Langerhans cell histiocytosis (histiocytosis X): causes, symptoms, diagnosis, treatment

Langerhans cell histiocytosis (Langerhans cell granulomatosis; histiocytosis X) is a proliferation of dendritic mononuclear cells with diffuse or focal organ infiltration. The disease occurs primarily in children. Manifestations include pulmonary infiltration, bone lesions, skin rash, liver, hematopoietic, and endocrine dysfunction. Diagnosis is based on biopsy. Treatment includes supportive care, chemotherapy, or local therapy with surgery, radiation therapy, depending on the extent of the disease.

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Epidemiology

Histiocytosis X occurs with a frequency of 1:50,000, and most of those affected are young children, although there are cases of children in adolescence. However, adults, old people, and mainly men, often get sick.

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Risk factors

Factors predisposing to an unfavorable prognosis include age under 2 years and dissemination of the process, especially involvement of the hematopoietic system, liver and/or lungs.

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Pathogenesis

Langerhans cell histiocytosis (LCH) is a disorder of dendritic cell function. Distinct clinical syndromes of this disorder have historically been described as eosinophilic granuloma, Hand-Schüler-Christian disease, and Letterer-Siwe disease. Because these syndromes may be different manifestations of the underlying disorder, and because most patients with LCH have more than one syndrome, defining distinct syndromes is now largely historical.

Histiocytosis X is characterized by the development of abnormal proliferation of dendritic cells in one or more organs. Bones, skin, teeth, gum tissue, ears, endocrine organs, lungs, liver, spleen, lymph nodes, and bone marrow may be affected. Organs may be affected by proliferating cells that cause their dysfunction, or these organs may experience pressure from neighboring, enlarged organs. In half of the cases, multiple organs are affected.

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Symptoms histiocytosis X

Symptoms and signs are varied and depend on which organs are infiltrated. Syndromes are described according to historical indications, but only a small number of patients have classic manifestations of the disease.

Eosinophilic granuloma

Solitary or multifocal eosinophilic granuloma (60-80% of histiocytosis X cases) occurs predominantly in older children and young adults, usually under 30 years of age; peak incidence occurs between ages 5 and 10 years. Bones are most commonly affected, often with pain, inability to bear weights, and the formation of a tender, soft swelling (often warm).

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Hand-Schüller-Christian disease

This syndrome (15-40% of histiocytosis X cases) occurs most frequently in children aged 2 to 5 years and less frequently in older children and adults. It is a systemic disorder that classically affects the flat bones of the skull, ribs, pelvis, and scapula. The long bones and lumbosacral spine are less commonly involved; the wrists, hands, feet, and cervical vertebrae are rarely affected. Patients classically present with exophthalmos due to an orbital tumor mass. Vision loss or strabismus is rare and is caused by involvement of the optic nerve or orbital muscles. Tooth loss due to apical and gingival infiltration is common in older patients.

The typical manifestation of the disease is chronic otitis media and otitis externa caused by involvement of the mastoid process and petrous part of the temporal bone with partial obstruction of the auditory canal. Diabetes insipidus is the last component of the classic triad, which includes flat bone involvement and exophthalmos, diagnosed in 5-50% of patients, more often in children who have systemic involvement of the orbit and skull. Up to 40% of children with systemic disease are characterized by short stature. Infiltration of the hypothalamus can lead to the development of hyperprolactinemia and hypogonadism. In rare cases, other symptoms are possible.

Letterer-Sieve disease

This systemic disease (15-40% of histiocytosis X cases) is the most severe form of histiocytosis X. It usually appears in children under 2 years of age as an eczematoid rash with scaly exfoliation and seborrhea, sometimes purple in color, affecting the scalp, ear canals, abdomen, and also characteristically has areas of diaper rash in the neck and face. Skin de-epithelialization can promote microbial invasion, leading to sepsis. Otitis, lymphadenopathy, hepatosplenomegaly, and, in severe cases, liver dysfunction with hypoproteinemia and impaired synthesis of coagulation factors often develop. Anorexia, irritability, developmental disorders, and pulmonary symptoms (eg, cough, tachypnea, pneumothorax) are common. Severe anemia and sometimes neutropenia occur; thrombocytopenia is a poor prognostic sign. Parents often report premature teething, which is when the gums actually come through and immature dentin is exposed. Parents may be careless and rough with their child.

