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 a spectrum of rare disorders characterized by overproduction (proliferation) and accumulation of a specific type of white blood cell (histiocyte) in the various tissues and organs of the body (lesions). The lesions may include certain distinctive Langerhans cells involved in certain immune responses, as well as other white blood cells (e.g.,lymphocytes, monocytes, eosinophils). Associated symptoms and findings may vary from case to case, depending upon the specific tissues and organs affected and the extent of involvement. Most often the bone lesions are painful. Skin rashes may itch or cause painful ulcers especially under the arms or groin area. The pathogenesis (medical cause) is not clearly understood and an ongoing debate continues regarding its cause as a reactive immunologic or neoplastic (cancer-like) process. No infectious agent (virus, bacteria, or fungus) has been associated with LCH. Patients often have a strong family history of immune diseases such as thyroid disease, arthritis, or lupus.
Most affected individuals have single or multiple bone lesions characterized by lytic lesions (holes in the bones). Although the skull is most commonly affected, there may also be involvement of other bones, such as those of the spine (vertebrae) and the long bones of the arms and legs. Affected individuals may have no apparent symptoms (asymptomatic), or may experience associated pain and swelling, and/or develop certain complications, such as fractures or secondary compression of the spinal cord. Other organs may also be affected, including the skin, lungs, liver, spleen, bone marrow, thymus, thyroid,intestines and brain. In some individuals, LCH may be associated with involvement of the pituitary gland leading to diabetes insipidus, growth failure, hypothyroidism, or insufficitne production of sex hormones.
Langerhans cell histiocytosis was selected by the Histiocyte Society to replace the older, less specific term histiocytosis X. Histiocytosis X encompassed three entities known as eosinophilic granuloma, Hand-Schuller-Christian disease, and Letterer-Siwe disease that were characterized by the accumulation of histiocytes. The "X" denoted that the cause and development of the disorder was not understood. Langerhans cell histiocytosis was chosen because it seemed that the Langerhans cells might play a central role in the development of these disorders. However, new research (Allen 2010) has shown that the skin Langerhans cell is not the cell of origin, but a myeloid dendritic cell.
Langerhans cell histiocytosis represents a spectrum of disorders whose symptoms and physical features vary greatly from case to case. Affected individuals will not have all of the symptoms detailed below. Some affected individuals may exhibit no symptoms (asymptomatic); others may experience severe, life-threatening complications.
The severity of LCH depends upon the specific tissues and organs affected and the extent to which they are affected. Individual cases of LCH are classified into two separate groups: unifocal or single-system, if only one specific area of the body is affected, and multifocal or multisystem, if more than one area of the body is affected.
General symptoms associated with LCH may include fevers, headaches, a general feeling of ill health (malaise), weight loss, and fatigue.
Most individuals with LCH develop single or multiple bone lesions (eosinophilic granulomas) caused by the abnormal accumulation of Langerhans cells, lymphocytes, macrophages, and eosinophils. In some cases, these lesions may not be accompanied by any symptoms (asymptomatic). However, in most cases, the lesions are associated with bone pain and swelling of adjacent tissue. The skull, spine, and long bones of the arms and legs are most often affected. Secondary complications may also occur including spontaneous fractures of the long bones or vertebral collapse and compression of the spinal cord. In some cases, structures in the ear may be affected, potentially resulting in degeneration of certain bones in the ear. In such cases, middle ear infections (otitis media) and the abnormal discharge of pus often occur. In severe cases, deafness may result. In some cases the mouth and jaw may be affected, potentially resulting in pain and swelling of the face, loose teeth, and swollen, bloody gums.
LCH may affect the lungs. Some affected individuals will not have any symptoms or may experience chest pain, coughing up of blood (hemoptysis), and difficulty breathing (dyspnea). In severe cases, the formation of fibrosis tissue (fibrosis) in the lungs and a collapsed lung (pneumonthorax) may occur. In rare cases, life-threatening respiratory failure may occur. Cases of LCH that affect the lungs may be referred to as pulmonary eosinophilic granuloma or pulmonary Langerhans cell histiocytosis. Isolated pulmonary LCH may occur in some teen-agers and adults who smoke regularly.
