Information on the following diseases can be found in the Related Disorders section of this report:

• Rosai-Dorfman Disease
• Mastocytosis
• Erdheim-Chester Disease
• Seborrheic Dermatitis
• Lymphoma
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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 and eosinophils. In some cases, these lesions may be not by accompanied by any symptoms (asymptomatic). However, in most cases, the lesions are associated with bone pain and swelling of adjacent tissue. In many cases, loss of the calcium of bone (osteolysis) may also occur. 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 occur. 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. In the past, the term eosinophilic granuloma or eosinophilic granuloma of bone was used to describe individuals with these distinctive bone lesions.

In some cases, bony lesions may affect the lungs. Some affected individuals will not have any symptoms. However, affected individuals 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 sacs containing pus (vesicles), 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 characteristic lesions associated with LCH may also affect other systems of the body including the gastrointestinal (GI) tract, central nervous system, liver, spleen, and endocrine system, especially the pituitary gland. Involvement of the GI tract may result in yellowing of the skin and the whites of the eyes (jaundice), abdominal pain, vomiting, and 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 liver and spleen may lead to abnormal enlargement of these organs (hepatosplenomegaly).

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
A specific form of LCH may occur 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.

LETTERER-SIWE DISEASE
A severe form of LCH occurs in some infants and is characterized by bony lesions affecting the skull and several organ systems of the body, including the skin, lungs, and central nervous system. Abnormal 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). In some cases, secondary complications of Letter-Siwe disease 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
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. In affected individuals with this form of LCH, bony lesions may also affect the liver, spleen, and lymph nodes.
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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 may play a role.

Researchers at the Children’s Hospital of Philadelphia studied 35 children diagnosed with LCH and determined that the human herpesvirus 6 (HHV-6) was present in 25 of 35 tissue samples. However, more research is necessary to determine what role, if any, HHV-6 plays in the development of LCH in some children.

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.
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Symptoms of the following disorders can be similar to those of Langerhans cell histiocytosis. Comparisons may be useful for a differential diagnosis:

Rosai-Dorfman disease is a rare disorder characterized by histiocytosis affecting the sinuses and the lymph nodes, resulting in abnormal enlargement of the lymph nodes (lymphadenopathy). In some cases, other organ systems of the body may be affected including the central nervous system, skin, and, in rare cases, the kidney or other areas. The exact cause of Rosai-Dorfman disease is unknown. The disorder may also be known as sinus histiocytosis with massive lymphadenopathy. (For more information on this disorder, choose "Rosai-Dorfman" as your search term in the Rare Disease Database.)

Mastocytosis is a rare disorder characterized by abnormal accumulation of mast cells in skin, bone marrow, and internal organs such as the liver, spleen and lymph nodes. The skin abnormalities associated with mastocytosis are known as urticaria pigmentosa and are characterized by small, brownish, flat or elevated spots (lesions) that may be surrounded by reddened, itchy skin. In many cases, only the skin is involved. However, the disorder may also affect various organ systems resulting in abnormally enlarged liver and spleen (hepatosplenomegaly); gastrointestinal problems such as abdominal pain and diarrhea; and cardiovascular problems such as high blood pressure (hypertension). In some cases, bones may be affected resulting in bone pain and fractures. The exact cause of mastocytosis is unknown. (For more information on this disorder, choose "Mastocytosis" as your search term in the Rare Disease Database.)

Erdheim-Chester disease (ECD) is a rare multisystem disorder of adulthood. It is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. Histiocytes are large phagocytic cells (macrophages) that normally play a role in responding to infection and injury. (A phagocytic cell is any "scavenger cell" that engulfs and destroys invading microorganisms or cellular debris.) In those with ECD, sites of involvement may include the long bones, skin, tissues behind the eyeballs, lungs, brain, pituitary gland, and/or additional tissues and organs. Associated symptoms and findings and disease course depend on the specific location and extent of such involvement. The specific underlying cause of ECD is unknown. (For more information on this disorder, choose "Erdheim-Chester" as your search term in the Rare Disease Database.)

Seborrheic dermatitis is a skin disorder characterized by reddish, scaly patches affecting the scalp. The disorder may spread to affect the neck, face, and other areas of the body. Individuals with LCH that present with skin symptoms may be misdiagnosed with seborrheic dermatitis. The exact cause of seborrheic dermatitis is not known.

Lymphoma is a general term for cancer affecting the lymphatic system. Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. Abnormal enlargement of the lymph nodes, liver, and spleen may occur. A malignant lymphoma may spread to affect other areas of the body such as the central nervous system and gastrointestinal tract. Affected individuals may experience fevers, fatigue, and weight loss. Some cases of Letterer-Siwe disease may mimic some forms of malignant lymphoma.

Diagnosis
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 may 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.

In some cases, intralesional injections of steroids or surgical excision of bony lesions may be necessary. Low-dose local radiation may also be used to treat unifocal LCH. Topical steroids 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).

