Introduction

This chapter will review rare histiocytic disorders that affect the lungs of adults, focusing on Langerhans cell histiocytosis (LCH), Erdheim-Chester Disease (ECD), and Rosai-­ Dorfman Destombes Disease (RDD). The histiocytic syndromes are a heterogenous collection of rare diseases characterized by proliferative abnormalities of myeloid cell lineages that lead to organ in ltration [1–3], most commonly of the skin (Table 16.1). While historically considered to be benign, polyclonal, infammatory processes [4], recent discoveries of mutations in the mitogen-activated protein kinase (MAPK) pathways have led to the reclassi -

cation of several histiocytoses as low-grade infammatory neoplasms [1–3] (Fig. 16.1). Clinical manifestations range from asymptomatic and indolent to debilitating and lifethreatening [6]. The annual incidence of all histiocytic neoplasms is likely less than ve per million persons [4]. The best known and most common of these diseases is Langerhans cell histiocytosis (LCH), a disorder that primarily affects children. Pulmonary LCH (PLCH) is an adult variant of LCH that primarily affects smokers and results in cystic lung destruction. ECD and RDD can also affect the lung but are characterized by the absence of dendritic cells and a tendency to involve bone and lymph nodes, respectively (Table 16.1).

a

Nucleus

C-fos/Jun DNA binding

Groth, Proliferation,

Cytokine/Chemokine Expression

Histiocytes and Dendritic Cells

The term histiocyte is used to describe tissue-resident immune cells that arise from bone marrow-derived precursors of two myeloid lineages: macrophages, which play key roles in innate immune responses, and dendritic cells, which have important functions in antigen presentation and cell-­ mediated immunity. Monocytes originate in the bone marrow, migrate to the lung parenchyma and differentiate into macrophages, where they reside within alveoli and in the interstitium [7]. Dendritic cells are also derived from circu-

lating monocytes and populate multiple compartments in the lungs including the airway mucosa and lung parenchyma. Langerhans cells are a specialized form of tissue-resident dendritic cells that are found primarily in the mucosa and submucosa of the airways. Immunohistochemical evaluation of macrophages reveals positivity for CD68 and CD163, while dendritic cells also express S100, and CD11c (Table 16.2). Langerhans cells also express S100, CD1a, and langerin and contain rod-shaped intracellular inclusions called Birbeck granules that are visible by electron microscopy [1, 4, 7, 11].

Table 16.2  Immunohistochemistry

References in text [1, 5, 8–10] a Derived from epidermal dendritic cells

b Found in mucous membranes throughout the body; roles in innate and speci c immunity

c Interdigitating and follicular dendritic cells

d Found in skin, mucous membranes, bone marrow, reticuloendothelial organs (spleen, thymus, lymph nodes); important in the initiation of T-cell mediated immune response

While there are several similarities between these populations of myeloid cells, there are also several important differences. Langerhans dendritic cells, in contrast to non-Langerhans dendritic cells, are not terminally differentiated, exhibit continuous self-renewal, and are established in the skin before birth independent of bone marrow hematopoiesis [12]. Gene expression studies have also revealed that LCH cells are less mature in comparison to Langerhans dendritic cells and share gene expression pro-les with myeloid dendritic cells [13–15]. Finally, the detection of MAPK pathway mutations in circulating myeloid precursors has identi ed early myeloid dendritic cells with Langerhans cell-like features as the pathognomonic cell in many of the histiocytic diseases [16] and suggests that the point in myeloid cell differentiation at which mutations occur may determine both the histiocytic disorder that results and the level of disease aggressiveness (Fig. 16.2).