Langerhans cell histiocytosis (overview)C96.0; C96,5; C96.6

Langerhans cell histiocytoses (LZH) are mono- or polyorganic, semimalignant, "granulomatous" systemic diseases belonging to the histiocytoses and characterized by clonal proliferation of dendritic cells. The proliferating cell, originally designated as "X", stains immunohistologically with so-called Langerhans cell markers(CD1a, CD207/Langerin) and also exhibits electron microscopic features, the Birbeck granules.

In addition to these similarities with epidermal Langerhans cells, there are also important morphological and functional differences in the cell proliferates (clear immaturity of the cells, absence of dendrites, absence of migratory ability). Whereas the assumption of a reactive-granulomatous nature of proliferates used to be in the foreground, the neoplastic nature of cell proliferates is now increasingly crystallizing. This is underlined by their gene expression profile. Thus, an activated BRAF V600E mutation is found in >50% of all lesions. This mutation is monoallelic and acts as a dominant driving oncogene. Approximately 10% to 15% of patients have MAP2K1 mutations. In addition, activation of the RAS-RAF-MEK-ERK signaling pathways can almost always be detected, usually via mutations of the RAF protein. Because of these mutations, LCH is now considered an oncogene-driven malignancy of the myeloid lineage.

Involvement of the organ skin is the most common manifestation of Langerhans cell histiocytosis (LCH) in childhood. Much evidence suggests that patients with dermatologically accentuated or limited LCH have a better prognosis than those in whom systemic involvement is disease-predominant.

Langerhans cell histiocytoses (LHZ) are divided into:

Classical Langerhans cell histiocytoses(CD1a+, Birbeck granula+):

• Abt-Letterer-Siwe disease: mono- or polyorganic Langerhans cell histiocytosis of varying severity with cutaneous predominance in infants and young children (DD. seborrheic dermatitis).
• Hand-Schüller-Christian disease: chronic multifocal and multiorgan Langerhans cell histiocytosis; childhood and adulthood, diabetes insipidus, exophthalmos, ostzeolytic bone foci, xanthomatous skin changes are (rarely) possible.
• Eosinophilic granuloma: unifocal or multifocal, monoorganic Langerhans cell histiocytosis; late adolescence and in adults; preferential skeletal involvement. Skin very rarely affected!
• Pulmonary Langerhans cell histiocytosis: monoorganic lung involvement, young adults, almost always cigarette smokers, exertional and resting dyspnea, development of pulmonary fibrosis with honeycomb pattern. Good prognosis with nicotine abstinence.

Progenitor Langerhans cell histiocytoses (CD1a+; Birbeck granules -):

• Congenital self-healing reticulohistiocytosis Hashimoto-Pritzker (CD1a+;Birbeck granules+/-).
• Histiocytosis of indeterminate cells (CD1a+; Birbeck granula+).

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Instead of the previously listed classification according to entities (probably the different clinical pictures are not entities but only different manifestations and courses of a single disease complex), a stratification for the classical Langerhans cell histiocytoses has proven to be useful, especially for therapy studies:

"single-system disease":

• monoorganic affection of the skin - monotopic skeletal affection (especially skull) - monotopic lymph node affection, solitary lung affection.
• disseminated (organ) infestation: multilocular skeletal infestation/lymph node infestation/skin infestation.

"multi-system disease":

• polyorganic infestation pattern (multiple organ systems).
• High risk: patient > 2 years; no involvement of hematopoietic system, liver, lung, or spleen.
• Patient < 2 years, or patient > 2 years with involvement of the hematopoietic system, liver, lung, or spleen.

The incidence rate of LCH in children is approximately 2-9/ per million population per year (Jezierska M et al. 2018; Simko SJ et al. 2014). Cutaneous LCH occurs more frequently in boys (60%) than in girls (40%). Rarely, disease occurs in adulthood.

Although the exact cause of Langerhans cell histiocytosis is unclear, somatic mutations in RAS-ERK signaling pathways, particularly the BRAF V600 gene, have been found to play a major role in the development of this disease (Jezierska M et al. 2018; Simko SJ et al. 2014).

Furthermore, an intercellular communication defect with cytokine imbalance between T cells and Langerhans cells leading to clonal proliferation of dendritic cells is discussed.

Currently, it is assumed that dendritic cells are derived from hematopoietic progenitor cells and not from epidermal Langerhans cells.

Langerhans cell histiocytosis can affect a wide range of ages, including neonates, infants, and adults. In children <2 years of age , most LCH cases occur with cutaneous involvement (cutaneous LCH/ Abt-Letterer-Siwe disease). This type of manifestation is uncommon in adults.

The mean age of cutaneous LCH patients in larger collectives was 24.4 months (range 4-48 months).

In cutaneous manifestation, the lesions occur on the scalp, face, chest, back, groin, abdomen, and extremities.