LCH may also affect the skin and, in many cases, skin lesions are the first sign of the disorder. Affected individuals may develop small solid reddish-brown elevations on the skin (papules), or knots visible under the skin (nodules). A red, scaly rash is characteristic in many cases. In some cases, these growths may develop into swollen open sores (ulcerations). The scalp is the site most often affected. The LCH rash may look like a staphyloccocal bacterial infection, psoriasis, eczyma, or a viral rash.
LCH may also affect other systems of the body including the gastrointestinal (GI) tract, central nervous system, bone marrow, liver, spleen, and endocrine system, especially the pituitary gland. Involvement of the liver and spleen may lead to abnormal enlargement of these organs (hepatosplenomegaly). Involvement of the liver may result in yellowing of the skin and the whites of the eyes (jaundice). When the intestines are involved the patient will have abdominal pain, vomiting, or diarrhea. Involvement of the central nervous system may result in tremors, difficulties coordinating voluntary muscle movements (ataxia), dizziness, difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and mental deterioration. Involvement of the pituitary gland may result in diabetes insipidus, a metabolic condition in which insufficient secretion of antidiuretic hormone (ADH) by the pituitary gland leads to passing of large amounts of dilute urine (polyuria) and excessive thirst (polydipsia). (ADH normally reduces the amount of water lost in urine. The pituitary gland produces several hormones, including ADH; it is controlled by, and connected to, a region of the brain called the hypothalamus.) In some cases, pituitary gland involvement may result in delayed or precocious puberty and/or growth deficiency, resulting in short statute.
Hashimoto-Pritzker disease is an old term used to describe a specific form of LCH that occurs in newborns or young infants. This form of LCH is characterized by the formation of numerous reddish-brown skin lesions (papules or nodules) or sac-like lesions (vesicles). In some cases, these growths may develop into ulcerations. The face, limbs, palms and soles are most often affected. These skin lesions usually heal without treatment within a few weeks or months. These cases may also be referred to as congenital self-healing histiocytosis or pure cutaneous histiocytosis, but these patients must be followed by an experience physician very carefully since 50% will develop LCH in other sites.
Letterer-Siwe disease is an old term used to describe a severe form of LCH that occurs in some infants and is characterized by bony lesions affecting the skull and several organ systems of the body, including the skin, lungs, enlargement of the liver, spleen, and lymph nodes (hepatosplenomegaly and lymphadenopathy) may also occur. Affected infants may also experience an abnormal decrease in the number of blood platelets (thrombocytopenia) and low levels of circulating red blood cells (anemia) when the bone marrow is involved. In some cases, secondary complications of this condition may result in life-threatening complications such as multi-organ failure. This form of LCH may also be known as acute disseminated Langerhans cell histiocytosis.
Hand-Schuller-Christian disease is an old term used to describe multifocal LCH occurring in association with diabetes insipidus and protrusion or bulging of the eyeballs (exophthalmos). In these cases, multiple bony lesions most often affect the skull and they often have diabetes insipidus.
The exact cause of Langerhans cell histiocytosis is unknown. The Langerhans cell is a normal cell that responds to a variety of immune system stimuli. Possible causes also include infections or immune system abnormalities, but these theories have not been proven. Environmental factors have not been shown to be involved. There is an increased incidence of thyroid disease in families of LCH patients.
In rare cases more than one case of LCH has appeared in the same family, although no clear inheritance pattern has been identified.
Cigarette smoking may be associated with the development of some cases of pulmonary LCH. The exact role smoking plays in the development of pulmonary LCH is not completely understood.
Langerhans cell histiocytosis affects males more often than females. The disorder may affect individuals of any age, but most often occurs in children. The estimated incidence of LCH in childhood ranges from 3.5 to 7 cases per million each year. The estimated incidence of LCH in the general population ranges from 5 to 5.4 per million each year. LCH appears to occur with greater frequency among Caucasians.
The most severe form of LCH (acute disseminated LCH) most often occurs in children under two years of age. Unifocal LCH occurs most often in children between five and 15 years of age. Isolated pulmonary LCH occurs most often in teen-agers and adult who smoke heavily.
A diagnosis of LCH may be suspected from a thorough clinical evaluation and a detailed patient history. A diagnosis may be confirmed by surgical removal and microscopic examination of affected tissue (biopsy). More tests, such as additional biopsies, blood tests, x-rays of the chest, and CT scans are performed to determine the extent of the disease.
