Langerhans cell histiocytosis (LCH) – Brief information

Author:  Dr. med. Anke Barnbrock, Prof. Dr. med. Thomas Lehrnbecher, Maria Yiallouros, Editor:  Maria Yiallouros, English Translation:  Dr. med. Gesche Riabowol (geb. Tallen), Last modification: 2025/08/21 https://kinderkrebsinfo.de/doi/e242647

General disease information

Langerhans cell histiocytosis (LCH) usually occurs in childhood and adolescence and is classified as a malignant disease. According to current knowledge, LCH originates from certain precursor cells of the white blood cell series in the bone marrow‎ and can affect almost any organ or region of the body.

The most commonly involved organs are the skeleton (in 80% of cases), the skin (30% of cases) and the pituitary gland‎ (with up to 25%). Bone involvement can be present in almost all parts of the skeleton; however, the skull and long bones are most commonly affected. Other relatively commonly affected organs are the liver, spleen, hematopoietic system, and lungs (with 15% each). In addition, the lymph nodes‎ (5–10%) and the central nervous system‎ (2–4%) can also be involved.

LCH can have different degrees of severity and also vary in terms of the course of the disease. In this context, the decisive factor is whether only one or more organs or organ systems are affected and which ones they are. Patients in whom only one organ / organ system is affected – for example, only the bone or only the skin (so-called monosystemic LCH) – usually have a more favorable prognosis‎ than patients in whom several organs / organ systems are affected (multisystemic LCH).

Good to know: Some patients do not require treatment, while others need chemotherapy; the treatment decision is determined by the location and spread of the disease (see chapter "Treatment").

Incidence

Langerhans cell histiocytosis (LCH) is a rare disease. It accounts for far less than 5 % of all malignant diseases in childhood and adolescence. It is estimated that around 80 to 100 children and adolescents aged younger than 18 years (3 to 5 per million) are diagnosed with LCH in Germany per year. However, due to possible spontaneous recoveries, the number of reported new cases probably does not correspond to the number of cases that actually occurred.

Though LCH may occur at any age, it is mainly diagnosed in childhood, most frequently in infants and toddlers up to the age of four. The frequency of the dise-ase decreases with increasing age. Overall, boys are affected slightly more often than girls (gender ratio: 1.3:1).

Symptoms

Since Langerhans cell histiocytosis (LCH) can affect almost any organ or region of the body (see chapter "General disease information"), the range of possible signs of disease (symptom‎s) is wide. They depend primarily on the location and extent of the disease.

Some patients are symptom-free and the diagnosis is based on an incidental finding, as it is sometimes observed with individual foci of disease (lesions) on the skull bone. Other patients have skin changes of varying degrees (individual skin lesions to extensive or whole-body rashes), while others have a severe clinical presentation with multi-organ involvement.

The possible symptoms include:

• if the bones are affected: bone pain, sometimes swelling and/or restricted movement (e.g. limping); protrusion of the eyeball (exophthalmus‎) (if the bony eye socket is affected)
• if the skin is affected: persisting skin changes/rashes (exanthema) of various kinds (e.g. nodular, scaly, weeping, ulcer-like or crust-forming), for example on the scalp, in the diaper area or on the arms, legs and torso; also possible: small punctiform skin bleedings, discharge of secretions from the ear or polyps in the ear canal
• in case of involvement of the mucous membranes: mucous membrane changes in the mouth and external genital area, such as swelling, ulcers
• if the lungs / respiratory truct are/is affected: breathing difficulties such as coughing, shortness of breath, chest pain
• in case of involvement of the liver, spleen and/or lymph nodes: enlargement of the affected organs / organ systems, which are noticeable, for example, by a extended abdomen and/or (very rarely) lymph node swelling
• in case of pituitary gland involvement: hormonal deficiencies, which can be noticed, among other things, by severe thirst and frequent urination (indication of diabetes insipidus‎) or by growth disorders / disorders of sexual development (puberty‎)
• if the hematopoietic bone marrow is affected: infection‎s, pallor and/or signs of bleeding
• if the central nervous system is affected: neurological‎ symptoms such as visual and/or hearing disorders, impaired gait, concentration and/or behavioural disorders

Good to know: The symptoms of LCH can vary greatly from patient to patient. It is also important to know that the occurrence of one or more of above-mentioned symptoms does not necessarily mean that they are caused by LCH. Many of these symptoms also occur in benign diseases that have nothing to do with LCH. Nevertheless, it is strongly recommended to have the child or teenager see a paediatrician as soon as possible in case such symptoms persist or progress.

