Langerhans Cell Histiocytosis

Updated: Mar 07, 2017
  • Author: Christopher R Shea, MD; Chief Editor: William D James, MD  more...
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Overview

Background

Langerhans cell histiocytosis (LCH) is a group of idiopathic disorders characterized by the presence of cells with characteristics similar to bone marrow–derived Langerhans cells juxtaposed against a backdrop of hematopoietic cells, including T-cells, macrophages, and eosinophils.

In 1868, Paul Langerhans discovered the epidermal dendritic cells that now bear his name. The ultrastructural hallmark of the Langerhans cell, the Birbeck granule, was described a century later. The term Langerhans cell histiocytosis is generally preferred to the older term, histiocytosis X. This newer name emphasizes the histogenesis of the condition by specifying the type of lesional cell and removes the connotation of the unknown ("X") because its cellular basis has now been clarified. [1]

Although the epidermal Langerhans cell has been presumed to be the cell of origin in LCH, recent studies have called this belief into question. Specifically, a variety of other cellular populations have been identified that possess phenotypic characteristics similar to Langerhans cells, including expression of CD207 and Birbeck granules. Therefore, in addition to epidermal Langerhans cells, other potential cellular origins for LCH include dermal langerin+ dendritic cells, lymphoid tissue-resident langerin+ dendritic cells, and monocytes that can be induced by local environmental stimuli to acquire a Langerhans cell phenotype. [2, 3]

Notably, LCH cells have been found to express markers of both resting epidermal Langerhans cells (CD1a, intracellular major histocompatibility complex II [MHCII], Birbeck granules) and activated Langerhans cells (including CD54 and CD58). As a result, the pathologic cells of LCH have been hypothesized to represent Langerhans cells in a state of arrested maturation. [3] Taken together, these findings have led some to speculate that LCH is not a specific disease of epidermal Langerhans cells, but rather one of mononuclear phagocyte dysregulation. [3]

The working group of the Histiocyte Society has divided histocytic disorders into 3 groups: (1) dendritic cell histiocytosis, (2) macrophage-related disorders, and (3) malignant histiocytosis. [4] LCH belongs in group 1 and encompasses a number of diseases. On one end, the clinical spectrum includes an acute, fulminant, disseminated disease called Letterer-Siwe disease, and, on the other end, solitary or few, indolent and chronic lesions of bone or other organs called eosinophilic granulomas. The intermediate clinical form called Hand-Schüller-Christian disease is characterized by multifocal, chronic involvement and classically presents as the triad of diabetes insipidus, proptosis, and lytic bone lesions. A congenital, self-healing form called Hashimoto-Pritzker disease has also been described.

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Pathophysiology

The pathogenesis of Langerhans cell histiocytosis (LCH) is unknown. It has been debated whether LCH is a reactive or neoplastic process. Arguments supporting the reactive nature of LCH include the occurrence of spontaneous remissions, the extensive elaboration of multiple cytokines by dendritic cells and T-cells (the so-called cytokine storm) in LCH lesions, and the good survival rate in patients without organ dysfunction. [5] Furthermore, a rigorous investigation of potential chromosomal aberrations in LCH via analysis of ploidy, karyotype, single-nucleotide polymorphism arrays, and array-based comparative genomic hybridization did not reveal consistent abnormalities; these findings were considered to support the idea of LCH as a reactive process. [6]

On the other hand, the infiltration of organs by a monoclonal population of aberrant cells, the possibility of lethal evolution, and the cancer-based modalities of successful treatment are all consistent with a neoplastic process. [7, 8] In addition, the demonstration, by use of X chromosome–linked DNA probes, of LCH as a monoclonal proliferation supports a neoplastic origin for this proliferation; however, the presence of this finding in distinct subtypes with different evolutions demands further investigations to elucidate its significance. Of note, recent genomic studies demonstrate activating, somatic BRAF mutations in the majority of human specimens. These observations support the concept of LCH as a myeloid neoplasm. [9]

A 2010 study comparing gene expression of cells expressing CD207 (a marker of Langerhans cells) in LCH lesions with epidermal CD207+ control cells identified differential expression of more than 2000 genes between these 2 subsets. These differences were found in genes involved in cell cycle regulation, apoptosis, cell signaling, metastasis, and myeloid differentiation. [10] Interestingly, this analysis found no differences in expression of proliferation markers between these subsets of CD207+ cells, consistent with the hypothesis that LCH may be a disease of abnormal cellular accumulation.

The extensive variability in gene expression between these 2 cellular populations has prompted speculation that LCH cells may develop from a population of cells distinct from epidermal Langerhans cells. Specifically, it is hypothesized that "misguided" blood-derived myeloid dendritic cells are recruited to specific anatomic sites and their subsequent stimulation of T-cell trafficking and local immunomodulation is responsible for the characteristic lesions of LCH. [10] Notably, this hypothesis is consistent with either an oncogenic or reactive etiology for LCH, because what stimulates these misguided cells remains unclear.

