Langerhans Cell Histiocytosis in Children

Langerhans cell histiocytosis (LCH) is the most common of the histiocytic disorders and occurs when the body accumulates too many immature Langerhans cells, a subset of the larger family of cells known as histiocytes.

Langerhans cell histiocytosis (LCH) is the most common of the histiocytic disorders and occurs when the body accumulates too many immature Langerhans cells, a subset of the larger family of cells known as histiocytes.  Langerhans cells are a type of white blood cell that normally help the body fight infection.  In LCH, too many Langerhans cells are produced and build up in certain parts of the body where they can form tumors or damage organs.  The cause of this disease is unknown, although many possibilities have been explored, including viruses, exposure to toxins in the environment, family history and geography. Most data support the concept that LCH is a diverse disease characterized by a clonal growth of immature Langerhans cells that appear to have mutations of BRAF in about half the cases. LCH is not caused by a known infection.  It is not contagious, nor is it believed to be inherited. Scientific discussions on the definition of LCH continue to be debated in terms of its classification as either an immune dysfunction or a rare cancer (neoplastic and malignant or not malignant). There remain differing opinions among experts as to whether it is definitively a cancer or not.

As of 2020:  According to most experts, Langerhans cell Histiocytosis (LCH) is currently classified as a rare cancer. However, this doesn't necessarily mean that all of the worrisome implications that come along with the term “cancer” are true of LCH for every patient; LCH and other histiocytic disorders have a wide spectrum of presentations.

Histiocytosis was first described in the medical literature in the mid to late 1800s.  Through the years, it has been known by various names, such as histiocytosis X, eosinophilic granuloma, Letterer-Siwe disease, Hashimoto-Pritzker disease, and Hand-Schüller-Christian syndrome.  In 1973, the name Langerhans cell histiocytosis (LCH) was introduced.  This name was agreed upon to recognize the central role of the Langerhans cell.

LCH is believed to occur in 1:200,000 children, but any age group can be affected, from infancy through adulthood.  In newborns and very young infants, it occurs in 1-2 per million.  It is, however, believed to be under-diagnosed, since some patients may have no symptoms, while others have symptoms that are mistaken for injury or other conditions.  It occurs most often between the ages of 1-3 years and may appear as a single lesion or can affect many body systems, such as skin, bone, lymph glands, liver, lung, spleen, brain, pituitary gland and bone marrow.

Information has been collected in various studies which show that bone involvement occurs in approximately 78% of patients with LCH and often includes the skull (49%), hip/pelvic bone (23%), upper leg bone (17%) and ribs (8%).  Skin LCH is seen in as many as 50% of patients.  Lung lesions are seen in 20% to 40% of patients, while 30% of patients have lymph node involvement.

Symptoms depend on the location and severity of involvement.  It is usually diagnosed with a tissue biopsy, in addition to other testing, such as x-rays and blood studies. A biopsy of an involved site is necessary to make a definitive diagnosis.

While some limited cases of histiocytosis may not require treatment, for patients with more extensive disease, chemotherapy may be necessary.  Hematologists and oncologists, who treat cancer, also treat children with Langerhans cell histiocytosis.

Most patients with LCH will survive this disease.  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 minority of cases, the disease can be life-threatening.

Certain factors affect the chance of recovery and options for treatment.  These factors include the extent of the disease, whether “risk organs” (liver, spleen, bone marrow) are involved, and how quickly the disease responds to initial treatment.

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, endocrine abnormalities, dental issues or neurological and neurocognitive dysfunction. Read more about Permanent Consequences and Late Effects of LCH.

The Histiocytosis Association works closely with the Histiocyte Society, which is dedicated to studying the histiocytic disorders.  Through this unusual partnership, understanding of this disease has greatly increased, and survival rates and quality of life continue to improve.