Causes

The causes of Langerhans cell histiocytosis (LCH) are still largely unclear. It is known that the disease is caused by the modification of a certain (myeloid) precursor cell of white blood cells and its subsequent replication. The altered cells sometimes make up less than 10% of all cells in the LCH tumour foci, which otherwise consist mainly of normal inflammatory cells of the immune system‎ (T lymphocytes‎, granuloytes‎ and so-called multinuclear giant cells).

In LCH cells, certain genetic‎ deviations (mutations) in the genetic material are often observed. For example, in about two-thirds of the diseased patients, gene‎ changes in certain signaling pathways of the LCH cells can be detected, which are important for the control of cell growth, cell development and cell survival. The gene changes in the LCH cells are mainly the so-called BRAF V600E mutation‎, less often a MAP2K1 mutation. Both mutations cause a permanent activation of the above-mentioned signal transmission pathways and promote the development of the disease by disrupting cell function.

Good to know: Finding such mutations has not only contributed to a better understanding of the disease, it also opens up completely new diagnostic and therapeutic approaches for the future (see chapter "Treatment – New therapy options"). LCH needs more research. However, it is important to know that such mutations occur spontaneously, i.e. they are not inherited or hereditary.

Diagnosis

If the paediatrician suspects Langerhans cell histiocytosis (LCH) based on the patient's medical history (anamnesis‎) and physical examination‎, he will, depending on the type of finding, either first recommend imaging‎ procedures, such as an X-ray examination‎, an ultrasound‎ examination (sonography) or magnetic resonance imaging‎ (MRI), or first arrange for a tissue sample to be taken (biopsy‎). The latter is usually done by sampling from easily accessible areas, such as the skin.

In order to confirm the diagnosis‎, the removal and examination of tissue is required in any case, and the subsequent precise determination of the spread of the disease (staging) requires specific imaging procedures. The paediatrician will therefore refer the patient to a hospital specialising in cancer and blood disorders in children and adolescents (Clinic for Paediatric Oncology/Haematology) for any subsequent examinations and potential therapeutic management.

The various diagnostic procedures are then explained in more detail. Whether and in what order these examinations are carried out depends on the specific situation and on any existing findings.

History and physical examination

Both a specific medical history and a complete, specific physical examination‎ are crucial after the diagnosis has been confirmed (primarily by tissue sampling, see below). The examining physician will pay particular attention to pain, swelling, impaired range of motion, rashes and mucosal changes, discharge from the ear, fever, loss of appetite, vomiting, diarrhea, weight loss or failure to thrive. In addition, attention is paid to abnormalities regarding drinking behaviour (extremely large amount of drinking) and/or urine formation (extremely high urine production), signs of shortness of breath and neurological‎ abnormalities.

Blood tests and imaging diagnostics

Specific blood serum markers that provide indications of LCH or may serve to monitor the course of the disease have not yet been identified. The diagnosis of the disease and the assessment of its potential spread ("staging") is therefore carried out, in addition to various standard blood test, primarily by imaging‎ procedures (radiological diagnostics‎) at the time of diagnosis (and later also for progress assessment and follow-up).

As part of the routine blood work, the blood cell counts, liver and kidney function and coagulation parameters are examined. The imaging procedures include an ultrasound‎ examination of the abdomen and an X-ray examination‎ of the lungs or skeletal system, because LCH preferably affects the bones. In order to keep radiation exposure‎ as low as possible, many clinics use whole-body MRI; however, if there are uncertainties regarding the evaluation, an X-ray or computed tomography‎ (CT) is sometimes necessary.

In addition to these basic diagnostic procedures, additional examinations may be necessary for special indication‎s, i.e. in some disease situations, such as an eye test, a hearing test (audiogram‎), a lung function test, hormone‎ tests, certain MRI examinations or an endoskopy‎.

Tissue sampling (biopsy) to secure diagnosis

The final diagnosis of LCH is based on microscopic examination of tissue from the area(s) affected by the disease using a conventional light microscope‎ and on the immunhistochemic‎ detection of special molecule‎s (so-called markers) on the surface of the LCH cells (CD1a antigen‎ and/or langerin (CD207)).

An additional molecular genetic‎ examination with regard to common gene‎ changes (mutations), such as BRAF V600E, is recommended especially for patients with multisystem involvement, but is not initially necessary for therapy planning. The diagnosis of LCH is usually confirmed by another expert (so-called reference assessment); however, this is not always necessary (for example, in the case of clear results).

