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Histiocytosis, also referred to as Langerhans Cell Histiocytosis (LCH), and formally called Histiocytosis X, represents a group of rare disorders involving specific cells that normally have important roles as part of the immune system. While the cause of LCH is unknown, LCH can frequently behave like cancer and so is treated by cancer specialists.
Histiocytosis is a generic name for a group of syndromes characterized by an abnormal increase in the number of certain immune cells called histiocytes. These include monocytes, macrophages, and dendritic cells.
A histiocyte is a normal immune cell that is found in many parts of the body especially in the bone marrow, the blood stream, the skin, the liver, the lungs, the lymph glands and the spleen. In histiocytosis, the histiocytes move into tissues where they are not normally found and cause damage to those tissues. These proliferating immune cells may form tumors, which can affect various parts of the body.
LCH is often classified as single system, when the disease affects only one part of the body, or multisystem, when it affects more than one part of the body. In children, histiocytosis usually involves the bones and may consist of single or multiple sites. The skull is frequently affected. Children over five years of age usually have the single system disease, with just bone involvement. Young children, especially infants, are more likely to have the multisystem disease.
Most cases of histiocytosis affect children between the ages of one and 15 years, although people of all ages can develop LCH. The incidence peaks among children between 5 and 10 years old. Histiocytosis is thought to affect roughly one to two out of 200,000 people each year. The exact cause of histiocytosis is unknown. However, recent studies indicate that it is caused by the development and expansion of an abnormal Langerhans cell that subsequently leads to the accumulation of other cells of the immune system, resulting in collections or tumors in various areas of the body. Some forms are genetic.
The first sign of histiocytosis is often a rash on the scalp, similar to cradle cap. There may be a pain in a bone, discharge from the ear, loss of appetite and fever. Sometimes the stomach is swollen and painful. Occasionally, an area of the brain known as the pituitary gland is affected, and this can lead to the child passing large amounts of urine and being very thirsty. Other potential signs and symptoms include: weight loss, jaundice, vomiting, limping, short stature, delayed puberty, mental deterioration, headache, dizziness, seizures, protruding eyeballs, and/or a generalized rash.
The tumors produce a "punched-out" appearance on bone X-rays. Sometimes, children experience spontaneous fractures as a result of these bone lesions. There is often systemic involvement as well, which may affect the whole body and cause rashes, lung problems, gum infiltration, lymph gland swelling, hormonal problems, enlargement of the spleen and liver, and anemia.
Diagnostic tests include: a biopsy, in which a small sample of skin and/or bone is taken and examined under a microscope for abnormal cells; routine and sometimes specialized X-rays and scans of the bones, the skull, and the lungs; and blood tests. These tests will help the doctor determine if the disease is the single system or multisystem type.
An X-ray of the entire skeletal system may be done to determine how extensive the disease is and whether or not the systemic involvement is indicated.
Depending on the extent of the disease, LCH is often treated with chemotherapy and steroids to suppress the function of the immune system and the production of histiocytes. The length of treatment will vary from child to child. Many patients are eligible for international as well as local institutional trials.
Radiation therapy, treatment with targeted X-rays, or limited surgery may also be used to treat bone lesions in some situations.
The majority of patients who develop histiocytosis have complete recoveries. Sometimes the disease can recur, so the patient will have regularly scheduled follow-up visits in the outpatient clinic as a precaution.
New ideas are being tested to determine the causes of LCH as well as why some patients respond better to treatment than others. New types of therapies are being developed, including new types of drugs, as are approaches that direct antibodies or small molecules to the abnormal Langerhans cell while sparing the normal tissues.
Clinically, juvenile xanthogranuloma (JXG) is characterized by multiple cutaneous nodules consisting of dermal dendrocytes. These lesions sometimes involute spontaneously and no treatment is required. Occasionally there is systemic involvement. When this occurs therapy similar to that for LCH is used. When the disease is disseminated, it can be referred to as xanthoma disseminatum.
Erdheim-Chester Disease (ECD) occurs primarily in adults but can occur rarely in young individuals. ECD is characterized by accumulations of xanthomatous macrophages particularly in the retroperitoneum which often can lead to renal failure. In addition, ECD commonly affects the lungs heart along with bilateral long bone involvement leading to severe and chronic pain. In addition, ECD can lead to diabetes insipidus and other CNS signs and symptoms similar to LCH. Treatment for patients with ECD usually involves alpha-interferon or treatments similar to those used to treat patients with LCH.
