Langerhans cell histiocytosis (LCH), formerly known as histiocytosis X, is a group of diseases characterized by the widespread proliferation and infiltration of histiocytes, primarily Langerhans cells, within the mononuclear phagocyte system. It commonly affects bones, lungs, liver, spleen, bone marrow, lymph nodes, and skin. Traditionally, the disease is classified into three clinical syndromes: Letterer-Siwe disease, Hand-Schüller-Christian syndrome, and eosinophilic granuloma of bone. In modern classifications, it is divided into localized and disseminated disease groups based on the extent of organ involvement. The localized form is confined to a single organ system, such as bones, skin, or lungs, and is more common in older children. It progresses slowly and has a better prognosis. The disseminated form involves multiple systems, primarily affects infants and young children, progresses rapidly, and has a higher mortality rate. The exact pathogenesis of LCH remains unclear, but it is currently believed to result from cytokine-mediated reactive clonal proliferation. Viral infections may also play a role in its development.

bubble_chart Clinical Manifestations

1. Common manifestations include fever, pallor, and exhaustion, often seen in patients with multisystem involvement.
2. Skeletal lesions frequently affect the skull, including the calvarium, jawbone, and orbital bones. Palpable map-like defects may be felt at the affected areas of the calvarium. Lesions are also commonly found in the ribs and tubular bones of the limbs. The condition may involve a single bone or multiple bones. Involvement of adjacent soft tissues may lead to mass formation. Local symptoms of bone lesions may include pain, swelling, difficulty walking, or fractures. Vertebral involvement with nerve compression may result in corresponding neurological signs.
3. Hepatosplenomegaly and lymphadenopathy are common, with jaundice observed in a minority of cases.
4. Specific rashes may appear on the trunk, limbs, and head-neck skin due to infiltration, typically presenting as dark red 2–3 mm maculopapules with pointed or hemorrhagic tips, or eczematoid rashes. Yellowish xanthoma-like maculopapules may also occur.
5. Pulmonary infiltration often manifests as recurrent cough, with severe cases showing dyspnea and cyanosis. Lung auscultation may reveal abnormal sounds, and complications such as pulmonary emphysema or pneumothorax may occur.
6. Involvement of tissues adjacent to affected bones may lead to specific manifestations, such as ear discharge from mastoid or middle ear involvement, exophthalmos from orbital bone lesions, diabetes insipidus from sphenoid bone lesions, and loose or lost teeth from jawbone lesions.
7. Recurrent diarrhea.

bubble_chart Auxiliary Examination

1. Blood Picture: The blood picture may be roughly normal. Anemia may also be present. The white blood cell count can be normal, increased, or decreased, with a small number of cases showing a few immature cells in the differential count. Platelet levels may be normal or reduced.
2. Bone Marrow Picture: The bone marrow may appear roughly normal. In cases where the marrow is involved, light microscopy of bone marrow cell smears may reveal a higher number of well-differentiated histiocytes, while electron microscopy may show typical Langerhans cells with Birbeck granules in their cytoplasm.
3. Biopsy: Light and electron microscopy findings of tissue sections from lesions, lymph node sections, rash imprint smears, and aspirate smears from affected soft tissues at sites of bone defects are generally similar to the bone marrow changes.
4. Immunological Tests: There may be alterations in serum immunoglobulins and T-cell subsets. Immunohistochemical examination of lesional tissue cells reveals Langerhans cells positive for T-6 (CD1a) and S-100 markers.
5. X-ray Examination: Single or multiple geographic bone defects may be observed. Long bones may exhibit fusiform swelling or thinning of the cortical bone at the lesion site, with possible pathological fractures. The lung fields may show reticulonodular shadows, honeycomb-like small cystic areas, or bullous changes, and pneumothorax may be present.

bubble_chart Diagnosis

Credibility Grading Criteria

1. Presumptive Diagnosis: Presence of typical clinical manifestations, and conventional pathological examination reveals histiocytic proliferation and infiltration.
2. Enhanced Diagnosis: Based on the presumptive diagnosis, plus positive results in ≥2 of the following tests for pathological cells: (1) Positive ATPase staining; (2) Positive S-100 protein; (3) Positive α-mannosidase staining; (4) Positive peanut lectin binding.
3. Definitive Diagnosis: Electron microscopy observation of Birbeck granules in histiocytes or the presence of T-6 (CD1a) positive markers on the surface of pathological cells.