If tissue sampling (biopsy) poses a risk to the patient due to the location of the tumour focus (for example, in the area of the second cervical vertebra or in the pituitary stalk) or if sufficient tissue material cannot be obtained, the treatment team carefully weighs up the benefit-risk ratio for the respective patient. If a biopsy‎ is not performed, it is particularly important to ensure careful follow-up.

Good to know: Not every patient needs the complete check-up. On the other hand, tests might be added that haven't been mentioned here, depending on the individual situation of the patient. Your caregivers will inform you and your child, which diagnostic procedures are individually required in your situation and why.

Therapy planning

After the diagnosis has been confirmed and subsequent staging of the disease (see above) has been completed, therapy is planned. In order to provide a therapy that is specifically designed for the patient’s individual situation (risk-adapted therapy), the doctors will take into consideration certain factors that have been shown to have an impact on the prognosis‎‎ (so-called risk factors or prognostic factors).

Important prognostic factors‎ in patients with LCH are the extent of the disease (monosystemic, multisystemic, unifocal, multifocal) and the type of organs affected by the disease (taking into account so-called risk organs and the exact location of the disease in an organ, see below). In addition, the response of the disease to treatment (especially chemotherapy) also plays a role in the patient's prognosis.

Classification of LCH according to the degree of spread and type of organ affected

According to international studies, the classification of Langerhans cell histiocytosis (LCH) first takes into account whether only one organ / organ system is affected by the disease or whether the disease involves two or more organs / organ systems. The former is referred to as a single-system LCH (SS-LCH), the latter as a multi-system LCH (MS-LCH).

Monosystemic LCH

If monosystemic LCH is present, it is important for therapy planning whether the organ / organ system is affected in only one area (unifocal) or in multiple ones (multifocal). For example, in the case of bone involvement, unifocal bone foci ("single bone") are distinguished from multifocal bone disease (more than one bone), whereby the location of the bone involvement and the size of the foci of disease also play a role (see section "Organ involvement – Special Sites"). In addition to bones, monosystemic LCH can also affect the skin, lungs, the pituitary-hypothalamus‎ region, the central nervous system‎ and other organs (such as the thyroid gland, thymus gland‎).

Multisystemic LCH

In case of multisystemic LCH (infestation of two or more organs / organ systems), it is taken into account whether so-called "risk organs" are affected by the disease or not. The haematopoietic system as well as the spleen and liver are considered to be risk organs. As (therapy) studies have shown that an involvement of these organs is associated with a less favourable prognosis than the involvement of other organs and, therefore, must be taken into account regarding therapy and, in particular, the assessment of the response to therapy. The lungs, which used to be considered a risk organ, are no longer defined as such in the international LCH studies.

Lymph node involvement is considered to be a separate organ involvement if the lymph node(s) are not located in the drainage area of another LCH foci and are therefore not directly related to it.

Organ involvement – „special sites“

Regardless of whether monosystemic or multisystemic LCH is present, foci of the disease in very specific organs or organ locations are considered so-called "special sites" that are considered separately. These are foci of disease that, due to their location or size, are either difficult or inaccessible for surgical intervention (e.g. a large lesion in load-bearing bones), pose a threat to life (e.g. if certain vertebral bodies are affected) or, according to older study data, are associated with a higher risk of hormonal disorders, such as diabetes insipidus‎. The latter applies, for example, to certain facial or skull bones. If such "special sites" are affected in LCH disease, systemic‎ therapy, i.e. chemotherapy‎, is recommended.

Treatment

Treatment of children and adolescents with Langerhans cell histiocytosis (LCH) should only be carried out in centres that are familiar with the disease and its treatment. This is usually a children's hospital with a paediatric oncology/haematoloy program. In such a treatment centre, highly experienced and qualified staff (doc-tors, nurses and many more) is guaranteed, since they are specialised and focus on the diagnostics and treatment of children and teenagers with cancer according to the most advanced treatment concepts. The doctors (such as oncologists, radiologists, surgeons) in these centres collaborate closely with each other. Together, they treat their patients according to treatment plans (protocols) that are continuously optimised.

Depending on the spread and severity of the disease, there are different therapeutic approaches. The possible procedure for children with LCH depends, among other things, on whether one or more organ systems (e.g. skin, bones, liver, spleen) are affected and whether – in the case of bone involvement – one or more sites are affected and in what position (see chapter "Therapy planning"). It is also important whether it is a first diagnosis of the disease or a relapse of LCH.

