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.
Summary
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia caused by alterations (mutations) of several genes in the MAPKinase pathway. Several important studies published from 2010 to 2016 have immensely clarified the biology of LCH. (Badalian-Very, Berres, Chakrobarty) 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 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. Children and 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).
Introduction
The preferred name for the condition is Langerhans cell histiocytosis because the cell of origin (LC) is now known.
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 failing treatment is approximately 15%. 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 incidences 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) 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 inability to walk or 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. 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. (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 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 involved. Pulmonary disease: high resolution CT. Brain: MRI. Diabetes insipidus: water deprivation test or serum and urine osmolality.
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) Topical ointments and PUVA are not very effective.
Central nervous system involvement (pituitary or other mass lesions) is treated with cytarabine or cladribine.
Neurodegenerative syndrome is treated with cytarabine or intravenous immunoglobulin.
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 or Clofarabine). (Simko 2015, Weitzman, Bernard, Simko 2014 Ped Blood Cancer)
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).
It is preferable that patients be treated on 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. Treatments vary depending on the extent of disease and involve chemotherapy with prednisone, velban with or without 6-mercaptopurine and methotrexate have been the standards for several decades and are still being studied by the Histiocyte Society in the LCH-IV trial. Texas Children’s Histiocytosis Center has a randomized trial comparing the efficacy of vinblastine and prednisone versus cytarabine in newly diagnosed patients. Those patients with liver, spleen, lung, or bone marrow involvement are considered to be of “higher risk” for not responding to therapy. Patients with lesions in multiple bones or more than one “non-risk” organ have an excellent chance for responding to combination chemotherapy. Mastoid, orbit, temporal and sphenoid bones represent a special group known as “CNS Risk” because of the high incidence of diabetes insipidus and subsequent anterior pituitary hormone deficiencies and neurologic involvement. The latter could mean mass lesions or a nerve damage leading to only changes on the MRI brain scan or neurologic problems such as ataxia, dysmetria, dysarthria, learning difficulties and psychologic problems.
Treatment with drugs which specifically inhibit cells containing mutations in the MAP2K pathway (vemurafenib, dabrafenib) are being used by various institutions and a clinical trial is being organized.
Contact the Histiocytosis Association of America for details of treatment protocols: 1-800-858-2758 or www.histo.org. or Kenneth McClain M.D. Ph.D. klmcclai@txch.org
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
Email: prpl@cc.nih.gov
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/
TEXTBOOKS
McClain KL, Allen CE. Inflammatory and Malignant Histiocytoses. In Williams Hematology, 9th Edition. Editors: Kenneth Kaushansky, Marshall A. Lichtman, MD, Ernest Beutler, MD, PhD, Thomas J. Kipps, MD, PhD, Uri Seligsohn, and Josef Prchal, MD., McGraw-Hill Companies (McGraw-Hill), 2016.
McClain KL, Allen CE, Hicks MJ. The Histiocytoses. In Principles and Practices of Pediatrics 7th Edition. Oncology, Pizzo and Poplack eds. (Lippincott Williams & Wilkins) 2016.
McClain KL. Langerhans Cell Histocytosis in Children and Adults. Wellesley, MA. in: UpToDate. B.D. Rose, ed. UpToDate 2016.
JOURNAL ARTICLES
Allen CE, Li L, Peters TL et al. Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J.Immunol. 2010;184:4557-4567.
Allen CE, Ladisch S, McClain KL. How I treat Langerhans cell histiocytosis. Blood 2015;126:26-35.
Badalian-Very G, Vergilio JA, Degar BA et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010;116:1919-1923.
Berres ML, Lim KP, Peters T et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J.Exp.Med. 2014;211:669-683.
Cantu MA, Lupo PJ, Bilgi M et al. Optimal therapy for adults with Langerhans cell histiocytosis bone lesions. PLoS.One. 2012;7:e43257.
Chakraborty R, Hampton OA, Shen X et al. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 2014;124:3007-3015.
Diamond EL, Dagna L, Hyman DM et al. Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease. Blood 2014;124:483-492.
Donadieu J, Rolon MA, Thomas C et al. Endocrine involvement in pediatric-onset Langerhans’ cell histiocytosis: a population-based study. J Pediatr 2004;144:344-350.
Gadner H, Minkov M, Grois N et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 2013;121:5006-5014.
McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007.
Mittheisz E, Seidl R, Prayer D et al. Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 2007;48:50-56.
Phillips M, Allen C, Gerson P, McClain K. Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis. Pediatr.Blood Cancer 2009;52:97-101.
Prosch H, Grois N, Prayer D et al. Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis. Pediatr Blood Cancer 2004;43:594-599.
Ribeiro KB, Degar B, Antoneli CB, Rollins B, Rodriguez-Galindo C. Ethnicity, race, and socioeconomic status influence incidence of Langerhans cell histiocytosis. Pediatr.Blood Cancer 2015;62:982-987.
Ronceray L, Potschger U, Janka G, Gadner H, Minkov M. Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome. J.Pediatr. 2012;161:129-133.
Simko SJ, Garmezy B, Abhyankar H et al. Differentiating skin-limited and multisystem Langerhans cell histiocytosis. J.Pediatr. 2014;165:990-996.
Simko SJ, Tran HD, Jones J et al. Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease. Pediatr.Blood Cancer 2014;61:479-487.
Simko SJ, McClain KL, Allen CE. Up-front therapy for LCH: is it time to test an alternative to vinblastine/prednisone? Br.J.Haematol. 2015;169:299-301.
Vassallo R, Ryu JH, Colby TV, Hartman T, Limper AH. Pulmonary Langerhans’-cell histiocytosis. N.Engl.J Med 2000;342:1969-1978.
Weitzman S, Braier J, Donadieu J et al. 2′-Chlorodeoxyadenosine (2-CdA) as salvage therapy for Langerhans cell histiocytosis (LCH). results of the LCH-S-98 protocol of the Histiocyte Society. Pediatr.Blood Cancer 2009;53:1271-1276.
Wnorowski M, Prosch H, Prayer D et al. Pattern and course of neurodegeneration in Langerhans cell histiocytosis. J.Pediatr. 2008;153:127-132.
Zinn DJ, Grimes AB, Lin H et al. Hydroxyurea: a new old therapy for Langerhans cell histiocytosis. Blood 2016;128:2462-2465.
INTERNET
National Cancer Institute: General Information About Langerhans Cell Histiocytosis (LCH) Updated: October 3, 2016. http://www.cancer.gov/cancertopics/pdq/treatment/lchistio/Patient Accessed January 5, 2017.
Shea CR. Langerhans Cell Histiocytosis. Medscape. Updated: Feb 8, 2016. http://emedicine.medscape.com/article/1100579-overview Accessed January 5, 2017
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