Immunodeficiency is a state of reduced ability to produce an adequate immune response due to an insufficiency or absence of antibodies, immune cells, or both. Immunodeficiency disorders can be primary (inherited/congenital) or acquired. Acquired immunodeficiencies can result from HIV infection, solid organ or hematopoietic stem cell transplantation, and other iatrogenic conditions, such as chemotherapy.

Immunodeficiency is associated with an increased risk of benign and malignant lymphoproliferative disorders (LPDs) [1]. As a result, a wide range of clinical manifestations and diseases can develop. Pathologists may face a challenge in making an accurate diagnosis and classification of lesion tissues from these patients because of the different nature of their immune systems in this context. Therefore, it is important that the pathologist be informed of the underlying condition when evaluating specimens from these patients [1].

Acute leukemias of ambiguous lineage (ALALs) are leukemias that show no clear evidence of differentiation along a single lineage [1]. ALALs are rare and comprise 2–3% of acute leukemia (0.35 cases per 1 million person-years) [1–5]. They occur in both children and adults, with a male predominance [1,2,4].

ALALs represent a heterogeneous group of diseases. Cases of ALAL mostly fall into two broad categories: acute undifferentiated leukemia (AUL) and mixed-phenotype acute leukemia (MPAL) [1–5]. The current classification is mainly based on immunophenotypes and genetic features outlined in World Health Organization (WHO) classification system (Table 17.1) [1,2,5,6].

Idiopathic (immune) thrombocytopenic purpura (ITP) is an acquired disorder of antibody-mediated platelet consumption [1]. It can be categorized based on the presence of underlying disease (primary versus secondary) or onset rapidity (acute versus chronic) [2]

Enlarged lymph nodes are frequently encountered in children and often are transient. Persistently enlarged lymph nodes require biopsy and microscopic examination to classify the type of disease process. Lymphadenopathies are often characterized based on which lymph node compartment (paracortex, follicles, or medullary sinuses) is affected [1]. Thus, histologic evaluation of node architecture is paramount to determine the nature of the lymphadenopathy. In a large series of studies in children, approximately one-third showed evidence of infectious disease [2].

Lymphadenitis (lymphadenopathy due to infectious causes) is roughly characterized based on the type of microorganisms (bacteria, virus, fungus, etc.). Although many of these entities have well-described morphologic characteristics, others demonstrate a morphologic continuum with characteristics that overlap with one another, thus making the diagnosis based solely on morphologic grounds challenging. In the following discussion, the most common entities will be highlighted, recognizing that less common diseases do enter the differential of childhood lymphadenitis.

The immune system, a host defense system, recognizes foreign antigens and defends against invading microorganisms. It consists of primary (central) and secondary (peripheral) lymphoid organs. Primary lymphoid organs include the bone marrow and thymus, which contain lymphoid precursors and support initial antigen-independent differentiation from the immature stage to the mature stage. Secondary lymphoid organs comprise the lymph nodes, spleen, and sites of mucosa-associated lymphoid tissue, including the tonsils, appendix, and Peyer patches of the gastrointestinal tract, where antigen-dependent proliferation and differentiation of B- and T-lymphocytes take place [1].

Benign enlargement of the lymph nodes or other lymphoid organs (e.g., tonsil, spleen, thymus) is a consequence of hyperplasia of some or all of the cellular components, reflecting stimulation of the lymphoid cells or other cells by a variety of pathogens. The common causes include autoimmune disorders, drug or allergen exposures, foreign body reaction, infection with microorganisms, or undetermined etiologies. Its incidence and etiology vary with age. In the majority of children, lymph node enlargement is transient and reversible. When a biopsy is needed for clinical management purposes, the primary goal of histologic evaluation is to determine the nature of the process: whether it is a benign or malignant, hematopoietic or non-hematopoietic cell proliferation.

Non-hematopoietic tumors can involve the bone marrow (BM). BM metastasis represents advanced-stage disease and is associated with inferior outcomes [1]. Examination of the BM is a common procedure in the initial evaluation of children with solid tumors for tumor staging, subsequent treatment monitoring, and documentation of recurrent disease [1]. Less frequently, it provides a diagnosis from an occult primary site. The frequency of BM metastasis depends on the tumor type. Neuroblastoma, Ewing sarcoma, and alveolar rhabdomyosarcoma are more frequently present with BM metastases, whereas metastases from other soft tissue sarcomas, brain tumors, retinoblastomas, and hepatoblastomas are much less common. Some tumors, such as Wilms tumor, almost never metastasize to the BM and do not require BM examination in general.

Clinical presentations of solid tumor metastasis to the BM are variable. Bone pain, pathologic fractures, and cytopenia are frequently recorded, but they are non-specific.

Acute myeloid leukemia (AML) is a heterogenous group of diseases representing a clonal expansion of immature, non-lymphoid, bone marrow–derived cells that involve the bone marrow and blood and may also be present in other tissues [1,2]. In the pediatric population, AML is less common than lymphoblastic leukemia, accounting for approximately 18% of childhood leukemia diagnoses [3]. Although the cause of AML in many cases is unknown [1], as molecular genetics has been evolving over the last couple of decades, new molecular technology has enhanced our knowledge of the underlying genetic defects and gene mutations associated with the development of AML. It has been demonstrated that AML occurs more commonly in children with pre-existing genetic disorders, such as Down syndrome (DS) or Fanconi anemia, and familial cases of AML are now recognized [1]. A subset arises from pre-existing myelodysplastic syndrome (MDS) or after therapy for another neoplasm.

Hematolymphoid malignancies represent an area in which ancillary studies offer particularly valuable information for diagnosis, classification, and prognosis, as well as risk-stratified and targeted therapy. The results of multiple test modalities, including flow cytometry, immunohistochemistry, and cytogenetic and molecular genetic analyses, should be integrated and interpreted within the context of morphologic evaluation. In this chapter, the principles, general technical aspects, and clinical applications of these ancillary tests are discussed.

Anemia is defined as a hemoglobin (Hb) level or red blood cell (RBC) mass of less than the 5th percentile for age [1]. Approximately 20% of American children have anemia [1]. Most children with anemia are asymptomatic, and the condition is often discovered incidentally on routine laboratory testing.

Hemoglobin is a tetrameric protein composed of two pairs of globin chains complexed with four heme groups and is responsible for the transportation of oxygen of RBCs [2,3]. Normal adult RBCs contain 97% hemoglobin A (HbA; α2β2), 2% HbA2 (α2δ2), and 1% fetal Hb (HbF; α2γ2). At birth, HbF is predominant. Within the first year of life, it is largely replaced by HbA [3].