Depending on the criteria mentioned, the following procedures are possible in principle:

• "Watch-and-wait“ strategy
• Local therapy
• Systemic therapy

Due to possible long-term damage of healthy tissue, radiotherapy‎ is generally no longer recommended as a suitable therapeutic measure.

"Watch-and-wait" strategy

In the "watch-and-wait" strategy ("look/observe and wait"), a wait-and-see attitude is carried out under close follow-up checks and no treatment for the time being. This can be an option, for example, in the case of a single bone focus or an isola-ted skin lesion, among other things, because spontaneous regression is possible in such cases. In the follow-up checks, careful care is taken to detect the progression of a localized disease or the development into a multisystemic disease as early as possible. This is very important, especially in very young patients.

Local therapy

Local therapy can be considered for patients presenting with skin involvement only as well as in patients with unifocal bone involvement and without the involvement of other organs.

Patients who are only receiving local therapy should be closely monitored during therapy – as in the case of a "watch-and-wait" strategy – in order to detect pro-gression of the disease or a change to a multisystemic disease as early as possible.

Often, tissue removal (biopsy) is already considered as a local treatment, as the surgical procedure often leads to a spontaneous regression at that site of the disease. Complete removal or extensive surgery of the lesion is usually not recommended. In case of bone involvement, such a procedure could actually increase the bone defect, delay the healing process and thus cause permanent bone damage.

Systemic therapy

For many LCH patients, chemotherapy‎ is necessary due to the location and spread of the disease. This generally applies for multisystemic disease, but may also be necessary in patients with monosystemic LCH, unless (for example) there is a single local skin lesion or a unifocal bone lesion without any involvement of other organs (see chapter "Local therapy").

In chemotherapy, drugs (so-called cytostatics) are used that inhibit cell growth and thus contribute to the destruction of LCH cells. Since this therapy affects cells throughout the body, it is also known as systemic‎ therapy. In order to destroy as many LCH cells as possible, chemotherapy usually involves a combination of different cell growth-inhibiting drugs (cytostatics‎‎) that have proven particularly effective in combating this disease.

In the context of chemotherapy for LCH treatment, a distinction is made between first-line therapy and second-line therapy. Second-line therapy is only used if the first-line therapy is not efficient.

First-line therapy

First-line therapy for patients with LCH consists of two major phases of therapy: induction and maintenance therapy. In both phases, the drugs vinblastine (VBL) and prednisone are used.

The current standard therapy involves a six-week course of chemotherapy, consis-ting of six doses of the cytostatic drug vinblastine (once a week) and daily predni-sone administrations. Following the six-week treatment, the response of the disease to therapy (therapy response) is examined. If the treatment works well, induction therapy is ended. If, on the other hand, there is only a partial response to therapy and, in particular, there is still an involvement of high-risk organs, another six-week course of chemotherapy is generally recommended. In this second course, the drugs vinblastine and prednisone are used again: vinblastine is administered once a week, a total of six times, prednisone on days 1–3 of the six-week treatment period.

After the end of the induction therapy, which lasts six or twelve weeks, maintenance therapy follows, if there is sufficient response to therapy. It consists of vin-blastine/prednisone doses administered every three weeks on days 1–5.

The current total duration of therapy according to the standard of care (induction and maintenance therapy) is six months for patients with monosystemic LCH ("single-system LCH"), i.e. for example with unifocal or multifocal bone involvement. For patients with multi-system LCH, the standard therapy is twelve months in total. Both the optimal duration and the optimal intensity of maintenance therapy are currently being investigated in studies.

Second-line therapy ("Salvage“ therapy)

If, at the time of the sixth week of treatment, the response to therapy is not satis-factory or the disease is even progressing in organs at risk, an early change in therapy to "salvage" therapy should be considered, especially in patients with involvement of the haematopoietic system or the liver. These patients should be treated in a specialised centre.

Possible treatment options include chemotherapy drugs such as vincristine (VCR), cytarabine (Ara-C), clofarabine, a combination of 2-chlorodeoxyadenosine (2-CDA) and cytarabine (Ara-C), and/or a blood stem cell transplantation‎ (haematopoietic blood stem cell transplant). The use of newer drugs such as inhibitor‎s is currently being investigated (see below).

New therapeutic approaches

Due to the increasing characterisation of disease-activating signaling pathways in the altered cells (e.g. BRAF or MAPK2K1 gene changes, see chapter "Causes"), there is a growing interest in the research and use of drugs that block these signaling pathways (so-called checkpoint inhibitors). In observational studies (case series‎), checkpoint inhibitor‎s in children show very promising results.