Symptoms

Langerhans cell histiocytosis (LCH) may be limited to only one part of the body, such as a bone, or it can involve many organs.  The disease may be more serious in young infants or if “risk” organs such as liver, spleen, or bone marrow are involved. When LCH affects certain bones in the skull, the patients can be at higher risk of developing diabetes insipidus and/or neurological complications.

The following symptoms may indicate disease involvement but are not necessarily diagnostic of LCH.  This disease varies greatly from patient to patient, and some but not all of these symptoms may be present.

  • Skin
    Scaly, waxy rash or lesions, hair loss, diaper rash, oozing, tenderness.
  • Bones/Single or Multiple Sites (skull, bones around eyes, back bones, extremities, ribs, pelvis, feet/toes/fingernails/hands/fingers).
    Bone pain, lumps, headaches, fracture, limp, inability to walk, collapse of disc.
  • Bone Marrow
    Low blood counts (red blood cells, white blood cells, and platelets/clotting cells), increased infections, easy bruising.
  • Gastrointestinal Tract (stomach/intestines/colon)
    Abdominal pain, yellow skin, vomiting, diarrhea, blood in stool, weight loss, bleeding from the throat, child's growth falls below the standard expectation.
  • Liver/Spleen
    Enlarged liver, swelling of abdomen, pain, abnormal liver blood tests.
  • Endocrine System (pituitary gland/diabetes insipidus, hypothalamus, thyroid gland)
    Excessive thirst, excessive urination, dehydration, fatigue, sweats, temperature changes, weight gain, weight loss, short stature/growth failure, early or delayed/absent puberty.
  • Lung
    Chest pain, shortness of breath, difficulty breathing, collapsed lung, cough, weight loss, fatigue, coughing up blood.
  • Brain/Central Nervous System
    Diabetes insipidus, headaches, dizziness, seizures, blurred vision or loss of vision, difficulty walking, abnormal protrusion of eyeballs, difficulty swallowing or speaking, behavior changes, hot flashes, temperature variations, vomiting.
  • Mouth/Jaw/Gums
    Pain and swelling of face, loosening or loss of teeth, “floating” teeth, mouth ulcers, swollen or bleeding gums, swollen lymph nodes in neck.
  • Ears
    Loss of hearing, discharge from ear canal, redness, cysts.
  • Eyes
    Difficulty seeing, bulging of eyeballs.
  • Lymph Nodes (neck, groin, armpits)
    Enlargement, tenderness.  If the enlargement surrounds the respiratory area, it can result in cough, dyspnea, or turning blue.
  • Ovaries
    Pelvic pain, change in menstrual cycle.

The organs and tissues most commonly involved are the bones (including eye bones), skin, lymph nodes, bone marrow, lungs, hypothalamic-pituitary, spleen, liver and digestive tract.  Involvement of more than one system is common.  For example, bones can be affected alone or as part of multisystem disease.  Lymph nodes and skin involvement also can be either single-system disease or part of multisystem LCH.  Young infants with skin involvement should be followed closely by a knowledgeable physician, as some cases can spread to vital organs and quickly become life-threatening.  Central nervous system involvement (CNS), including the pituitary, is often part of systemic disease, although there are cases in which diabetes insipidus is the first presenting symptom.

It is important to remember that symptoms alone do not diagnose LCH, and a biopsy of an involved site is necessary.  Thus, it is important to consult a physician to receive an appropriate workup and accurate diagnosis.

Diagnosis and Treatment

The diagnosis of LCH is made following a biopsy of the affected tissue.  A small piece of the tissue is obtained so that it can be viewed under a microscope by a pathologist.  If the cells in the tissue have certain characteristics such as Birbeck granules (small tennis racket shaped membrane-bound granule) , and expression of specific proteins, the diagnosis of LCH can be made.  This procedure can be performed on any location but usually is done on the skin, bone, lymph nodes, liver, lung or bone marrow.

In addition, the following tests may be performed depending on particular symptoms in the child.

