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(See also Interstitial Lung Diseases: Pulmonary Langerhans' Cell Histiocytosis.)
Langerhans'
cell histiocytosis is a proliferation of dendritic mononuclear cells
with infiltration into organs locally or diffusely. Most cases occur
in children. Manifestations may include lung infiltrates, bone lesions,
skin rashes, and hepatic, hematopoietic, and endocrine dysfunction.
Diagnosis is based on biopsy. Factors predicting a poor prognosis include
age < 2 yr and dissemination,
particularly involving the hematopoietic system, liver, and/or lungs.
Treatments include supportive measures and chemotherapy or local
treatment with surgery or radiation therapy as indicated by the
extent of disease.
Langerhans' cell histiocytosis (LCH) is a dendritic cell disorder. It can produce distinct clinical syndromes that have been historically described as eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease. Because these syndromes may be varied manifestations of the same underlying disease, and because most patients with LCH have manifestations of more than one of these syndromes, the designations of the separate syndromes are now mostly of historical significance.
The prevalence of LCH is estimated to be 1:50,000, of whom most are infants and young children, although children up to age 15 are often affected. However, the disease also affects adults, even older adults, with a male predominance.
In LCH, abnormally proliferating dendritic cells infiltrate one or more organs. Bone, skin, teeth, gingival tissue, ear, endocrine organs, lungs, liver, spleen, lymph nodes, and bone marrow may be involved. Organs may be affected by infiltration, causing dysfunction, or by compression from adjacent enlarged structures. In about half of patients, multiple organs are involved.
Symptoms and Signs
Symptoms and signs vary considerably depending on which organs are infiltrated. The syndromes are described by their historical designation, but few patients present with classic manifestations.
Eosinophilic
granuloma:
Solitary or multifocal eosinophilic granuloma (60 to 80% of LCH cases) occurs predominantly in older children and young adults, usually by age 30; incidence peaks between ages 5 and 10 yr. Lesions most frequently involve bone, often with pain and/or the inability to bear weight and with overlying tender (sometimes warm) swelling.
Hand-Schüller-Christian
disease:
This syndrome (15 to 40% of LCH cases) occurs in children aged 2 to 5 yr and in some older children and adults. It is a systemic disease that classically involves the flat bones of the skull, ribs, pelvis, and scapula. Long bones and lumbosacral vertebrae are less frequently involved; the wrists, hands, knees, feet, and cervical vertebrae are rarely involved. In classic cases, patients have exophthalmos caused by orbital tumor mass. Vision loss or strabismus caused by optic nerve or orbital muscle involvement occurs rarely. Tooth loss caused by apical and gingival infiltration is common in older patients.
Chronic otitis media and otitis externa due to involvement of the mastoid and petrous portions of the temporal bone with partial obstruction of the auditory canal are fairly common. Diabetes insipidus, the last component of the classic triad that includes flat bone involvement and exophthalmus, affects 5 to 50% of patients, with higher percentages in children who have systemic disease and involvement of the orbit and skull. Up to 40% of children with systemic disease have short stature. Hyperprolactinemia and hypogonadism may be caused by hypothalamic infiltration. Many other rare symptoms are possible.
Letterer-Siwe
disease:
This syndrome (10% of LCH cases), a systemic disease, is the most severe form of LCH. Typically, a child < 2 yr presents with a scaly seborrheic, eczematoid, sometimes purpuric rash involving the scalp, ear canals, abdomen, and intertriginous areas of the neck and face. Denuded skin may facilitate microbial invasion, leading to sepsis. Frequently, there is ear drainage, lymphadenopathy, hepatosplenomegaly, and, in severe cases, hepatic dysfunction with hypoproteinemia and diminished synthesis of clotting factors. Anorexia, irritability, failure to thrive, and pulmonary symptoms (eg, cough, tachypnea, pneumothorax) may also occur. Significant anemia and sometimes neutropenia occur; thrombocytopenia is of grave prognostic significance. Parents frequently report precocious eruption of teeth, when in fact the gums are receding to expose immature dentition. Patients may appear abused or neglected.
Diagnosis
LCH is suspected in patients (particularly young patients) with unexplained pulmonary infiltrates, bone lesions, or ocular or craniofacial abnormalities; and in children < 2 yr with typical rashes or severe, unexplained multiorgan disease.
Radiographs are often obtained because of presenting symptoms. Bone lesions are usually sharply marginated and round or oval, with a beveled edge giving the appearance of depth. Some lesions, however, are radiographically indistinguishable from Ewing's sarcoma, osteogenic sarcoma, other benign and malignant conditions, or osteomyelitis.
Diagnosis is based on biopsy. Langerhans' cells are usually prominent, except in older lesions. These cells are identified by a pathologist experienced in the diagnosis of LCH according to their immunohistochemical charecteristics, which include cell surface CD 1a and S-100. Once diagnosis is established, the extent of disease must be determined by appropriate imaging and laboratory studies.
Prognosis
and Treatment
Disease restricted to skin, lymph nodes, or bone in patients > 2 yr has a good prognosis. Significant morbidity and mortality occur in young patients with multiorgan involvement. Disease risk is stratified in patients with multiorgan involvement. About 25% are classified as low risk. Low-risk criteria are age > 2 yr and no involvement of the hematopoietic system, liver, lungs, or spleen; at-risk criteria are age < 2 yr or involvement of these organs. The overall survival rate for multiorgan disease with treatment is about 80%. Mortality is virtually absent in low-risk patients and is most likely in at-risk patients who do not respond to initial therapy. Disease recurrence is common. A chronic remitting and exacerbating course may occur, particularly in adult patients.
Whenever possible, patients are referred to institutions experienced in the treatment of LCH. General supportive care is essential and may include scrupulous hygiene to limit ear, cutaneous, and dental lesions. Debridement and even resection of severely affected gingival tissue limit oral involvement. Seborrhea-like dermatitis of the scalp may diminish with use of a selenium -based shampoo twice/wk. If shampooing is ineffective, topical corticosteroids are used in small amounts and briefly in small areas.
Many patients require hormone replacement for diabetes insipidus or other manifestations of hypopituitarism. Patients with systemic disease are monitored for potential chronic disabilities, such as cosmetic or functional orthopedic and cutaneous disorders and neurotoxicity as well as for psychologic problems that may require psychosocial support.
Chemotherapy is indicated for patients with multiorgan involvement. Protocols sponsored by the Histiocyte Society are used; these vary according to the risk category. Almost all patients with a good response to therapy can stop treatment. Protocols for poor responders are under study.
Local surgery or radiation therapy is used for disease involving a single bone and, rarely, when multiple lesions or multiple bones are involved. Easily accessible lesions in noncritical locations undergo surgical curettage. Surgery should be avoided when it may result in significant cosmetic and/or orthopedic deformities and loss of function. Radiation therapy involving megavoltage equipment may be given to patients at risk of skeletal deformity, visual loss secondary to exophthalmos, pathologic fractures, vertebral collapse, and spinal cord injury or to patients with severe pain. Doses of radiation are considerably less than those used to treat cancer. Surgery and radiation therapy should be performed by specialists experienced in treating LCH.
Patients with multiorgan disease that progresses despite standard therapy usually respond to more aggressive chemotherapy. Patients who do not respond to salvage chemotherapy may undergo bone marrow transplantation, experimental chemotherapy, or immunosuppressive or other immunomodulatory therapy.
Last full review/revision November 2005
Content last modified November 2005
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