The ontogeny of native Langerhans cells (LCs) in the epidermis has been debated over the past decade, with most agreeing that such LCs are now best classified as specialized resident-tissue macrophages derived from the embryonic yolk sac that have a self-renewal capacity in the steady state, along with migratory dendritic cell (DC)–like properties (albeit with much slower migration as compared to conventional or classic DCs [cDCs]) (1). The diversity of the epidermal pool of resident and inflammatory macrophages and DCs may be greater than previously realized – with LCs, monocyte-derived LC-like cells, and inflammatory dendritic epidermal cells (IDECs) all acting as human antigen-presenting cells (1).

The appearance and phenotype of histiocytes can change with levels of maturation, activation, and the local tissue microenvironment, with only a few markers truly constitutive. Widely varying surface and cytoplasmic molecules are informative for these cells and are easily identified using flow cytometry, although many are not unique to these cell lines. Others are more useful for the identification of macrophages, dendritic cells, and their neoplastic counterparts in fixed tissues. Table 25.1 lists some antibodies informative for histiocytes by flow cytometry, only some of which are restricted to either macrophages or dendritic cells; many are common to both. Table 25.2 lists the common types of monocyte/macrophage and dendritic cells and the markers most useful in their identification in fixed tissues (1). Chapter 28 further highlights immunostain panels best adapted for neoplastic proliferations.

The term histiocyte (tissue cell) has evolved and is now often used as a collective term for two related groups of immune regulatory cells, the monocyte-macrophages and the dendritic cell (DC)–accessory antigen-presenting cells (1). The histiocytic proliferations of childhood encompass benign and malignant accumulations of monocyte-macrophages and hematopoietic-derived DC with a clinical spectrum of indolent to aggressive lesions. Although distinguishing between their reactive and neoplastic states can be challenging at times, molecular-based testing can help refine the diagnosis of neoplastic accumulations (see also Chapter 28) (2, 3).

Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Rosai-Dorfman-Destombes disease (RDD) can each manifest as a focal lesion, as multiple lesions, or as a widespread systemic disorder with organ involvement. Erdheim-Chester disease (ECD) is a rare systemic disease process in children, with more frequent adult presentations. New distinct emerging entities covered include ALK-positive histiocytosis and post-leukemia/lymphoma histiocytic lesions. These histiocytic lesions are now best classified as myeloid-derived inflammatory neoplastic disorders composed of clonal dendritic- or macrophage-/monocyte-derived cells that infiltrate tissues and are driven by recurrent kinase-activating alterations, most often in the mitogen-activated protein kinase (MAPK), PI3K-AKT, and receptor tyrosine kinase (RTK) signaling pathways, which have all had a long history of being associated with human neoplasia, with ERK overexpression noted in many of these neoplasms (Fig. 28.1; Table 28.1) (1–3). Furthermore, these oncological signaling cascades are critical to the intranuclear regulation of transcription factors that serve as key factors influencing cellular proliferation, survival, and differentiation (4).

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).