  • Physical examination and history: Recording of height, weight, temperature, pulse, family history, history of symptoms, past illnesses, etc.
  • Neurological examination: Testing of ability to walk, muscle testing, coordination, and cognition.
  • Complete blood count (CBC): Checking levels of red blood cells, white blood cells, and clotting cells.
  • Blood chemistry tests: Studies for kidney, coagulation, thyroid and immune function; abnormal level can be a sign of disease.
  • Liver function tests: Checking blood levels of substances released by the liver; an abnormal level can be a sign of disease in the liver.
  • Urinalysis: Testing the amount of red cells, white cells, protein and sugar in the urine.
  • Water deprivation test: Checks how much urine is made and whether it becomes concentrated when water is withheld; used when diabetes insipidus is suspected.
  • Bone marrow biopsy: The removal of bone marrow, blood and a small piece of bone by inserting a hollow needle into the hipbone; the sample is studied under a microscope to look for signs of LCH.
  • X-ray: Performed of the lungs or the bones to determine if there are abnormalities.
  • Bone scan: A scan for bone lesion in which a small amount of radioactive material is injected into a vein, collects in any abnormal parts of the bones and is shown on a scanner.
  • CT scan: For this x-ray dye may be injected into a vein or swallowed to help find any abnormalities; the scan takes a number of detailed pictures at different angles inside the body.
  • MRI: Using a substance called gadolinium injected into a vein to highlight areas of disease involvement, this scan then takes a number of detailed pictures inside the body.
  • PET scan: A small amount of radioactive sugar is injected into a vein, and diseased cells show up brighter on the scanner.
  • Ultrasound: High-energy sound waves are bounced off organs and tissue and make echoes, which form a picture of the internal body.
  • Endoscopy: When involvement of the digestive tract is suspected, a tube is passed into a body opening such as mouth or rectum to look at internal tissue; often, biopsies are also taken at the same time.

Treatment depends upon the individual patient and is planned after thorough testing to determine the extent of disease. In some cases with limited or single organ involvement, LCH may regress on its own without treatment. In others, minimal treatment such as steroids, NSAIDS (anti-inflammatory drugs), or even surgical removal will result in a positive outcome. Low-dose radiation may be helpful for some situations. In patients with more extensive disease, systemic chemotherapy is most often necessary. Several drugs and combinations have been shown in clinical trials to give excellent outcomes with minimal side effects. These drugs include steroids (prednisone), vinblastine, vincristine, etoposide (VP-16), methotrexate, cytosine arabinoside (Ara-C) and 6-MP. For patients with severe disease that progresses and is not responsive to initial treatment, chemotherapy with 2-CdA, alone or in combination with Ara-C, thalidomide or ultraviolet light (PUVA) for patients with only skin disease have been reported to have activity. Steroid or other types of creams may also help limited skin disease. In very rare cases, liver, lung, or even bone-marrow transplant has been necessary for recovery.

The goal of an overall treatment plan is to use as little treatment as possible to keep the disease under control and allow it to heal by itself.

Permanent Consequences

More recent advances in research and treatment of histiocytic disorders have provided a high survival rate for patients with this disease. At the same time, as more patients have been followed long-term, the risk for permanent consequences has become more obvious. It is now known that survivors can have significant consequences related to the disease and/or its treatment, sometimes following long-term remission. Most of these issues tend to be directly related to sites of original disease involvement and may affect quality of life. It is believed that more than half of patients will develop permanent consequences.

Also known as “late effects,” some consequences such as neurologic symptoms may not show up until 10 or more years after diagnosis, while other consequences such as diabetes insipidus can occur when histiocytosis is diagnosed, or even before. For this reason, “permanent consequences” has been suggested as a better term than “late effects.” Although some consequences such as tooth loss, bone defects, and scarring of the skin may be the result of surgical treatment, it is believed that the disease process itself is responsible for most of the effects.

Permanent consequences occur more often with multisystem patients but are also seen in patients with single-system disease at diagnosis. In one study, over 70% of multisystem LCH patients had one or more permanent consequences, compared to 24% of single-system patients. Children are more at risk to develop consequences because the disease can interfere with growth and development, and the consequences have a longer time to develop.

