LCH cells are monoclonal [15, 16] and sometimes show chromosomal deletion or gain [17]. However, recurrent genomic alteration was not detected for a long time due to the low percentage of LCH cells in the lesion [18]. However, a report published in 2010 revealed that LCH cells harbor an oncogenic mutation of the BRAF gene (V600E), which plays a role in the mitogen-activated protein kinase (MAPK) signaling pathway; it also showed that extracellular signal-regulated kinase (ERK), a molecule downstream of BRAF in this pathway, is phosphorylated constitutively in the presence or absence of this mutation [19]. This mutation is detected in about half of LCH patients, regardless of disease type [20]. The clinical significance of the BRAF V600E mutation is unclear, although it was reported recently that BRAF V600E mutation-positive patients may experience a higher rate of reactivation than mutation-negative patients [21]. More recently, oncogenic mutation of other genes within the MAPK signaling pathway, including ERBB3, ARAF, and MAP2K1, were identified in LCH cells [22–24] (Fig. 11.1). These MAPK signaling pathway-related mutations are mutually exclusive. Recurrent loss-of-function mutations in MAP3K1 (which encodes MEKK1) in the c-Jun N-terminal kinase pathway were also identified [25]. These mutations of MAP3K1 are not exclusive to the BRAF V600E mutation, and the mechanisms by which these variants promote neoplastic growth remain unknown.

Gene expression analysis of purified LCH cells revealed that the LCH cell of origin is not a skin Langerhans cell but a myeloid DC [26]. Compared with normal Langerhans cells, LCH cells are more proliferative and have a lower antigen-presenting capacity. During maturation, LCH cells arrests in an activated state, possibly due to the action of transforming growth factor-β and interleukin (IL)-10 [27]. LCH cells are the only DCs that co-express Notch1 and its ligands Jagged-1 and -2 [28]. The JAG-mediated Notch signaling pathway may also play an important role in maintaining LCH cells in an immature state. Leukemic cells and LCH cells in patients who develop T cell acute lymphoblastic leukemia before LCH harbor the same activating Notch1 mutation and T cell receptor rearrangements [29, 30], further supporting the possibility that Notch1 may contribute to LCH pathogenesis. This is also interesting when considering the origin of LCH cells.

BRAF V600E mutations are detected in bone marrow hematopoietic progenitors, peripheral monocytes, and myeloid DCs in active high-risk (RO-positive MS) LCH patients harboring a BRAF V600E mutation. Conversely, the mutation is restricted to lesional LCH cells in low-risk patients [21].

Forced expression of BRAF V600E in DCs is sufficient to drive LCH-like disease in mice [21]. Forced expression of BRAF V600E in CD11c⁺ cells (DC progenitors) results in the formation of aggressive LCH lesions similar to those observed in humans with high-risk LCH, whereas BRAF V600E expression in langerin-positive cells (differentiated DCs) results in disease that resembles low-risk LCH without detectable mutations in circulating myeloid cells. These data suggest that the extent of LCH may be determined by whether ERK-activating mutations arise at any stage of DC differentiation.

LCH lesions contain less than 10% (median value) LCH cells [21]; however, they contain many inflammatory cells, including eosinophils, T lymphocytes, plasma cells, macrophages, osteoclast (OC)-like multinucleated giant cells (MGCs), and neutrophils. Because LCH cells show immature DC characteristics, they may promote the expansion of regulatory T cells, which in turn results in the failure of the host immune system to eliminate LCH cells [31].

LCH cells express the immature DC marker CCR6 and secrete its ligand CCL20/MIP-3α, along with CCL5/RANTES (a CCR1/3/5 ligand) and CXCL11/I-TAC (a CXCR3 ligand) [32]. Interactions between these chemokine receptors and their ligands may play a role in the hematogenous migration of not only LCH cells but also of inflammatory cells into the lesions. These LCH cells and infiltrating cells in turn stimulate each other to produce cytokines such as GM-CSF, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-7, and IL-10 [33]. Moreover, LCH cells in lesions express high levels of CD40, whereas T cells express CD154 (the CD40 ligand): interactions between CD40 and CD154 are essential for activation of both antigen-presenting cells and T cells [34]. A recent report shows that LCH cells and lesional T cells express high levels of the pleiotropic cytokine osteopontin (OPN) [26], which promotes the generation of T helper (Th)1 and Th17 cells, recruits histiocytes/monocytes, and activates osteoclasts [35].

We found that the serum levels of lesional inflammatory cytokines/chemokines and DC/macrophage-activating factors such as IL-18, M-CSF, and CCL2 are markers of disease dissemination and severity [36]. Marked increases in serum IL-18 and soluble tumor necrosis factor receptors are reported in patients at risk for developing hemophagocytic lymphohistiocytosis [37]. In addition, we found that patients with MS LCH have much higher serum OPN levels than patients with SS LCH [38].

In LCH, OC-like MGCs are present not only in the bone but also in skin and lymph node lesions, and enzymes derived from OC-like MGCs may play a major role in chronic tissue destruction [39]. Both LCH cells and T cells in lesions produce the OC-inducing cytokines, receptor activator for nuclear factor kB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) [39]. We found that patients with SS LCH and multiple bone lesions had significantly higher ratios of soluble RANKL and osteoprotegerin (OPG), a decoy receptor of RANKL, than patients with MS LCH; moreover, the soluble RANKL/OPG ratios correlated positively with the number of bone lesions [40].

