bubble_chart Overview

Langerhans cell histiocytosis (LCH), formerly known as histiocytosis X, is a group of proliferative disorders of histiocytes with unknown etiology. Traditionally, it is classified into three clinical types: Letterer-Siwe syndrome (Litterer-Siwe disease, abbreviated as L-S disease), Hand-Schüller-Christian syndrome (Hand-Schüller-Christian disease, abbreviated as H-S-C disease), and eosinophilic granuloma of bone (EGB). The disease cause remains unclear, and recent studies have found that it is mostly related to immune regulation disorders in the body.

bubble_chart Clinical Manifestations

Clinical Manifestations The onset of this disease varies, with diverse symptom presentations ranging from isolated painless bone lesions in mild cases to widespread organ infiltration accompanied by fever and weight loss in severe cases.

(1) Skin Lesions Skin lesions are often the first symptom of diagnosis. The rash appears in various forms in acute infant patients, mainly distributed on the trunk, scalp hairline, and behind the ears. It begins as macules or papules, quickly progressing to exudation (similar to eczema or seborrheic dermatitis), possibly accompanied by bleeding, followed by crusting and scaling, ultimately leaving pigmented white spots that are slow to fade. Rashes at different stages may coexist or appear in waves, often accompanied by fever during eruptions. In chronic cases, rashes may be scattered across the body, initially appearing as faint-colored papules or wart-like nodules. When they subside, the center may become depressed and flattened, sometimes turning dark brown, closely resembling chickenpox scabs. Eventually, the local skin becomes thin, slightly depressed, with a slight sheen or minimal scaling. The rash may appear alongside other organ damage or exist as the sole manifestation, commonly seen in male infants under 1 year old.

(2) Bone Lesions Bone lesions are present in almost all LCH patients, with single bone lesions more common than multiple ones, primarily manifesting as osteolytic damage. Skull lesions are the most frequent, followed by the lower limb bones, ribs, pelvis, and spine. Jaw lesions are also quite common. On X-ray, they typically appear as irregularly edged bone dissolution. Skull destruction ranges from moth-eaten changes to large defects or punched-out lesions, irregularly shaped, round, or oval with jagged edges. Initial or progressing lesions have blurred boundaries, often accompanied by increased intracranial pressure, cranial suture separation, or communicating hydrocephalus, possibly with headaches. However, during the convalescence stage, the bone edges gradually become clear, with sclerotic bands appearing, uneven bone density, and the bone defect gradually shrinking until fully repaired without traces. Other flat bone X-ray changes include rib swelling, thickening, bone thinning, or cystic changes, followed by bone absorption, atrophy, and thinning. Vertebral destruction may lead to flattened vertebrae, but the intervertebral space does not narrow, and angular deformities are rare. Destruction of the vertebral arch may compress spinal nerves, with occasional paravertebral soft tissue swelling. Jaw lesions can manifest as alveolar or mandibular body types.

(3) Lymph Nodes LCH lymph node involvement can present in three forms: ① Isolated lymph node lesions, termed primary eosinophilic granuloma of the lymph nodes; ② Accompanying lesions of localized or focal LCH, often involving osteolytic damage or skin lesions; ③ As part of systemic disseminated LCH. It commonly affects isolated lymph nodes in the neck or groin, with most patients showing no fever, and only a few experiencing pain at the swollen lymph node site. Isolated lymph node involvement generally has a favorable prognosis.

(4) Ear and Mastoid External ear inflammation in LCH is often due to Langerhans cell proliferation and infiltration in the soft or bone tissues of the ear canal, sometimes difficult to distinguish from diffuse bacterial ear infections. Main symptoms include purulent discharge from the external ear canal, postauricular swelling, and conductive deafness. CT scans can reveal both bone and soft tissue lesions. Mastoid lesions may include mastoiditis, chronic otitis, sebaceous cyst formation, and hearing loss.

(5) Bone Marrow Normally, Langerhans cells (LC) are absent in the bone marrow, and even in multi-site LCH, bone marrow LC infiltration is rare. However, if LC invades the bone marrow, patients may develop anemia, leukopenia, and thrombocytopenia, though the degree of bone marrow dysfunction does not correlate with the extent of LC infiltration. The mere presence of LC in the bone marrow is insufficient for an LCH diagnosis.

(6) Thymus The thymus is one of the organs frequently affected by LCH.

(7) Lung LCH lung lesions can be part of systemic disease or exist independently, known as primary pulmonary LCH. Lung lesions can occur at any age, but are more common in infants during childhood, manifesting as varying degrees of dyspnea, hypoxia, and changes in lung compliance. Severe cases may present with pneumothorax and subcutaneous emphysema, with a high risk of respiratory failure leading to death. Pulmonary function tests often show restrictive impairment.