Treatment
The treatment of LCH is directed toward the specific symptoms that are apparent in each individual. In some individuals with unifocal LCH (i.e., bony lesions affecting one site or organ system), symptoms of LCH rarely improve without treatment (spontaneous remission). Non-steroidal anti-inflammatory drugs (NSAIDS) such as indomethacin may be used to relieve pain and reduce inflammation of areas affected by bony lesions, but specific therapy for the disease as noted below is best.
Patients should be enrolled in clinical trials of the Histiocyte Society to ensure optimal treatment and add to our knowledge of this disease. There are specific treatment recommendations for children with liver, lung, spleen, and bone marrow involvement (multi-system High Risk) as well as those with combinations of lymph node, skin, bone, intestine, and pituitary involvement (multisystem Low Risk) as well as those with multiple bone lesions. Mastoid, orbit, and temporal bone lesions represent a special group known as "CNS-Risk" because of the high incidence of diabetes insipidus and subsequent anterior pituitary hormone deficiencies and other neurologic involvement. The latter refers to mass lesions (tumors) and a demyelinating syndrome (neurodegenerative syndrome) that may present with only radiologic findings on MRI or progress to clinical signs of ataxia (trouble walking or balance problems) dysmetria (trouble writing), speech and learning difficulties. For these reasons chemotherapy with velban and prednisone for 6-12 months is the preferred treatment. Intralesional injections of steroids or surgical excision of single bony lesions may be necessary and could be sufficient therapy for lesions other than the "CNS-Risk" group. Low-dose local radiation may also be used to treat unifocal LCH. Topical steroids, oral methotrexate, and oral thalidomide may be used to treat skin lesions associated with LCH. Skin lesions may also be treated with topical nitrogen mustard or a procedure known as phototherapy with psoralen and ultraviolet irradiation (PUVA).
Standard therapies which have been used for treatment of LCH:
– Velban/prednisone 1 year of therapy for children (NOT adults) (Minkov)
– 2-CdA (2-chlorodeoxyadenosine) Children for second line therapy when only bones, skin, pituitary or brain are involved. Adults first or second line therapy for same locations (Weitzman, Dhall)
– Cytarabine at 100mg/m2. Children (with vincristine for second line therapy). Adults as primary therapy (Egeler)
– 2-CdA/Cytarabine at high doses for second line treatment of children and adults with "high risk" organ involvement: liver, spleen, bone marrow
(Berard)
– Cytarabine 150mg/m2 for neurodegeneative central nervous system LCH (Allen)
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 website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Research involving Langerhans cell histiocytosis (LCH) is being conducted in the United States by Dr. Kenneth McClain at Texas Children’s Cancer Center, Houston, TX. Phone: (832) 822-4208 Email: klmcclai@txch.org
Several centers in the United States offer treatment with the Histiocyte Society Clinical trials as well as stem cell transplant. Consult the Histicytosis Association of America for their locations.
Researchers have studied the drug pamidronate for the treatment of individuals with LCH who were unresponsive to other forms of treatment. Some reports show that treatment with the drug has resulted in pain relief and regression of lesions in a few individual cases. More research is necessary to determine the long-term safety and effectiveness of pamidronate for the treatment of LCH.
2-chlorodeoxyadenosine (2CDA) and cytosine arabinoside (ARA-C) have been investigated for the treatment of individuals with LCH who were unresponsive to other forms of treatment or in which the disorder recurred. Individual case reports and a phase II clinical trial have demonstrated positive initial results. More research is necessary to determine the long-term safety and effectiveness of 2-chlorodeoxyadenosine alone or incombination with ARA-C for the treatment of individuals with LCH.
Thalidomide has been studied as a possible treatment for LCH and some success has been reported. Extreme caution must be used in the administration of thalidomide, since this medication may interfere with normal fetal development during pregnancy (teratogen), potentially causing severe birth defects. Further studies are needed to determine the long-term safety and effectiveness of this drug in the treatment of LCH. For more information, contact:
Celgene Corporation
7 Powder Horn Dr.
Warren, NJ 07059
Phone (732) 271-1001
Toll-free info on Thalidomide: (888) 423-5436
Website: www.celgene.com
TEXTBOOKS
McClain KL. Langerhans Cell Histocytosis in Children and Adults. Wellesley, MA. Langerhans Cell Histiocytosis in Adults and Children in: UpToDate. B.D. Rose, ed. UpToDate 2011.
