliferation of neoplastic mast cells in one or more organ systems. It is broadly separated into two categories of cutaneous mastocytosis and systemic mastocytosis, of which the latter can include cutaneous involvement. In the 2016 World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues, mastocytosis was separated into its own category due to its heterogeneous clinical manifestations ranging from spontaneously resolving skin lesions in pediatric cutaneous mastocytosis to highly aggressive malignancies such as mast cell leukemia with short survival and multiorgan involvement [1, 2].

There is increasing recognition of the role inherited and de novo germline mutations play in the development of myeloid neoplasia [1], particularly in children, adolescents, and young/middle-aged adults [2, 3]. Germline mutation inheritance may be autosomal dominant with variable penetrance, X-linked, or autosomal recessive. Family history of neoplasia or cytopenia may be helpful in identifying potential cases with germline predisposition. However, variability in disease penetrance within family members harboring the same mutation may mask early recognition of familial disease. Additionally, patients harboring de novo germline mutations may have no family history of disease. The World Health Organization’s (WHO) 2016 classification of tumors of the hematopoietic and lymphoid tissues recognizes three major classifications of myeloid neoplasms with germline predispositions: myeloid neoplasms without preexisting disorder or organ dysfunction, myeloid neoplasms with preexisting platelet disorders, and myeloid neoplasms with other organ dysfunctions (including inherited bone marrow failure syndromes) [1].

Mature T-cell non-Hodgkin lymphomas (NHLs) in the pediatric population comprise about 10–15% of the NHLs. Natural killer (NK) cell neoplasms in this age group are even rarer. Both groups of lymphomas tend to present with a broad spectrum of clinical manifestations, including nodal, extranodal, and leukemic diseases, and are frequently associated with paraneoplastic phenomena such as hemophagocytosis, fevers, or rashes [1].

Hodgkin lymphomas (HLs) encompass two morphologically, immunophenotypically, and clinically distinct subtypes of B-lineage lymphoma – classical Hodgkin lymphoma (cHL) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) [1–5]. HLs usually affect lymph nodes. These lymphomas are composed of a small number of large dysplastic mononuclear and multinucleated neoplastic cells (Hodgkin, Reed-Sternberg [RS], and lymphocytic and histiocytic [L&H] cells) set in the background of benign inflammatory elements with or without abundant band-like and/or more diffuse collagen fibrosis [1].

Acute myeloid leukemia (AML) is a heterogeneous group of diseases representing a clonal expansion of immature, non-lymphoid, bone marrow-derived cells that involve the bone marrow, blood, and extramedullary tissues. In general, blood or bone marrow blast counts ≥ 20% () are required for diagnosing AML, except for AML with t (8;21) (q22; q22.1), AML with inv (16) (p13.1q22) or t (16;16) (p13.1; q22), and acute promyelocytic leukemia (APML) with PML-RARA [1–4]. The World Health Organization (WHO) classification incorporates morphologic, immunophenotypic, genetic, and clinical features to define prognostically significant disease [3–5].

Bone marrow studies may be requested to evaluate for hematopoietic or solid neoplasms, or to help elucidate the etiology of abnormalities in the peripheral blood or lesions identified by imaging studies. These bone marrow specimens may include aspirate smears, clot sections, particle preparations, core touch preparations, and core biopsies. These specimens (preferably aspirates) can also be used for ancillary studies such as flow cytometry, cytogenetics, and molecular analysis to supplement the morphologic picture.