August 30, 2021
Years published: 1987, 1989, 1992, 2002, 2003, 2004, 2007, 2009, 2012, 2017, 2021
NORD gratefully acknowledges Kenneth L. McClain, MD, PhD, Professor of Pediatrics, Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine, for assistance in the preparation of this report.
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia caused by alterations (mutations) of several genes in the MAPKinase pathway (MAPK). Important studies published from 2010 to 2021 have immensely clarified the biology of LCH. (Allen, Badalian-Very, Berres, Chakrobarty, Hogsted, Biggenwald) The cell of origin is a white blood cell known as a dendritic cell, although the historic designation of histiocyte is still used. (Allen 2010) The mutations BRAFV600E, MAP2K, and others) cause these dendritic cells to attract other white blood cells (lymphocytes, macrophages, and eosinophils) and cause a “lesion” in any organ of the body except the heart and kidneys. The mutation creates biologic changes in the histiocytes which prevent cell death and cause the disease cells to stay in a lesion. (Hogsted) These cells are also resistant to chemotherapy because of senescence (a “slumber-like state) (Biggenwald). Lymphocytes gathered in the lesions are ineffective at fighting malignant cells and also blunt the effect of chemotherapy. (Sengal) Children or adults may have LCH in skin (macular, papular, ulcerative, or seborrheic rashes), bones (painful lytic lesions), lymph nodes, brain (pituitary, cerebrum and cerebellum) lung, liver, spleen, and bone marrow. Systemic symptoms may include fever, bone pain, weight loss, draining ears, jaundice, diabetes insipidus or other diseases of the endocrine glands and malaise (a general feeling of ill-health).
The preferred name for the condition is Langerhans cell histiocytosis as the dendritic cell which causes the disease has microscopic and cell surface characteristics like the dendritic Langerhans cell in the skin.
LCH is a disorder presenting in either single or multiple locations and thus causing a variety of signs and symptoms from mild to life-threatening. Single system presentations may be exclusively in the skin, bone, pituitary, or lungs. Patients affected in multiple systems most often have skin and bone involvement with any combination of other sites. When the liver, spleen, and bone marrow are involved, these patients are given the designation “high risk” which means the chance of death is approximately 15%. All patients with LCH in sites other than the bone marrow, spleen, and liver can be cured. (Gadner, Allen 2015)
Bone involvement in children or adults presents as painful areas which may be swollen. In children, the skull is most often affected, followed by long bones of the upper and lower extremity, ribs and spine. When the temporal bones or mastoids are affected the patient may lose their hearing. These patients may present with pus draining from the ears and thought to have an infection. Other complications include fractures of long bones and compression of vertebrae causing extreme pain and possibly spinal cord damage. LCH in the mastoid, orbital, sphenoid and temporal bones are considered “CNS Risk” because of increased incidence of pituitary and brain involvement. Jaw involvement in children may result in early eruption of teeth as well as swollen and bleeding gums. Adults are more likely to have lesions in the mandible and maxilla with resulting loss of teeth.
Patients may have skin involvement with extensive seborrhia-like rashes on the scalp that mimic persistent cradle cap; an erythematous papular rash similar to Candida diaper rash; or deep ulcerative lesions in the groin or arm pits or purplish-brown lesions 3-6mm in diameter which are often mistaken for a viral infection. Many adult female patients have ulcerative lesions in the genitalia. LCH lesions on the tongue, gums, and inside the cheeks can resemble cold sores. It is very important that children presenting with skin LCH have a complete evaluation to ensure there is no other disease site. (Simko 2014 J.Peds.) Infiltration of the liver and spleen causes massive abnormal enlargement of organs (organomegaly). Liver dysfunction causes hypoproteinemia with swelling of the arms and legs or abdomen. Patients may also have jaundice (yellow color to the skin and the white part of the eyes). Lymph nodes in the cervical, axillary, and inguinal areas are most often affected, but mediastinal nodes may enlarge causing wheezing and respiratory compromise.
Lung involvement results in rapid breathing and leakage of air around the lung (pneumorthorax). (Vassalo, Ronceray) Pulmonary LCH is more prevalent in adults because of the association with smoking. Coughing up blood (hemoptysis) is rare. Intestinal infiltration leads to crampy pain and diarrhea, often with blood in it.
LCH in the bone marrow causes pancytopenia, but thrombocytopenia is often the most obvious problem with bleeding and anemia that may be exacerbated by an enlarged spleen.
Endocrine abnormalities from LCH include excessive thirst and urination caused by damage to the back part of the pituitary gland. (Donadieu 2004) This condition is known as diabetes insipidus. (Prosch) If the front part of the pituitary gland is damaged by LCH, the patient may have low levels of thyroid hormone, growth hormone, adrenal stimulating hormone and the hormones that lead to sexual maturation.
Patients with cerebellar involvement present with difficulty walking or with balance (ataxia), tremors of their hands with difficulty writing (dysmetria), trouble speaking (dysarthria) as well as difficulty learning and having abnormal behaviors. (Wnorowski), Mittheisz)
LCH is caused by mutations in a cell signaling pathway known as the MAPKinase pathway. Key genes mutated in this pathway include BRAF (65-70%), MAP2K (20%), and other rarer genes, all of which lead to abnormal activation of a gene known as ERK. (Durham) These mutations are “genetic accidents” which occur during DNA copying in dendritic cells and are not inherited. The maturation stage of the dendritic cell will determine what type of disease a patient will develop. If the mutation occurs when the dendritic cell is still in stem cell stage, this early precursor may go to any organ in the body-especially liver, spleen and bone marrow. Mutation in a more mature dendritic cell will lead to LCH in a variety of organs, but not the “high risk” ones mentioned before. An even more mature dendritic cell carrying this mutation may go to only skin and bone.
Family members of LCH patients have a higher incidence of thyroid disease. Smoking is strongly associated with lung LCH.
Hispanics have a higher incidence of diffuse LCH involvement and Blacks are less affected than Whites. (Riberio) The overall incidence of LCH is between 4 and 9 cases per million with males slightly more affected than females (1.2:1) and the highest number of cases presenting in the first four years of life. The incidence is adults is not known, but may be 1-2 per million.
The diagnostic work-up may include X-rays of the skull, a complete skeletal bone survey and PET scan, chest x-ray, complete blood count and differential, erythrocyte sedimentation rate, liver function tests including AST, ALT, bilirubin, and albumin; electrolytes and urinalysis. (Phillips) CT of the skull if mastoids, orbits, or sphenoid are involved. Pulmonary disease: high resolution CT. A brain MRI is needed for patients with pituitary or suspicion of other brain lesions. When symptoms of diabetes insipidus occur, a water deprivation test or serum and urine osmolality is required.
Single bone lesions (not in the CNS risk group) are treated with surgery alone or with injection of steroids.
CNS Risk bone lesions are treated with Velban and prednisone or cytarabine alone.
Multifocal bone or multifocal low risk lesions are treated with Velban/prednisone or cytarabine alone (Gadner, Simko 2015).
Multifocal High Risk lesions are treated with Velban/prednisone/6MP or cytarabine alone.
If only skin lesions are present and not extensive, treatment may not be necessary. If treatment is needed, hydroxyurea alone or with methotrexate is very effective. (Zinn) Oral methotrexate or thalidomide are also used (McClain 2007). Topical ointments and PUVA are not very effective.
Central nervous system involvement (pituitary or other mass lesions) is treated with cytarabine, cladribine, or MAPK inhibitors (McClain 2018).
Neurodegenerative syndrome is treated with cytarabine or MAPK inhibitors (McClain 2018).
If a patient does not respond to the standard therapy by the sixth week (or twelfth week for a partial response) they should be changed to the salvage therapy (Cytarabine, Cladribine, Cladribine/cytarabine, Clofarabine, or a MAPK inhibitor) (Simko 2015, Weitzman, Donadieu 2015, Simko 2014 Ped Blood Cancer, Eckstein).
Adults should not be treated with Velban and prednisone because these drugs are not effective and cause excessive toxicity. Cytarabine has been shown to be a better therapy and cladribine has also been effective (Cantu). Oral hydroxyurea with or without oral methotrexate has been effective in treating skin and bone LCH, with special efficacy for vaginal lesions (Zinn).
RDD patients are treated with a variety of chemotherapy agents including cladribine, clofarabine, and the MAPK inhibitors (Simko 2014 Ped. Blood Cancer, Diamond 2019).
JXG patients may be observed when having only a modest number of skin lesions as they may spontaneously resolve. Patients with organ involvement or massive numbers of skin lesions respond to treatment with clofarabine and the MAPK inhibitors (Simko 2014 Ped. Blood Cancer, Diamond 2019.)
Treatment of ECD patients is now primarily with BRAF or MAPK inhibitors.(Haroche, Diamond 2018) Some patients are successfully treated with alpha interferon or anakinra (Arnaud, Cohen-Aubert).
It is preferable that patients be treated in clinical trials so the biology and therapy of these rare patients can be advanced. The Histiocyte Society, the Children’s Oncology Group, and the North American Consortium for Histiocytosis sponsor these trials as well as some individual centers such as Texas Children’s Cancer and Hematology Centers in Houston, TX. Treatment with drugs which specifically inhibit cells containing mutations in the MAPK pathway (vemurafenib, dabrafenib, trametinib, cobimetinib) are being used by various institutions in clinical trials.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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