The clinical picture of all Langerhans cell histocytoses (see also under histiocytoses) is extremely variable and is decisively characterized by the different organ manifestations and their acuities (see under the different entities). The spectrum ranges from relative symptomlessness with rather discrete local findings to life-threatening, systemic, polyorganic manifestations with weight loss, failure to thrive, restlessness and fever, especially in children.

The most frequent clinical expression of Langerhans cell histocytosis affects the skeleton with about 80% (see below Eosinophilic granuloma of bone - skeletal manifestations affect the skull in 34%). This is followed by skin manifestations (30-40% - see also under Abt-Letterer-Siwe disease), liver, spleen, bone marrow, lungs (15% each). In adults, lung involvement is a common and well-described organ manifestation (see Pulmonary Langerhans Cell Histiocytosis below).

Skin manifestations: Skin involvement in Langerhans cell histiocytosis varies depending on the time of initial manifestation of the disease and the acute nature of the disease. They may be diagnostically prominent, so that clarification of the erkrnakung would be a dermatologic task. This is often the case with Abt-Letterer-Siwe disease. In this manifestation of Langerhans cell histiocytosis in children, disseminated, small, flat, yellow-brownish papules with a scaly to crusty surface are found. Tendency to necrotic disintegration and petechial hemorrhages, hemorrhagic-eczematoid; in some places also minor ulcers. The capillitium, intertriginous spaces, joint folds are particularly affected in children.

CNS: CNS involvement with often chronic course may occur. Diabetes insipidus, as a sign of hypothalamic-pituitary CNS involvement, may often occur years before or after disease manifestations in other regions.

Other organ manifestations: In disseminated forms, various combinations of rash, hepatosplenomegaly, generalized lymph node swelling, anemia or pancytopenia, pulmonary involvement, or bone involvement are seen (see Eosinophilic Granuloma below). Liver dysfunction (increased transaminases, hypoproteinemia, hypoalbuminemia, hyperbilirubinemia), lung (dyspnea, pneumothorax), and hematopoiesis (cytopenia with or without bone marrow involvement). General symptoms in osseous manifestations include local swelling, pain, or limitation of motion. Depending on further organ involvement, other symptoms such as otitis media, otorrhea, tooth loosening or loss, exophthalmos (see Hand-Schüller-Christian disease below), or pathologic fractures will be detectable.

Diagnosis is based on the characteristics of conventional light microscopy and immunohistochemical detection of CD1a and CD207 antigen on the cell surface. The diagnosis can also be confirmed electron microscopically by the detection of Birbeck granules.

Three histologic reaction types of LCH can be described that are associated with the clinical types of LCH. These histologic reactions are:

• proliferative
• granulomatous and
• xanthomatous.

The microscopic features of the skin manifestations show a granulomatous reaction in 80% of cases and a proliferative reaction in 20%.

Chemotherapy: Various study protocols are described. Cytostatic agents involved: 6-mercaptopurine; vinblastine; performed by pediatric oncologists.

Salvage therapy: Immunosuppressive therapy (induction: ATG, prednisolone; maintenance: ciclosporin A).

Allogeneic bone marrow transplantation in advanced stage.

Since about 50% of Langerhans cell histiocytoses have a BRAF V600E mutation (this is also true for systemic non-Langerhans cell histiocytoses ), very good therapeutic effects can be achieved with the BRAF inhibitor vemurafinib, among others.

Prognosis and organ involvement: The prognosis of Langerhans cell histiocytosis depends on the age of the patient, the extent of the disease, and the presence of organ manifestations with their dysfunction. Thus, the number of organs affected and the presence of high-risk organ involvement are more important in determining the prognosis of Langerhans cell histiocytosis than the histopathologic subtypes found. Multisystem involvement significantly worsens prognosis. Children <2 years of age with multisystem involvement and organ dysfunction have a mortality risk of 50% or more (Jezierska M et al. 2018); Simko SJ et al. 2014). In contrast, many cutaneous LCH cases heal spontaneously; they have a good prognosis. In 87-93% of patients with cutaneous LCH, other organs are affected, including bone, pituitary, liver, spleen, hematopoietic system, lung, lymph nodes, and central nervous system (Haupt R et al. 2013). The severe form of LCH involving multiple organs can progress rapidly. It is associated with increasing resistance to therapy (Allen CE et al 2015).

Most LCH patients with organ involvement(except bone marrow, spleen, and liver!) can be cured. Liver and spleen involvement (hepato-splenomegaly) results in liver dysfunction with hypoproteinemia (edema of the extremities/ascites as well as icterus). Bone marrow involvement manifests clinically as anemia, thrombocytopenia, or leukopenia.

Age at first manifestation and prognosis: An unfavorable course is often seen in children <2 years of age and especially in those with organs at risk. In older children, organs at risk are less commonly affected and prognosis is generally better. However, chronic courses with recurrent skeletal involvement and development of late sequelae are also possible in this age group.

Recurrences: Most reactivations occur in the first 3 years after diagnosis, although reactivations 10 years after initial disease have also been described.

Good initial response to systemic chemotherapy is a favorable prognostic criterion.

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