Evidence suggests a role for immune dysfunction in the pathogenesis of LCH, through the creation of a permissive immunosurveillance system. Specifically, findings from immunohistochemical and immunofluorescence analyses of LCH biopsy specimens have led to the hypothesis that semimature LCH cells stimulate the expansion of a polyclonal population of regulatory T cells. These regulatory T cells may, in turn, inhibit the immune system (in part via the elaboration of interleukin (IL)–10 and prevent it from effectively resolving LCH lesions. [11]

Detection of high serum levels of the proinflammatory cytokine IL-17A in patients with LCH has given rise to speculation that IL-17A is also involved in the pathogenesis of the disease. Further investigation into this phenomenon has led to the proposal that IL-17A induces dendritic cell/Langerhans cell fusion into multinucleated giant cells that in turn recruit other inflammatory cells and cause local tissue destruction, creating the characteristic lesions of LCH. [12] However, these findings have not been independently reproduced, and the role of IL-17A in the pathogenesis of LCH remains controversial. [13]

Some studies have also indicated that expression of vascular endothelial growth factor (VEGF); Bcl-2 family proteins; and FADD, FLICE, and FLIP proteins in the Fas signaling pathway may be involved in the pathogenesis of LCH. [14, 15, 16] The E-cadherin-beta-catenin-Wnt signaling pathway has also been implicated in LCH, and down-regulation of E-cadherin may be associated with disease dissemination. [3, 17]

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Epidemiology

Frequency

Langerhans cell histiocytosis (LCH) is a rare disease. The estimated annual incidence ranges from 0.5-5.4 cases per million persons per year. Approximately 1200 new cases per year are reported in the United States.

Race

The prevalence of Langerhans cell histiocytosis (LCH) seems to be higher among whites than in persons of other races.

Sex

The frequency of Langerhans cell histiocytosis (LCH) is greater in males than in females, with a male-to-female ratio of 2:1.

Age

Langerhans cell histiocytosis (LCH) affects patients from the neonatal period to adulthood, although it appears to be more common in children aged 0-15 years (reportedly approximately 4 cases per million population). [18] The age at onset varies according to the variant of LCH, as follows [3] :

  • Letterer-Siwe disease occurs predominantly in children younger than 2 years.
  • The chronic multifocal form, including Hand-Schüller-Christian syndrome, has a peak of onset in children aged 2-10 years.
  • Localized eosinophilic granuloma occurs mostly frequently in children aged 5-15 years.
  • Pulmonary LCH is more common during the third and fourth decades of life. [3]

Also see Histiocytosis.

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Prognosis

More than half the patients younger than 2 years with disseminated Langerhans cell histiocytosis (LCH) and organ dysfunction die of the disease, whereas unifocal LCH and most cases of congenital self-healing histiocytosis are self-limited. Multifocal chronic LCH is self-limited in most cases, but increased mortality has been observed among infants with pulmonary involvement.

The clinical course of Langerhans cell histiocytosis (LCH) is variable. Patients with unifocal disease generally have an excellent prognosis. After initial bone scanning and radiographic survey to assess the extent of the disease, follow-up studies after treatment should be performed at 6-month intervals for 3 years. If no additional lesions are present at 1 year, the development of subsequent lesions is unlikely. A full recovery is also expected in cases of solitary lymph node involvement or isolated skin disease.

Multifocal LCH has a variable prognosis, especially in patients at the extremes of age with pulmonary involvement. The prognosis is worse than in patients with unifocal disease but better than those with disseminated disease. Sixty percent of patients with multifocal disease have a chronic course, 30% of patients undergo complete remission, and 10% of patients with multifocal LCH die from the disease. [19] Response to chemotherapy in the first 6 weeks (induction therapy) is among the most important prognostic indicators for multifocal LCH. A good response to chemotherapy during this period is associated with significantly improved survival. [4, 20] Conversely, hematologic involvement or involvement of organs such as the lungs, spleen, and liver is associated with worse long-term outcomes. [4]

Letterer-Siwe disease (disseminated) has a high mortality rate. The prognosis in these patients depends on the patient's age, the extent of disease, and the degree of organ dysfunction. The mortality rate is 50% or higher.

The congenital form of histiocytosis tends to resolve spontaneously within weeks to months. [21] Although the absence of systemic disease at presentation and the tendency of resolution of the disease are favorable, long-term follow-up care to detect evidence of relapse or progression in these patients is suggested. [21] Relapse in these patients has been reported up to 5 years after the initial disappearance of the disease. Cutaneous lesions usually disappear by 3 months, leaving residual hypopigmentation.

Infrequently, cases originally diagnosed as chronic focal LCH may progress to multifocal or even disseminated disease.

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