Some examples of permanent consequences include:

  1. Diabetes insipidus (DI)
  2. Stunted growth/failure to achieve sexual maturity
  3. Defects of bone/skull defects/facial asymmetry
  4. Loss of spinal height
  5. Loss of teeth/part of jawbone
  6. Bulging of the eyes
  7. Hearing loss
  8. Scarring of the skin
  9. Scarring of the liver
  10. Scarring of the lung
  11. Secondary cancers
  12. Neurologic/cerebellar problems, which can include:
    • Poor coordination/difficulty walking
    • Bad handwriting
    • Tremor/abnormal eye movements
    • Difficulty with balance/unsteadiness/clumsiness
    • Problems with speech and/or swallowing
    • Loss of short-term and/or long-term memory
    • Learning difficulty/poor school performance
    • Difficulties with concentration/attention/processing
    • Lower IQ score
    • Organizational difficulties
    • Behavior changes including aggression, eating disorders, depression, and difficulties with interpersonal relationships

The exact incidence of diabetes insipidus (DI) is not known, but it is believed to be in the range of 5% to 50% of LCH patients, depending on the location and extent of disease. The risk of developing DI in patients with multisystem LCH is 4 to 6 times greater than those with single-system disease. Patients with skull, facial, and/or eye bone lesions are at much higher risk of developing DI, and this risk is increased further if the disease remains active for a longer period or if it recurs. Although once established, diabetes insipidus cannot be cured, it can be successfully treated with a hormone called DDAVP.

Stunted growth is the most common endocrine abnormality and occurs in approximately 10% of children with histiocytosis. It was shown in one study to occur in 43% of patients who had diagnoses of both LCH and diabetes insipidus. Stunted growth can be successfully treated with daily injections of growth hormone, usually for as long as the child is growing. This treatment appears to be safe and effective and is not associated with an increased risk of disease reactivation.

Orthopedic problems from lesions of the spine, leg bones, and arm bones are one of the more common consequences and may be seen in 20% of patients. These problems include collapse of the vertebrae, instability of the spine that may lead to abnormal spinal curvature, decreased spinal height, fractured bones, and inequality of leg length. In addition, since the skull and facial bones are frequent sites of lesions, abnormalities and asymmetry of the face may occur. Some bone/facial abnormalities can be corrected by orthopedic or cosmetic surgery.

Dental problems with loss of teeth have been a significant problem for some patients, either directly related to disease affecting the jaw or related to aggressive surgery for jaw disease. The potential for restoration/cosmetic repair can be discussed with a knowledgeable physician. Residual eye bulging can affect one or both eyes. Hearing loss was found in one study to affect 16% of children treated for LCH. Of those with CT or MRI abnormalities of the mastoid, 59% had hearing loss. Inner ear involvement has been known to cause loss of balance. Hearing aids or surgically inserted electronic hearing devices (cochlear implants) may be necessary.

Liver disease may lead to scarring and destruction of the liver and, in rare cases, liver failure which may require transplantation. Lung disease is believed to occur in less than 10% of patients, causes scarring and damage of lung tissue, and can result in long-term poor lung function with a higher risk for infections, shortness of breath, and lung collapse. In cases of severe damage, a lung transplant may be necessary for survival. Permanent damage, however, is less common in children, whose lung tissue can more easily regenerate. Patients with a history of lung involvement may have a lifelong susceptibility to lung disease associated with cigarette smoking.

Patients with histiocytosis have a slightly higher chance of developing secondary cancers when compared to the unaffected population; secondary cancers could include leukemia, brain tumors, and cancer of the lung, liver, bone, lymph nodes, and eyes. It has not been determined whether this is caused by treatment or a genetic predisposition. Cancer can occur at the same time as histiocytosis or can occur years afterwards.

