Langerhans cell histiocytosis

The cause of Langerhans cell histiocytosis (LCH) is unknown in many cases. However, somatic mutations in the BRAF gene have been identified in the Langerhans cells of about half of people with LCH. Somatic gene mutations are acquired during a person's lifetime, which means they are acquired after conception and are only present in certain cells. Because they are not present in the germ cells (egg and sperm), they are not passed on to the next generation (are not inherited).

The BRAF gene provides instructions for making a protein that is normally switched on and off in response to signals that control cell growth and development. Somatic mutations cause the BRAF protein in affected cells to be continuously on and to transmit messages to the nucleus even in the absence of these chemical signals. The overactive protein may contribute to the development of LCH by allowing the Langerhans cells to grow and divide uncontrollably.

The protein produced by the BRAF gene is part of a signaling pathway known as the RAS/MAPK pathway, which controls several important cell functions. Specifically, the RAS/MAPK pathway regulates the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self- destruction of cells (apoptosis). Chemical signaling through this pathway is essential for normal development before birth.

The BRAF gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. Changes in other genes such as the MAP2K gene (20% of the cases), and other rarer genes (also involved in the RAS/MAPK pathway), have also been identified in the Langerhans cells of some people with LCH. Some researchers believe that additional factors, such as viral infections and environmental toxins, may also influence the development of this complex disorder.

Family members of LCH patients have a higher incidence of thyroid disease. Smoking is strongly associated with lung LCH.

Testing for Langerhans cell histiocytosis (LCH) may include bronchoscopy with biopsy, x-ray, skin biopsy, bone marrow biopsy, complete blood count, skeletal X-rays survey, pulmonary function tests and liver funcion tests, as well as MRI and CT scanning of the head to evaluate possible abnormalities of the hypothalamus and the pituitary gland. A fluorodeoxyglucose (FDG) positron- emission tomography (PET) scanning may also be used when evaluating patients for LCH, specially bone lesions.

Additional information about the diagnosis of LCH can be viewed on the Histiocytosis Association's website.

Although Langerhans cell histiocytosis is generally considered a sporadic, non-hereditary condition, it has reportedly affected more than one individual in a family in a very limited number of cases (particularly identical twins).

Langerhans cell histiocytosis is generally treated by a team composed of health care professionals from different specialties. However, over the years, cancer treatments have been used in patients with histiocytosis. Therefore, hematologists and oncologists are usually part of the multidisciplinary team. The disease is not cancer. Radiation therapy, if used, is given in much lower doses than that which cancer patients receive.

You can learn more about ongoing clinical research studies on the ClinicalTrials.gov Web site, a site developed by the U.S. National Institutes of Health, through the National Library of Medicine. Currently, there are several clinical trials identified as enrolling individuals with LCH. To find these trials click here. You can also search for studies by clicking on ClinicalTrials.gov and using 'Langerhans cell histiocytosis' as your search term. After you click on a study, review its 'eligibility' criteria to determine its appropriateness. Use the study’s contact information to learn more. Check this site often for regular updates.

Most often an oncologist/hematologist takes the main role in treating patients with LCH. However, since LCH can affect so many areas of the body, sometimes a team approach may be appropriate, and the oncologist may enlist the help of various types of specialists, including radiologists, surgeons, pulmonologists, dermatologists, dentists, and others.

Langerhans cell histiocytosis (LCH) is a disorder that primarily affects children, but is also found in adults of all ages. People with LCH produce too many Langerhans cells or histiocytes, a form of white blood cell found in healthy people that is supposed to protect the body from infection. In people with LCH, these cells multiply excessively and build up in certain areas of the body, causing tumors called granulomas to form. The symptoms of LCH vary from person to person, depending on the areas of the body affected. LCH may be found in many areas of the body, including but not limited to the skin and nails, mouth, bones, lymph nodes, pituitary gland, and thyroid gland. When it is found in multiple areas of the body, it is known as multisystem disease. The cause of this disease is unknown, although most data suggest that it is characterized by a growth of immature Langerhans cells that appear to have mutations of the BRAF gene in about half the cases. LCH is not caused by a known infection, is not contagious, nor is it believed to be inherited. There remain differing opinions among experts as to whether it is definitively a cancer or not. Treatment for LCH varies and may include surgery, chemotherapy, radiation therapy, and use of certain medications.

LHC includes four variants, with different degrees of severity:

• Hashimoto-Pritzker disease, a congenital self-healing form
• Letterer-Siwe disease, a severe, acute and disseminate form
• Hand-Schüller-Christian disease, an intermediate chronic form with multiple lesions characterized by diabetes insipidus, bulging of the eye and localized lesions in the bone
• Eosinophilic granuloma, a less severe form, characterized by solitary or few, and chronic lesions of bone or other organs.