However, these treatment strategies and the optimal duration of therapy with these substances are still unclear, and in the majority of patients, the disease returns when the drugs are discontinued. For this reason, studies are currently being designed to test a combination of signaling pathway blockers with chemotherapy.

Since the long-term side effects of such drugs are still unclear on the one hand and chemotherapy works well in most patients on the other, these drugs should initially only be used in acutely life-threatening situations or in the absence of a response to conventional therapy. Also, any additional procedure should be discussed with experts.

Treatment for relapse of LCH

At present, all therapy recommendations in case of disease recurrence‎ are based on experience from clinical practice as well as on expert opinions. The therapeutic decision depends on the time of relapse and the spread of the disease.

If only one organ / organ system is affected, the decision on the appropriate treatment strategy is based on similar criteria as for the initial disease. Even if the recurrence affects more than one organ / organ system after the first-line therapy has been completed, a resumption of treatment with vinblastine and steroids (prednisolone) may be successful within the framework of the chemotherapy required in this case (see chapter "Treatment").

In the case of relapses in the bone area, smaller case series with LCH patients also have found indomethacin or bisphosphonates‎ to be effective treatment options, although these strategies have not yet been tested in randomised trials [see randomisation‎]. In the event of therapy failure or a relapse during ongoing therapy, the further course of action is decided on an individual basis. The study director can support the treating institution with therapy recommendations.

Therapy optimising trials and registries

In order to continuously improve the treatment options for children and adolescents with Langerhans cell histiocytosis (LCH), all patients with LCH should be included in an ongoing (therapy optimising) study or registry.

Therapy optimising trials are standardised and controlled clinical trials that aim at continuously developing and improving treatment concepts for patients based on the current scientific knowledge. Patients who cannot participate in any study, for example because none is open for them at that time or since they do not meet the required inclusion criteria, respectively, are often included in a so-called registry.

Until recently, the LCH-REG-DE 2013 registry was available in Germany for patients with LCH, but it was closed for administrative reasons; the registry is scheduled to be reopened as LCH-REG-DE 2025 at the end of 2025.

All LCH patients under the age of 18 can then be included in the "LCH-REG-DE 2025" registry – as was previously the case in the LCH-REG-DE 2013 registry (which was available at the end of 2022 after patient enrolment in the therapy optimising trial "LCH IV-G 2016" had been completed). This applies to patients with initial LCH disease as well as to patients with relapse of the disease.

The registry primarily serves to scientifically accompany the therapy of patients and to obtain answers to various questions. There are no therapy specifications within the framework of the registry; patients receive standard treatment tailored to their form of disease. If necessary, the LCH study group advises the treating physicians on the selection of the optimal diagnostics and therapy in each case.

The LCH study group is headed by Prof. Dr. Thomas Lehrnbecher at the University Hospital Frankfurt (Main), Germany. Further members of the study centre are PD Dr. Konrad Bochennek and Dr. Anke Barnbrock as well as the neuroradiologist Prof. Dr. Luciana Porto.

Prognosis and course of the disease

Langerhans cell histiocytosis (LCH) is a diverse clinical condition that can be associated with different disease courses and prospects of recovery (prognosis). Both the course and the prognosis‎ of disease depend largely on the degree of spread of the disease and its response to therapy. On the one hand, there are courses of the disease that can be accompanied by spontaneous healings. On the other hand, LCH can also keep recurring or, rarely, even rapidly progress to a fatal outcome.

As a rule, the prognosis for patients with monosystemic LCH is very good – in the older studies, such as the international study LCH III, all children survived –, while in multisystemic LCH up to 10% of patients still pass away. However, these are almost exclusively small children (under 2 years of age) in whom important organs (liver, spleen, bone marrow) are affected and whose disease has responded poorly or not at all to the initial treatment (induction). It remains to be seen to what extent the use of inhibitors can improve this. The majority of patients, however, respond well to conventional treatment and then remain disease-free.

In about one third of patients, a relapse of the disease occurs after a disease-free phase (of varying duration). LCH relapses are mainly limited to bones, skin and pituitary gland‎ and are therefore usually not life-threatening. However, they can be accompanied by protracted (chronic) problems (long-term effects). Late effects of the disease are observed in 30–40% of patients, and a chronic course of the disease significantly increases the risk of those (see our information on "Late sequelae").

PDF Brief information on Langerhans cell histiocytosis (LCH) (452KB)
Author: Maria Yiallouros
Status: 20/08/2025