Neurologic problems with cognitive deficits, behavioral disturbances, and neuromotor dysfunction, also known as central nervous system (CNS) involvement, are reported to affect at least 10% of all LCH patients (19% of all multisystem patients). (For other histiocytic disorders, studies of greater numbers of patients are necessary to better define how often this occurs.) It is believed that this phenomenon is more frequently recognized now that more patients with histiocytosis are being followed long-term. It is characterized by symptoms in the brain that may not manifest until 10 or more years after initial diagnosis. Although this is usually seen on MRI scans, it may occur when there are no abnormal findings on MRI. The CNS complications can remain stable for years or can be progressive and become debilitating. No effective treatment has yet been developed; however, various forms of rehabilitation and teaching assistance can be helpful for these patients. These include assistance with learning and life skills; education about permanent consequences; teaching of repetition, reinforcement, and organizational skills; and placement of school/job accommodations. While the neurologic issues cannot be reversed, caregivers can provide tools that will help the patient increase his/her level of success.

In addition to compromised physical/cognitive function, histiocytosis survivors may experience quality-of-life issues such as anxiety/fear about possible relapse, sadness, anger, and depression. These feelings may be especially strong before follow-up visits, on illness-related anniversaries, or with onset of symptoms not related to the disease. For many people, these feelings will go away over time, while others may need psychological or psychiatric support. Finding a supportive network of other histiocytosis survivors can also be helpful.

  • On-line: You can subscribe to receive our emails so that you receive our newsletters, and you will also receive important announcements regarding the latest information and research developments on the histiocytic disorders. The Association also maintains a Facebook page and private Facebook group for families and patients with this disease.
  • Local support: The hospital where you or your child is being treated may have a support group for survivors of histiocytic disorders, rare diseases in general, or even cancer. Establishing face-to-face relationships with others going through similar experiences can be helpful.

Because of the possible impact of permanent consequences on school/job performance, ability to lead an independent life, and overall quality of life, it is important that the patient be evaluated and followed long term, especially those with multisystem disease. Early recognition of any deficit will be important, so that appropriate rehabilitation and assistance can be planned and put into place.

After years of research and discussion among researchers, there are still considerable gaps in the understanding of histiocytosis and its neurological complications. Some authorities believe it is a process separate from disease activity, and others believe that early, effective therapy may prevent or reduce the complications.

In order to make further progress in this field, the Histiocyte Society has developed a clinical trial/study called LCH-IV which opened for registration in 2012 and is on-going. This includes new guidelines for diagnosis and treatment of CNS LCH, including repeated MRIs, standardized neurologic evaluation, and neuropsychological tests for all patients with CNS disease. The study will test whether longer therapy for active disease will reduce the rate of reactivation and development of complications. You may consult your health care provider to find out about possible treatment options.

If you are a histiocytosis survivor with permanent consequences, it will be important to educate yourself about available resources and stay updated about the latest research findings. This information will help you make informed decisions and play an active role in acquiring the best support and services available. In doing so, you will create the best chance for a successful outcome.

FAQ

What Do I Do Now?

A new diagnosis of Langerhans cell histiocytosis (LCH) can bring feelings of being overwhelmed, bewildered, scared, angry, sad, disappointed, helpless, and sometimes even feelings of guilt.  It is a time filled with unknowns, change, and new people and situations.  Most parents feel ill-equipped to understand what is happening to their child and how to navigate through the illness to recovery.  There are, however, strategies and resources that can help you, your child, and other family members get through the uncertain times that lie ahead.  One step at a time, you can gather information, create a support system, learn how to cope with stress, and become a strong advocate for your child as part of the medical team.  The following tips and suggestions are provided to help guide you through this journey toward your child’s good health.

Printable Fact Sheets

Learn more about the different types of histiocytic disorders from these helpful fact sheets. Printing these for family and friends is a quick and easy way to teach them about the disease. More extensive information can be found in the Disease Information section of our website.

Choose from the following Fact Sheets: