Langerhans cells are bone marrow–derived dendritic cells that function as an immunologic barrier to cutaneous and mucosal insults by foreign antigens (see Chapter 4).³ In normal skin, they are seen as stellate cells with long dendritic processes that form a meshwork throughout the epidermis, being particularly numerous in the stratum spinosum. Following exposure to a foreign antigen, Langerhans cells migrate through dermal lymphatics to regional lymph nodes where they localize to the T-cell-rich paracortex, upregulate costimulatory molecules, and prime T cells through antigen presentation.^4,5 Langerhans cells characteristically express CD1a and langerin (CD207), the latter of which is associated with the presence of Birbeck granules.

Historically, there has been some contention over whether LCH represents a neoplastic or reactive process. Most cases of LCH are currently thought to represent clonal proliferations of Langerhans cells.^6,7 This proposition was initially supported by the identification of cytogenetic abnormalities in LCH,^8,9 but these findings were not reproduced in a later multimodality study that found an absence of gross chromosomal abnormalities in 72 cases of LCH.¹⁰ However, recent identification of BRAF V600E and MAP2K1 (MEK1) mutations (see Genetics below) implicates aberrations of the MAPK signaling pathway in the pathogenesis of LCH and strongly suggests a neoplastic origin.

Interestingly, one study found that the majority of cases of pulmonary LCH were nonclonal.¹¹ Given that pulmonary LCH has a specific clinicopathologic presentation—it typically occurs in middle-aged adults, is strongly associated with smoking, is most often restricted to the lung, and often regresses with cessation of smoking—the lack of clonality argues for a reactive process. However, clonality is seen in approximately 30% of cases of pulmonary LCH.¹¹ Furthermore, spatially separate pulmonary lesions have been shown to demonstrate oligoclonality, suggesting that clonal LCH populations may arise out of nonclonal Langerhans cell proliferations.¹¹ The presence of BRAF V600E mutations in 5 of 12 cases of pulmonary LCH may be evidence of the clonal nature of LCH, but the presence of BRAF mutation arising within a polyclonal background has also been hypothesized.¹² Unlike adults, pulmonary involvement in children generally occurs in the setting of disseminated disease.

The overall incidence of LCH based on large epidemiologic studies is approximately 4 per million per year, with an incidence approaching 10 per million per year in those <1 year of age.^13,14 In large epidemiologic studies on pediatric patients, the approximate median age at diagnosis is 3.5 to 5 years and the male:female ratio is 1.2–1.5:1.^13,14 In a large series of 1,741 patients with LCH, the most frequent organs involved were bone (77%), skin (39%), and lymph nodes (19%), followed by liver, spleen, and bone marrow.¹ Multisystem disease is seen in 31% to 69% of cases of LCH.^1,2,15,16 The median age at diagnosis is approximately 5.2 to 6.7 years for single system disease, 3.2 to 3.4 years for multisystem disease without risk-organ involvement (liver, spleen, or bone marrow; discussed below), and 0.7 to 1.4 years of age for multisystem disease with risk-organ involvement.^13,17

Skin involvement occurs in 25% to 39% of all cases of LCH and in approximately half the cases with multisystem disease.^1,2,15 The frequency of skin involvement by LCH is highest in the <1-year age group (55% in one study) and gradually decreases with increasing age.¹⁷ Among children who present with cutaneous LCH, age >18 months has been associated with multisystem disease.¹⁸ In cases of LCH with skin involvement and coexisting LCH elsewhere, the commonest extra-cutaneous sites involved are bone (64%), pituitary (32%), lung (25%), and lymph node (17%).² Isolated skin involvement is seen relatively infrequently with published rates of <5% of total cases.^2,15