Manifestations of sinus histiocytosis with massive lymphadenopathy (SHML) in¬clude the following: Worldwide occurrence with higher incidence among blacks; onset usually within the first two decades of life; massive painless bilateral cervical lymphadenopathy with involvement of other groups of lymph nodes. Snoring, when there is involvement of retropharyngeal lymphoid tissue; possibility of sleep apnea; extranodal infiltration in approximately 25% of patients (skin, orbit, eyelid, liver, spleen, testes, CNS, salivary glands, bone, respiratory tract); immunologic abnormalities with manifestations of autoimmune disorders (e.g., hematologic antibodies, glomerulonephritis, amyloidosis, or joint disease) in 10% of patients; fever; increase white blood cell count, but with low neutrophils neutropenia, mild anemia, elevated ESR; polyclonal hypergammaglobulinemia.
Diagnosis is made by a biopsy. Lymph node shows marked dilatation of sinuses by proliferation of benign histio¬cytes with prominent phagocytosis of lymphocytes, plasma cells, and erythrocytes by sinus histiocytes. Plasma cell infiltrates in the medullary cords and capsular fibro¬sis may also be evident.
Twenty percent of patients have spontaneous resolution or improvement within 3–9 months. The majority of patients have stable and persistent disease lasting up to several years. Seven percent of patients have a fatal outcome, especially if immuno¬logic abnormalities and extranodal involvement are present.
No treatment is generally warranted because this it is a self-limited disease. However, when patients require treatment, steroids along with chemotherapy and sometimes, alpha-interferon are used.
Hemophagocytic lymphohistiocytosis (HLH) falls into two categories: 1. Familial hemophagocytic lymphohistiocytosis (FHLH) (familial or sporadic): This is an autosomal-recessive disease that affects immune regulation. Although it is commonly termed familial HLH, because the disease has an autosomal¬ recessive inheritance, sporadic cases with no obvious family inheritance occur. The signs and symptoms of FHLH may be triggered by infections; 2. Non-familial HLH: A lymphohistiocytic proliferation with hemophagocytosis may also develop from marked immunological activation during viral, bacterial, and parasitic infections (Infection-Associated Hemophagocytic Lymphohistiocy¬tosis). This may also be associated with malignancies, prolonged administration of lipids, rheumatoid arthritis (macrophage activation syndrome), immune deficiencies associated with cytotoxic T and/or NK cell dysfunction such as DiGeorge Syndrome (del 22q11.2), Chédiak–Higashi syn¬drome, Griscelli syndrome, X-linked lymphoproliferative disease (XLP) and lysinuric protein intolerance (LPI). Hermansky-Pudlak syndrome has been reported to be associated with HLH.
These disorders are characterized by defects in the immune system. FHLH is inherited as an autosomal recessive disorder.
Clinical features include the following: 1. The age of onset is usually less than 1 year of age. There is no known upper age limit for the onset of disease; 2. Signs and symptoms of FHLH include: a. Fever, splenomegaly and hepatomegaly are the most common early findings; b. Lymph node enlargement, skin rash, and neurologic abnormali¬ties may also occur.
Neurologic findings including irritability, bulging fontanel, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, blindness, and unconsciousness; 3. Multisystem involvement includes lungs, bone marrow, and leptomeninges. Occasionally, ocular, heart, skeletal muscles, and kidney involvement have been noted.
Patients should be treated as per modern protocols (e.g., HLH 2004 of the Histiocytic Society*) that includes chemotherapy and immunosuppressive medicines. Non-familial disease is initially and commonly treated in a similar manner. Without treatment, FHLH is usually rapidly fatal, with a median survival of about 2 months. Chemotherapy and immunosuppressive therapy may prolong survival in FHLH but only stem cell transplantation may be curative. Patients with known familial disease or severe or persistent acquired disease should then receive hematopoietic stem cell transplantation. The 3-year actuarial survival in familial HLH with this approach has been reported as approximately 50% to 55% overall but 64% following HSCT.
Malignant sarcomas of both the macrophage and the dendritic/Langerhans cell can occur and present as single tumors or can be quite widespread. These are usually quite aggressive diseases and clinically behave like different types of lymphoma.
Pateints are usually best treated with combinations of chemotherapy, such as used for lymphoma and aggressive histiocytic disorders. For localized disease, sometimes surgery with or without radiation therapy, are effective.