McClain KL, Allen CE. Inflammatory and Malignant Histiocytoses. In Williams Hematology, 8th 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), 2010.
McClain KL, Allen CE, Hicks MJ The Histiocytoses. In Principles and Practices of Pediatrics Oncology,Pizzo and Poplack eds. (Lippincott Williams & Wilkins) 2010.
McClain KL. Langerhans Cell Histiocytosis. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:392-93.
JOURNAL ARTICLES
Allen CE, Leung HCE,Yu A, Man TK, Gurusiddappa S, Peters TL, Phillips M, HicksMJ, Merad M, and McClain KL. Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared to epidermal Langerhans cells. Journal of Immunology. 2010;184:4557-67.
Allen CE, Flores R, Rauch R, Dauser R, Murray JC, Puccetti D, Hsu D, Hetherington M, Goldman S, Sondel P, McClain KL. Neurodegenerative Central Nervous System Langerhans Cell Histiocytosis and Coincident Hydrocephalus: Treated with Vincrisitne Cytosine Arabinoside Treatment. Pediatr Blood Cancer 2010;54:416-23.
Phillips, M., Allen, C., Gerson, P., and McClain, K. Comparison of FDG-PET Scans to Conventional Radiography and Bone Scans in Management of Langerhans Cell Histiocytosis. 2008;52(1):97-101.
Wnorowski M, Prosch H, Prayer D, et al. Pattern and Course of Neurodegeneration in Langerhans Cell Histiocytosis. J Peds 2008;153(1):127-32.
Gadner H, Grois N, Potschger U, et al. Improved outcome in multisystem Langerhans cell histiocytosis is associated with theapy intensification. Blood. 2008;111:2556-2562.
Senechal B, Elain G, Jeziorski E et al.: Expansion of regulatory T cells in patients with Langerhans cell histiocytosis. PLoS Med. 2007;4(8):e253.
McClain KL, Li L, and Kozinetz C: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer. 2007;48(1):44-49.
Grois N, Potschger U, Prosch H et al.: Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr Blood Cancer. 2006;46(2):228-233.
Lau L, Krafchik B, Trebo MM et al.: Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer. 2006;46(1):66-71.
Weitzman S, McClain KL, Arceci R: Salvage Therapies for Langerhans Cell Histiocytosis, in Egeler RM, Weitzman S (eds): Histiocytic Disorders of Children and Adults. Cambridge, Cambridge Press. 2005;254-271.
Bernard F, Thomas C, Bertrand Y et al.: Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction. Eur J Cancer. 2005; 41(17):2682-2689.
Braier J, Latella A, Balancini B, et al. Outcome in children with pulmonary Langerhans cell histiocytosis. Pediatr Bloood Cancer. 2004;43:765-769.
Prosch H, Grois N, Prayer D et al.: Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis. Pediatr Blood Cancer. 2004;43(5):594-599.
Donadieu J, Rolon M-A, Thomas C. et al. Endocrine Involvement in Pediatric-Onset Langerhans’ Cell Histiocytosis: A Population-Based Study. J Pediatr. 2004;144:344-50.
Nanduri VR, et al. Cognitive outcome of long-term survivors of multisystem langerhans cell histiocytosis: a single-institution, cross-sectional study. J Clin Oncol. 2003;21:2961-67.
Vassallo R, et al. Clinical outcomes of pulmonary Langerhans’ cell histiocytosis in adults. N Engl J Med. 2002;346:484-90.
Gadner H, et al. A randomized trial of treatment for multisystem Langerhans’ cell histiocytosis. J Pediatr. 2001;138:728-34.
Farran RP, et al. Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol. 2001;23:54-56.
Egeler RM, de KJ, and Voute PA: Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol. 1993;21(4):265-270.
INTERNET
National Cancer Institute: General Information About Langerhans Cell Histiocytosis (LCH) Last Modified: 1/10/12 http://www.cancer.gov/cancertopics/pdq/treatment/lchistio/Patient Accessed February 7, 2012.
Shea CR. Langerhans Cell Histiocytosis. Updated October 29, 2010. http://emedicine.medscape.com/article/1100579-overview Accessed February 7, 2012.
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