About histiocytosis x

What is histiocytosis x?

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.



What are the symptoms for histiocytosis x?

Skin rash with scaly papules symptom was found in the histiocytosis x condition

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. 

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.  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. 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)



What are the causes for histiocytosis x?

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.



What are the treatments for histiocytosis x?

LCH

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.

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. Oral methotrexate or thalidomide are also used. 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.

Neurodegenerative syndrome is treated with cytarabine or MAPK inhibitors.

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.

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. Oral hydroxyurea with or without oral methotrexate has been effective in treating skin and bone LCH, with special efficacy for vaginal lesions.

RDD

RDD patients are treated with a variety of chemotherapy agents including cladribine, clofarabine, and the MAPK inhibitors.

JXG

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.

ECD

Treatment of ECD patients is now primarily with BRAF or MAPK inhibitors. Some patients are successfully treated with alpha-interferon or anakinra .



What are the risk factors for histiocytosis x?

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.



Is there a cure/medications for histiocytosis x?

Histiocytosis X, also known as Langerhans cell histiocytosis, is a condition caused by the proliferation of abnormal Langerhans cells. It can occur at any age but is most common in kids younger than 15. It is rare and occurs in 1 or 2 newborns in a million. Abnormal Langerhans cells are dendritic antigen-presenting cells with abnormal proliferation and decreased capacity for antigen presentation. Histiocytosis X is either reactive or neoplastic. Symptoms of the disease depend on the organ involved at the time of presentation. The most common symptom is skin rash with scaly papules, plaques, or nodules. The involvement of the pituitary gland results in polyuria, polydipsia, dilute urine, and hypernatremia. Lesions in bones cause pain in the skull, femur, hip/pelvis, and ribs. Cure/medication Treatment depends on the organs involved. Usually, histiocytosis that presents in infancy (congenital self-healing reticulo-histiocytosis) resolves on its own. • Isolated skin manifestations may be treated with topical steroids, oral methotrexate, or thalidomide. • Systemic involvement responds to radiation and chemotherapy. • Chemotherapy has multiple protocols, which include Prednisone and vinblastine Vincristine, cytosine arabinoside, prednisone, cladribine, or pamidronate • Surgical interventions Surgical options include partial resection or a complete excisional biopsy of the lesion biopsy, followed by low-dose radiation to the lesion, usually with 6–10 Gy



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