The clinical presentation of LCH is variable. Historically, the disease was categorized into distinct subtypes—Letterer–Siwe disease, Hand–Schüller–Christian disease, and eosinophilic granuloma—based on extent of disease and rapidity of progression. These diseases were grouped together under the designation “Histiocytosis X.”¹⁹ Letterer–Siwe disease, an acute disseminated form of LCH, typically occurs as progressive multiorgan disease in neonates and infants, typically with skin involvement, and is often fatal in a short time period. Hand–Schüller–Christian disease is a chronic disseminated form of LCH that is seen most frequently in children and is characterized by multiorgan involvement or multifocal single organ involvement, usually including bone, with a minority of cases demonstrating the classical triad of osteolytic skull lesions, exophthalmos, and diabetes insipidus. Eosinophilic granuloma of bone is the least clinically aggressive of the classical forms of Histiocytosis X and occurs as one or multiple lytic bone lesions without extraskeletal involvement. Pulmonary eosinophilic granuloma, as described above, may represent an entity distinct from other forms of LCH and is typically a reversible disease. Though the above designations and the term “Histiocytosis X” have largely been abandoned in favor of the broader label of Langerhans cell histiocytosis, there remains to be clinical utility in subclassifying LCH into multisystem disease, unisystem but multifocal disease, and unifocal disease, as the extent of disease has prognostic value and impacts treatment decisions (see below).

The skin lesions seen in LCH, much like the overall clinical spectrum of LCH, are variable. Cutaneous involvement is most common in disseminated multisystem disease in infants and children.¹⁷ In multisystem disease, the skin lesions are erythematous and maculopapular (Fig. 67-1) or nodular, sometimes with ulceration; they often involve the scalp, intertriginous areas, and trunk, and involvement of the perineal, perianal, and perivulvar regions is not infrequent.^1,20 The skin lesions can sometimes resemble seborrheic dermatitis or eczema.¹⁸ Petechiae may be seen in the involved skin (Fig. 67-1).²¹ Erosive intertrigo of the axilla, perianal region, and other flexural folds is well-described, and may mimic diaper rash in infants.²¹ Involvement of the scalp may mimic seborrheic dermatitis (“cradle cap”), with irritation, scaling, and crusting.²¹ Skin-limited LCH occurs in the form of one or multiple, often asymptomatic but occasionally erosive, papules or nodules with surrounding erythema,^20,22 rarely forming tumor-like masses with or without ulceration.²³ One study documented mucosal involvement—most frequently the oral or genital mucosa—in 21% of cases with otherwise isolated skin LCH.² Systemic symptoms including fever, lymphadenopathy, hepatosplenomegaly, and cytopenias can be seen in multisystem disease, along with clinical manifestations of organ dysfunction such as diabetes insipidus with pituitary involvement.^1,15,17

Occasionally LCH may occur synchronously or asynchronously with another malignancy, including lymphomas, leukemias, and solid tumors.²⁴ Some such cases are thought to be therapy-related. Interestingly, several studies have documented identical T-cell receptor or IGH gene rearrangements in LCH arising in patients with prior or concurrent T-cell acute lymphoblastic lymphoma, chronic lymphocytic leukemia, and follicular lymphoma, suggesting that these cases of LCH arose through transdifferentiation of a lymphoid or leukemic clone or precursor.^25,26,27

Regardless of site, the histopathology of LCH is characterized by large aggregates or a diffuse infiltrate of Langerhans cells with abundant pale eosinophilic cytoplasm and irregular nuclei, often with a longitudinal groove that results in the classical “coffee bean” appearance (Fig. 67-2). Nucleoli are inconspicuous. Unlike normal epidermal Langerhans cells, the cells of LCH do not possess dendritic processes, instead appearing as epithelioid cells with ill-defined cytoplasmic borders. Binucleate and multinucleate forms may be seen.²⁸ A background inflammatory infiltrate is variably present and is often dominated by eosinophils (Fig. 67-2). Eosinophils are particularly prevalent in unifocal LCH, the classical “eosinophilic granuloma,” and are a good clue to the diagnosis. In disseminated and multifocal forms of LCH, eosinophils may be less prevalent and the diagnosis often depends on recognition of the cytomorphologic features of the Langerhans cells. Occasional background small lymphocytes, plasma cells, and neutrophils are variably present. Petechial lesions also show red blood cell extravasation (Fig. 67-2). Mitotic figures may be seen, usually numbering fewer than 20/10 HPF (high-power fields) but occasionally being more frequent.²⁸ Cytologic atypia is typically minimal but a subset of cases (6 of 17 cases in one study) may show a moderate degree of nuclear pleomorphism and/or prominent nucleoli.²⁸ Atypical mitotic figures or marked cytologic atypia should raise concern for LCS (see below).²⁹ Small foci of necrosis may be present and are often associated with eosinophilic microabscesses.²⁹