Courey et al. showed that patients with active LCH have high serum levels of IL-17A, which is mainly produced by LCH cells [41]. In vitro, serum IL-17A causes fusion of immature DCs, which results in formation of OC-like MGCs [41]. This IL-17A-dependent fusion activity correlates with LCH activity. An IL-17A autocrine model of LCH was suggested. We also found that patients with LCH have higher serum levels of IL-17A than controls, although the serum IL-17A levels of patients with MS LCH and SS LCH did not differ significantly. However, we also observed that LCH cells in MS disease expressed higher levels of IL-17A receptor (IL-17RA) than those in SS disease and that IL-17RA expression levels help distinguish between LCH subclasses [42]. In addition, we found that the cleaved form of OPN plays a critical role in driving immature DC differentiation into OC-like MGCs in an autocrine and/or paracrine fashion [43].

Merkel cell polyomavirus (MCPyV, a common dermotropic virus) sequences are detected in not only skin but also in bone and soft tissue lesions of LCH patients; also, the amount of MCPyV DNA in peripheral blood cells is increased in patients with high-risk (RO-positive MS) LCH but not in patients with low-risk LCH [44]. MCPyV infection may induce LCH cells with an oncogenic mutation to secrete IL-1; this leads to activation of LCH cells in an autocrine manner [45]. This suggests that MCPyV infection may trigger LCH.

Nicotine stimulation increases the production of both OPN and GM-CSF by alveolar macrophages. Bronchoalveolar lavage cells from patients with pulmonary LCH produce abundant amounts of OPN. Forced expression of OPN in rat lungs induces lesions similar to pulmonary LCH, with marked accumulation of Langerhans cells [46]. These findings suggest that increased OPN production upon stimulation by nicotine is responsible for pulmonary LCH.

Intracranial tumorous lesions may occur in the meninges, choroid plexus, and brain parenchyma; these lesions can mimic brain tumors [65]. Cladribine (2-CdA), which penetrates the blood–brain barrier, may be an effective treatment for these lesions [66].

Infiltration and dysfunction of the pituitary gland and/or adjacent hypothalamus is observed in 25% of all patients with LCH and in 50% of patients with MS disease [65]. The most frequent manifestation is CDI, which usually follows (but sometimes precedes or co-occurs with) other symptoms and signs of the disease. The cumulative incidence of CDI continues to increase, even 10 years after a diagnosis of LCH [67]. CDI occurs more often in patients with craniofacial bone lesions (with the exception of the vault), ear, eye, and/or oral lesions [68]; thus these lesions are known as CNS-risk lesions. Patients with MS disease that includes bone lesions are more likely to have CNS-risk lesions than patients with bone lesions alone [49]. LCH involvement of the pituitary gland can be shown by MRI, namely, pituitary stalk thickening and loss of the physiological high-intensity signal in the posterior pituitary lobe on T1-weighted images. Appropriate systemic chemotherapy may effectively inhibit the development of CDI [67, 68]. Systemic chemotherapy rarely cures CDI, but LCH patients with newly diagnosed CDI should be treated with systemic chemotherapy to prevent anterior pituitary hormone loss and neurodegenerative disease. About half of patients with CDI develop anterior pituitary hormone deficiencies and/or ND-CNS disease during follow-up, usually after a disease course of several years [69]. Patients with hypothalamic-pituitary lesions may present with non-endocrine hypothalamic dysfunction, such as eating disorder, thirst, fatigue, autonomic disturbance, temperature instability, memory deficit, and disturbed consciousness [70]. Hypothalamic lesions are observed on MRI as gadolinium-enhanced masses [71].

ND-CNS disease may develop during the years after disease onset, often when the disease is considered quiescent [72, 73]. Three years after a diagnosis of LCH, more than half of patients with CNS-risk lesions and/or CDI demonstrate abnormities on MRI (radiological ND-CNS disease), including bilateral symmetrical lesions in the cerebellar white matter and/or basal ganglia [74]. These brain MRI abnormalities gradually deteriorate and are irreversible. One quarter of patients with brain MRI abnormalities present with neurological symptoms (neurological ND-CNS disease), which includes ataxia, tremor, dysarthria, dysphagia, and hyperreflexia, within several years, which is followed by further deterioration. Patients with neurological ND-CNS disease eventually become bedridden. Histologically, ND-CNS disease is characterized by the presence of a CD8-positive T cell infiltrate, activation of microglia, gliosis, and neuronal and axonal destruction with secondary demyelination, as observed in autoimmune encephalitis. CD1a-positive LCH cells may be absent [75]. Currently, there is no established therapy for ND-CNS disease, although promising evidence suggests that intravenous immunoglobulin [76, 77] can prevent progression. Although first-line therapies for LCH that include cytarabine (Ara-C) cannot prevent development of ND-LCH completely [78], treatment with Ara-C might be effective for ND-CNS disease [79].