Langerhans Cell Histiocytosis: Symptoms, Diagnosis, & Prognostic Categories
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Langerhans cell histiocytosis is a rare disease involving an excess of Langerhans cells, abnormal immune cells from bone marrow and can migrate from the skin to lymph nodes.
What is langerhans cell histiocytosis?
Langerhans Cell Histiocytosis (LCH) is a rare disorder characterized by dysfunction and proliferation of a particular type of immune cell. Collections of these dysfunctional cells infiltrate various tissues in the body leading to a wide variety of disease presentations. The most common areas infiltrated by these cells are the skin, bones, and lung tissue; however, these cells can infiltrate anywhere in the body including the central nervous system.
Some symptoms include painful nodules on the bones anywhere in the body, lesions of the skin or mouth, hearing loss, cough and shortness of breath, or behavioral changes. LCH is most commonly diagnosed in children ages 1 to 3. Another form of the disease commonly diagnosed in adults is mainly isolated to the lungs and seems to be related to cigarette smoking.
LCH can be treated with steroids or chemotherapy which have been shown to improve disease progression in some cases. However, LCH is a chronic disease without a cure, and most people have long-term consequences depending on the particular systems or tissues involved.
You should visit your primary care physician within the next few days.
Langerhans cell histiocytosis symptoms
Because LCH is caused by dysfunctional cells that have the ability to infiltrate many different areas of the body, there are many different symptoms. Most people with LCH will only have one of these categories of symptoms, and others will have symptoms in multiple categories.
Any bone can be affected by pain and lesions described below; however, some locations are more likely than others.
- Painful, raised areas over bones: The most common locations of these nodules are the femur in the leg, the ribs, the vertebrae in the back, or the humerus in the arm.
- Other locations where painful, raised areas are found: The facial bones, skull and jaw may also have nodules.
- Bone deformities or fractures: These can occur if the lesions infiltrate the bone enough.
- Loose teeth or bleeding gums: Due to bone lesions in the jaw.
- Hearing loss or ear infections: Due to lesions in the ear bones.
Skin symptoms may present as bumps, a rash, or lesions.
- Small, raised bumps: Brown or purplish small, raised bumps on the skin may appear.
- Red, scaly rash: The rash looks similar to eczema found in the groin, abdomen, back, or chest.
- Lesions: These may occur on the inside of the mouth.
A few lung-related symptoms may develop, such as:
- Shortness of breath
- Chest pain
- Weight loss
A few other symptoms may occur, including:
- Swollen lymph nodes in the neck
- Tumor or cystic lesions seen in liver or spleen
- Excessive thirst
- Excessive urinating
- Behavioral problems
- Cognitive dysfunction
- Difficulty with balance or walking
Langerhans cell histiocytosis causes
Langerhans Cell Histiocytosis is considered rare, affecting one to two people in every 100,000. The exact cause is unknown in most cases and is not considered to be inherited.
About the genetic mutation
LCH is caused by the dysfunction of a specific type of immune cell called a myeloid cell that originates in the bone marrow, the site of origination of most of the immune system in the body. The mutation is in the BRAF gene, which is a proto-oncogene that directs cell growth and is mutated in many known human cancers. The reason why this mutation happens is unknown and the mutation is fortunately not hereditary.
The mutation causes increased growth and proliferation of faulty immune cells that then infiltrate various organs in the body, creating destructive lesions and causing symptoms dependent on the organ they are residing in, listed below.
- Skin and bone nodules: These often painful nodules result from dysfunctional cells involved with the skin and bones. These can even erode the bone and lead to fractures or deformities.
- Lung involvement: Shortness of breath and cough result from dysfunctional cells in the lungs.
- Pituitary involvement: The pituitary gland is part of the endocrine (hormonal) system and dysfunction commonly leads to diabetes insipidus (not diabetes mellitus) resulting in excessive urination and thirst.
Almost all people that develop LCH with lung involvement in adulthood smoke cigarettes. However, it is unclear exactly how cigarette smoking and LCH are related.
Treatment options and prevention
As discussed previously, LCH has a very broad range, from minimal symptoms contained within one organ system to a disease that affects many organ systems with significant associated damage. Methods of diagnosis, prognosis, and treatment options are found below.
The primary diagnostic method is through biopsy; however, further testing may be necessary to locate and monitor which areas of the body are being affected by the dysfunctional cells.
- Biopsy: A biopsy is when a small piece of tissue is removed from the affected organ and examined microscopically. LCH lesions have a specific microscopic appearance, and this is the only way to definitively diagnose LCH.
- Blood work: Laboratory studies to look at blood cell counts, liver, and renal function, and hormonal function are part of the initial evaluation if you are suspected to have LCH.
- Bone marrow aspiration: Young children and anyone with suspected involvement of the liver and spleen should have bone marrow aspiration to look directly at the dysfunctional immune cells that cause LCH.
- Genetic testing: People with suspected LCH should have genetic testing to look for the BRAF mutation. Not everyone with LCH has this specific mutation.