Because all the variants have many common symptoms it is thought that they may be manifestations of LCH and not separate syndromes.

You can visit the following link to view resources related to Langerhans cell histiocytosis.
http://rarediseases.info.nih.gov/GARD/Disease.aspx?PageID=4&diseaseID=6858

• More than 50 percent of cases are observed in children under 15 years old, with a peak incidence at 1 to 4 years of age. However, Langerhans cell histiocytosis can affect people of all ages.
• There is no ethnic association.
• The prevalence is slightly higher in males.

The prognosis (chance of recovery) for people with Langerhans cell histiocytosis (LCH) can vary greatly from patient to patient, but in the majority of children, the disease goes away by itself. Prognosis seems to be dependent mainly on the number of organ systems involved, the severity of organ involvement, and to a lesser rate, the age at which symptoms occur.

In general, patients who are young and those in which the disease is present in many parts of the body and organ dysfunction tend to have a poorer prognosis. Newborns who present only with skin lesions tend to do well. Therefore, the age at presentation is only important when multiple organs are affected.

Individuals who have liver, spleen, lung, or bone marrow involvement usually have a worse prognosis. In a study looking at patients from several centers, it was shown that the best prognostic indicator was the patient's response to chemotherapy during the first six weeks of therapy. Therefore, it has been recommended by some that individuals who do not respond positively within the first six weeks of treatment should be treated more aggressively.

LCH in the skin, bones, lymph nodes or pituitary gland usually gets better with treatment and is called “low-risk.” Some patients have involvement in the spleen, liver and bone marrow. This is called “high-risk disease” and may be more difficult to treat. Some patients may develop long-term side effects such as diabetes insipidus, stunted growth, loss of teeth, bone defects, hearing loss, or neurologic problems; while other patients remain without side effects. In a few cases, the disease can be life-threatening.

Patients with LCH should usually have long term follow-up care to detect late complications of the disease or treatment. These may include problems of skeletal deformity or function, liver or lung problems, hormone abnormalities, dental issues or neurological and neurocognitive dysfunction. Read more about Permanent Consequences and Late Effects of LCH.

Survival rates and quality of life continue to improve.

Due to a lack of clinical trials, there are limited recommendations available for adults with Langerhans cell histiocytosis (LCH). Much of the knowledge about treatment is based on pediatric studies. Most researchers have previously recommended treatment according to the guidelines for standard treatment of children with LCH. However, it has been unclear whether adult LCH responds as well as the childhood form of the condition. Additionally, some drugs used in the treatment of children may be less well- tolerated in adults.

Due to the lack of information, a number of experts recently developed the first recommendations for management of adult patients with LCH. Their management recommendations were published in the Orphanet Journal of Rare Diseases; the free, full-text article can be viewed here. Due to the technical nature of this information, we recommend reviewing this article with a qualified healthcare provider.

Because the course of LCH is very diverse, even recommendations which are established as standard of care may need to be assessed on a case-by-case basis. Treatment for this condition depends on the site(s) and severity in each individual. Consultation with a LCH expert is recommended.

Additional information about the treatment of adult LCH can be viewed on the National Cancer Institute's Web site.

Treatment for Langerhans cell histiocytosis (LCH) depends upon the individual patient; it may differ depending on the type and severity of the condition as well as what part(s) of the body are affected. In some cases, the disease will go away without any treatment at all. In other cases, depending on the extent of the disease, limited surgery and small doses of radiation therapy or chemotherapy may be needed. Treatment is planned after complete evaluation of the patient, with the goal of using as little treatment as possible to keep the disease under control.

No consensus exists for the best therapy for LCH, especially when multiple organs are involved. However, the Histiocyte Society has done many clinical trials to evaluate the effect of several treatments, which have resulted in recommendations by the Histiocyte Society.

Generally, the choice of treatment is based on disease severity. The International LCH Study of the Histiocyte Society proposes classifying LCH cases by the number of systems involved and by the number of sites within that system (e.g., involving one or more bones, involving one or multiple lymph nodes). Although most of the trials are in children, the recommendations can also be used for adults.

Detailed information about the treatment of LCH can be viewed on Medscape Reference's Web site.

Satter EK, High WA. Langerhans Cell Histiocytosis: A Review of the Current Recommendations of the Histiocyte Society. Pediatric Dermatology (2008) Vol. 25 No. 3 291-295.