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Based on the age of onset, extent, and severity of lesions, it is divided into the following 4 grades to assess prognosis and guide treatment.

bubble_chart Treatment Measures

(1) Local Treatment

Applicable to grade I and II lesions, including surgical curettage of the lesion and radiotherapy. For initial treatment of a single localized bone lesion, curettage alone may be used. For severe local lesions or bone lesions under heavy load, recurrent lesions, multiple bone lesions with soft tissue involvement, or pulmonary eosinophilic granuloma, radiotherapy may be combined. Diabetes insipidus with a disease course of less than half a year can also be treated with local radiotherapy, with a total dose of 600 cGy, administered in fractions of 200 cGy each.

(2) Systemic Chemotherapy

The goal of chemotherapy is to minimize organ damage, using steroids and antimetabolites as much as possible, and avoiding or using low doses of cytotoxic drugs to control the disease. However, the intensity of chemotherapy should correspond to the severity of the disease. For grade I and II lesions, two drugs (e.g., the VP regimen) or a single drug (e.g., prednisone) may be used for 6–8 weeks, followed by alternating with another two drugs (e.g., 6-MP and MTX) or a single drug for 1–2 years. For grade III and IV lesions, three drugs (e.g., the VCP regimen) are used in combination for 8–12 weeks, and after improvement, another two-drug combination (6-MP and MTX) is alternated for 2–3 years. For refractory sexually transmitted disease cases, combination chemotherapy regimens including VP-16 or VM-26 can achieve good efficacy. Common chemotherapy drug doses and methods are as follows.

1. VP Regimen: VCR (vincristine) 1.5–2 mg/m², once weekly, IV, or Madagascar periwinkle alkaloid 5–10 mg/m², once weekly, IV; Pred (prednisone) 40 mg/(m²·d), administered orally in divided doses. The two drugs are combined for 4–6 weeks as one course.
2. VCP Regimen: VCR and Pred as above; CTX (cyclophosphamide) 75 mg/(m²·d), orally on days 1–7 and 15–21, or 200 mg/m² per dose, IV, once weekly. The three drugs are combined for 4 weeks as one course. 3. 6-MP (6-mercaptopurine) 75 mg/(m²·d), administered orally in divided doses, continuously for 3–4 weeks as one course.
3. MTX (methotrexate) 20 mg/m2, once weekly, orally or IV. Often combined with 6-MP for 3–4 weeks as one course.
4. VP-16 (etoposide) 50–150 mg/m², administered for 3 days every 2 weeks, IV. 6. VM-26 (teniposide) 100–60 mg/m², administered twice every 2 weeks, IV. Regimens including chlorambucil, procarbazine, cytarabine, and daunorubicin may also be used.

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For grade III and IV lesions, thymosin 1–5 mg/d may be used concurrently with chemotherapy, administered intramuscularly after a negative skin test. After symptoms disappear, it is reduced to three times per week and may be continued for 3–6 months. In recent years, reports have shown that drugs such as cyclosporine A and α-interferon can modulate immune responses, block cytokine release and their mediated cell activation, and treat grade III and IV LCH that is refractory to conventional therapies.

(4) Supportive and Symptomatic Treatment

Strengthen nutrition and care. Use antibiotics rationally to treat infectious diseases. Actively manage respiratory failure and treat pneumothorax. Provide necessary dental treatment or appropriate use of 1-desamino-8-D-arginine vasopressin for diabetes insipidus, etc.

bubble_chart Prognosis

The prognosis is poor in patients with onset age <2 years, multiple organ involvement, and organ dysfunction. Prognosis can be significantly improved with appropriate treatment. Some cases may still develop sequelae such as diabetes insipidus, short stature, intellectual disability, and other neurological symptoms after treatment.