- Imaging: Radiographs (X-rays) of all bones and a PET or bone scan will be done on anyone with LCH to look for possible lesions. A PET scan is the preferred imaging scan and will be repeated following treatment to monitor progression. CT and MRI scans may be used to evaluate specific areas of the body and look for LCH lesions.
- Pulmonary function testing: People with LCH with lung involvement should have their lung function tested.
There are three prognostic categories of LCH listed below, as this disease has a broad range of outcomes.
- Single-system LCH: In most cases, people with the involvement of only a single system typically have isolated lesions to the bones or skin and have better outcomes overall. However, long-term consequences of single organ involvement can still be severe, ranging from destruction of bone to hearing loss, to reduced pulmonary function causing shortness of breath and exercise intolerance.
- Multisystem LCH: People with the involvement of more than one organ system have a worse prognosis. These people have similar consequences to the single-system LCH individuals but have multiple problems from the disease. These people have higher disease-related mortality, meaning they are more likely to die from their disease.
- High-risk LCH: Some organ systems are noted to be particularly high-risk and increase mortality related to LCH. These systems include the lungs, bone marrow, liver, and spleen.
Treatment for limited or isolated lesions
For more isolated lesions or lesions that are less frequent, options include:
- Steroid injection: Injection of steroids is common for isolated lesions to the bones, particularly in children. This treatment may improve pain and range of motion in the affected bone.
- Systemic steroids: Often people with high-risk single lesions or multiple lesions will be treated with systemic steroids. Steroids decrease the body's immune response, and since LCH is caused by excess growth of immune cells, steroid treatment is a reasonable option.
Treatment for large lesions or more severe LCH
For larger lesions or cases that have more extensive damage caused by LCH:
- Surgical stabilization: Large lesions to the bones in the legs or spine may cause the bones to collapse. If a bone is at risk of collapse, the lesion may require surgical intervention for stabilization. A bone with an LCH lesion may need to be stabilized with rods and screws.
- Chemotherapy: Chemotherapy is the mainstay of treatment for LCH. Since LCH is an abnormal proliferation of immune cells, chemotherapy is a way to prevent that proliferation and therefore prevent invasion of the abnormal cells into tissues. The most common agent used is called vinblastine. Side effects include constipation and possible hair loss. Typically, vinblastine is given in conjunction with steroids for a six-week course.
- Radiation: If individual lesions are disrupting bone, skin, or other structures, they may benefit from direct radiation to kill the infiltrating cells and preserve the function of the organ.
- Surgical removal: Certain types of LCH lesions can be surgically removed to prevent further infiltration or destruction of the organ.
Possible future treatment options
Although these options are in the early stages of study, they may be available in the future for treating LCH.
- Stem cell transplant: Stem cell transplant has been considered as a possibility for the treatment of LCH, but so far has not been thoroughly investigated or studied.
- Clinical trials: The treatment of LCH is currently evolving. There are many different ongoing clinical trials looking at new and different forms of treatment for LCH.
When to seek further consultation
If you or your child have been diagnosed with LCH, you should seek expert consultation. Once diagnosed:
- For children: Children diagnosed with LCH likely need to be evaluated by a Pediatric Hematology and Oncology specialist.
- For adults: Adults diagnosed with LCH likely need to be evaluated by a Hematology/Oncology specialist. Additionally, depending on the other symptoms and affected organs, an adult with LCH may want to be evaluated by a Pulmonologist (specialist in lungs), Orthopedic specialist (specialist in bones) or Endocrinologist (specialist in hormones).
Questions your doctor may ask to diagnose
- Have you been feeling more tired than usual, lethargic or fatigued despite sleeping a normal amount?
- Any fever today or during the last week?
- Have you lost your appetite recently?
- How long has your current headache been going on?
- Have you experienced any nausea?
Self-diagnose with our free Buoy Assistant if you answer yes on any of these questions.
Dr. Martin is an Emergency Medicine resident at the University of Washington in Seattle. She received her undergraduate degree from Stanford University where she majored in Human Biology, and received her MD from the University of Pennsylvania. She’s interested in Emergency Medical Services and Flight Medicine, and is currently a resident flight physician with Airlift Northwest. In her free time, she enjoys playing ultimate frisbee, cycling, rock climbing, and trail running!
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- Allen CE, Merad M, Mcclain KL. Langerhans-cell histiocytosis. N Engl J Med. 2018;379(9):856-868. NEJM Link
- Langerhans cell histiocytosis. Genetic and Rare Diseases Information Center. GARD Link
- Vinblastine (intravenous route). Mayo Clinic. Updated October 1, 2018. Mayo Clinic Link
- Treatment of resistant langerhans cell histiocytosis with enbrel. ClinicalTrials.gov. Updated August 24, 2006. ClinicalTrials.gov Link
- Denosumab for the treatment of adult LCH. ClinicalTrials.gov. Updated September 11, 2017. ClinicalTrials.gov Link