Therapy with certain anticancer drugs (chemotherapy), sometimes in combination with steroids, may be recommended for individuals with LCH that affects multiple organ systems. Chemotherapy may be used in individuals with unifocal LCH who are unresponsive to other treatment.

There is no specific chemotherapeutic regimen accepted as best for treating individuals with LCH. Clinical trials have been performed to determine the effectives of different chemotherapeutic regimens such as treatment with vinblastine and etoposide alone or in combination with a specific corticosteroid (i.e., prednisolone) or vinblastine and mercaptopurine with prednisolone. More research is necessary to determine the most effective chemotherapeutic regimens for individuals with LCH.

Individuals who only experience skin symptoms associated with LCH should receive regular examinations since skin lesions often occur before other symptoms associated with LCH. In addition, skin lesions may clear up but return later during life along with additional LCH symptoms.

Other treatment is symptomatic and supportive.
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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. Cooperative treatment groups in Germany/Austria and Italy have also studied various treatment procedures. The use of immune system modulators and bone marrow transplantations are currently being investigated as a possible treatment for this disorder. More research is necessary before these therapies can be recommended.

The drug etanercept (Enbrel) is currently (2004) in a phase II trial for LCH. It is being investigated as an alternative treatment option for patients whose disease has failed to respond to standard therapy. For information, use the previously listed NIH contact information or contact the principal investigator, Kenneth McClain, M.D., Ph.D., Texas Children’s Hospital, at:

Phone: (832) 824-4208
Email: kmcclain@bcm.tmc.edu

The Herbert Irving Comprehensive Cancer Center is the location of two phase II trials for LCH. One study involves the use of umbilical cord blood and placental blood transplantation to replace immune cells destroyed by chemotherapy and radiation therapy in LCH patients. The other study is investigating peripheral stem cell transplantation as a means of replacing immune cells destroyed by chemotherapy or radiation. Information on these two studies is available through the NIH listing or by contacting the study chair for both trials, David G. Savage, MD, at (212) 305-9327.

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.

The drug 2-chlorodeoxyadenosine (2CDA) has 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 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

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:604856; Last Update:1/23/01.
Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604856

TEXTBOOKS
McClain KL. Langerhans Cell Histiocytosis. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:392-93.

Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:395, 955-56.

Fauci AS, et al., eds. Harrison's Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:1465.

Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:1997-99.

REVIEW ARTICLES
Velez-Yanguas MC, et al. Langerhans’ cell histiocytosis. Orthop Clin North Am. 1996;27:615-23.

Veyssier-Belot C, et al. Histiocytosis. Rev Med Interne. 1996;17:911-23.

JOURNAL ARTICLES
Glotzbecker MP, et al. Langerhans cell histiocytosis: a primary viral infection of bone? Human herpes virus 6 latent protein detected in lymphocytes from tissue of children. J Pediatr Orthop. 2004;24:123-9.

Goh NS, et al. Successful treatment of Langerhans cell histiocytosis with 2-chlorodeoxyadenosine. Respirology. 2003;8:91-94.

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.

Ottaviano F, Finlay JL. Diabetes insipidus and Langerhans cell histiocytosis: a case report of reversibility with 2-chlorodeoxyadenosine. J Pediatr Hematol Oncol. 2003;25:575-77.

Vassallo R, et al. Clinical outcomes of pulmonary Langerhans’ cell histiocytosis in adults. N Engl J Med. 2002;346:484-90.

Farran RP, et al. Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol. 2001;23:54-56.

Henter JL, et al. Successful treatment of Langerhans’-cell histiocytosis with etanercept. N Engl J Med. 2001;345:1577-78.

Watanabe R, et al. Clinico-epidemiological features of pulmonary histiocytosis X. Intern Med. 2001;40:998-1003.

Jarquin-Valdivia AA, et al. Delayed diagnosis of pediatric Langerhans’ cell histiocytosis: case report and retrospective review of pediatric cases seen at Mayo Clinic. J Child Neurol. 2001;16:535-38.

Gadner H, et al. A randomized trial of treatment for multisystem Langerhans’ cell histiocytosis. J Pediatr. 2001;138:728-34.

Grau J, et al. Results of treatment with 2-chlorodeoxyadenosine in refractory or relapsed Langerhans cell histiocytosis. Study of 9 patients. Med Clin (Barc). 2001;116:339-42.

Bianchi M, et al. Pneumothorax secondary to pulmonary histiocytosis X. Minerva Chir. 1999;54:531-36.

Larralde M, et al. Congenital self-healing histiocytosis (Hashimoto-Pritzker). Int J Dermatol. 1999;38:693-96.

Lieberman PH, et al. Langerhans cell (eosinophilic) granulomatosis. A clinicopathologic study encompassing 50 years. Am J Surg Pathol. 1996;20:519-52.

Stull MA, et al. Langerhans cell histiocytosis of bone. Radiographics. 1992;12:801-23.

Komp DM. Langerhans cell histiocytosis. N Engl J Med. 1987;316:747-78.

INTERNET:

eMedicine-Langerhans Cell Histoicytosis: Article by M Angelica Selim, MD
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