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Diagnostics histiocytosis X

Histiocytosis X is suspected in patients (especially young ones) with unexplained pulmonary infiltration, bone lesions, eye lesions, or facial bone abnormalities, and in children under 2 years of age with typical rash or severe unexplained multiorgan pathology.

If characteristic symptoms are detected, an X-ray examination is performed. The bone lesions usually have sharp edges, are round or oval in shape, with a beveled edge, creating the impression of depth. Some lesions are sometimes indistinguishable from Ewing's sarcoma, osteosarcoma, other benign and malignant pathologies, or osteomyelitis.

The diagnosis is based on biopsy. Langerhans cells are usually clearly visible, except in older lesions. These cells are identified by a pathologist experienced in the diagnosis of histiocytosis X according to their immunohistochemical characteristics, which include detection of surface CD1a and S-100. Once the diagnosis is made, the extent of the disease must be determined by appropriate laboratory and imaging techniques.

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Treatment histiocytosis X

Patients should regularly visit specialized medical institutions to correct the treatment of histiocytosis X. General supportive therapy is of great importance and includes careful personal hygiene to limit damage to the ears, skin, and oral cavity. Surgical treatment and even resections in severe lesions of the gum tissue limit the extent of damage to the oral cavity. The use of selenium-containing shampoos 2 times a week is an effective remedy for seborrheic dermatitis of the scalp. In the absence of a positive effect from the use of shampoo, glucocorticoids are applied locally in small quantities in small areas of damage.

Many patients require hormone replacement therapy for diabetes insipidus or other manifestations of hypopituitarism. Patients with systemic manifestations of the disease require monitoring for chronic dysfunction, particularly cosmetic or functional orthopedic and skin problems, neurotoxicity, and psychological problems, and may require psychosocial support.

Chemotherapy is indicated for patients with multiorgan involvement. The protocols recommended by the Histiocytosis Society are used, divided according to risk category. In almost all patients with a good response to therapy, treatment can be stopped. Protocols for poor response to therapy are under development.

Local surgery or radiation therapy is used for disease involving a single bone or, less commonly, multiple bone lesions. When lesions are accessible in non-critical areas, surgical curettage is performed. Surgery should be avoided if there is a risk of functional impairment or significant cosmetic or orthopaedic complications. Radiation therapy may be indicated in patients at risk of skeletal deformity, loss of vision due to exophthalmos, pathological fractures, destruction of the spine and spinal cord injury or in patients with severe pain. The doses of radiation therapy used are comparatively lower than those used in the treatment of oncological diseases. Surgery and radiation therapy should be used by specialists experienced in the treatment of histiocytosis X.

In patients with multi-organ involvement and progression of the process, standard therapy is ineffective and more aggressive chemotherapy is necessary. Patients who do not respond to second-line therapy (salvage therapy) may undergo bone marrow transplantation, experimental chemotherapy, or immunosuppressive and immunomodulatory therapy.

Forecast

The disease limited to skin, lymph nodes and bones in patients under 2 years of age has a good prognosis. A significant level of morbidity and mortality is observed in young patients with multiorgan involvement. Patients with multiorgan involvement belong to the high-risk group. About 25% of patients are in the low-risk group. Low-risk criteria are age over 2 years, no involvement of the hematopoietic system, liver, lungs, spleen. Risk criteria are age under 2 years or involvement of these organs. Overall survival in patients with multiorgan involvement with treatment is about 80%. Fatal outcomes are virtually absent in the low-risk group of patients, but are possible in the high-risk group of patients who did not respond to initial therapy. Relapses of the disease are common. Periods of exacerbation of the chronic course of the disease may occur, especially in adult patients.

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