(8) Liver Diffuse LCH often involves the liver, with the affected areas typically located in the hepatic portal region. The extent of involvement can range from grade I bile stasis to severe tissue infiltration in the hepatic portal area, leading to hepatocyte injury and bile duct involvement. This manifests as abnormal liver function, jaundice, hypoalbuminemia, ascites, and prolonged prothrombin time, which may progress to sclerosing cholangitis, hepatic fibrosis, and liver failure.

(9) Spleen Diffuse LCH often presents with splenomegaly, accompanied by single or multiple cytopenias in the peripheral blood. The cause may be the enlarged spleen volume, which leads to the sequestration of platelets and granulocytes rather than increased destruction. The sequestered blood cells can still achieve a dynamic equilibrium with peripheral blood cells, so bleeding symptoms are not common.

(10) Gastrointestinal lesions are frequently seen in systemic diffuse LCH, with symptoms largely dependent on the affected site. The small intestine and ileum are most commonly involved, presenting as vomiting, diarrhea, and malabsorption, which can lead to growth retardation in children over time.

(11) Central Nervous System CNS involvement in LCH is not uncommon, with the most frequently affected area being the hypothalamic-posterior pituitary region. Diffuse LCH may also involve brain parenchymal sexually transmitted disease changes. Neurological symptoms in most patients appear years after LCH has affected other sites, commonly including ataxia, dysarthria, ocular tremor, hyperreflexia, dysdiadochokinesia, dysphagia, and blurred vision. Diabetes insipidus caused by hypothalamic and/or pituitary granulomas may precede, coincide with, or follow brain symptoms, or it may be the sole manifestation of CNS involvement.

bubble_chart Auxiliary Examination

(1) Blood Picture Patients with disseminated LCH often exhibit grade II to grade III or higher anemia, with reticulocytes and white blood cells possibly elevated to grade I, and decreased platelets. A minority of cases may show decreased white blood cells.

(2) Bone Marrow Examination Most LCH patients have normal bone marrow hyperplasia, while a minority may show active or reduced hyperplasia. A small number of LCH cases involve bone marrow infiltration, manifesting as anemia and decreased platelets. Therefore, this examination should only be performed when abnormalities in peripheral blood are detected.

(3) Erythrocyte Sedimentation Rate (ESR) Some cases may show an increased ESR.

(4) Liver and Kidney Function Some cases exhibit abnormal liver function, indicating a poor prognosis. This includes elevated SGOT, SGPT, alkaline phosphatase, and bilirubin, decreased plasma protein, prolonged prothrombin time, and reduced fibrinogen levels and partial thromboplastin generation test. Kidney function tests include urine osmolality, and for patients with diabetes insipidus, urine specific gravity and water deprivation tests should be performed.

(5) X-ray Examination Chest X-rays often show a reticular or stippled shadow of lung markings, with blurred granular edges not following bronchial branching. Some lung fields may appear ground-glass-like, but most cases exhibit increased lung translucency, commonly with small cystic emphysema, and severe cases may resemble honeycomb lung. This may be accompanied by interstitial emphysema, mediastinal emphysema, subcutaneous emphysema, or pneumothorax. Many patients may also develop pneumonia, which increases the likelihood of cystic lung changes. After pneumonia resolves, cystic changes may disappear, but reticulonodular changes become more pronounced. Long-term cases may develop pulmonary fibrosis. Bone X-ray changes are as described earlier.

(6) Blood Gas Analysis Significant hypoxemia suggests impaired lung function.

(7) Pulmonary Function Tests Patients with severe lung lesions may exhibit varying degrees of pulmonary insufficiency, often indicating a poor prognosis.

(8) Immunological Tests Given that this condition often involves immune regulation dysfunction, such as abnormal T-lymphocyte subset counts and an abnormal ratio of T-helper to T-suppressor cells, qualified institutions should perform T-subset phenotypic analysis, lymphocyte transformation tests, and quantitative serum immunoglobulin assays.

(9) For patients with newly emerged rashes, a rash imprint smear should be performed. If possible, a skin biopsy of the rash site is more reliable. For those with lymphadenopathy, a lymph node biopsy can be done. For those with bone destruction, curettage of the lesion can be performed, with the specimen sent for pathology, or a thick-needle aspiration can be done at the site of bone destruction, with the smear sent for examination.

(10) Immunohistochemical Staining As mentioned earlier, recent studies have shown that Langerhans cells exhibit an immunophenotype of CD1a. Immunohistochemical staining with anti-CD1a monoclonal antibodies shows a specific positive reaction. Additionally, positive reactions may also be observed for the following four enzymes: S-100 protein, α-D-mannosidase, ATPase, and peanut agglutinin.

bubble_chart Diagnosis

The diagnostic method is primarily based on clinical, X-ray, and pathological examination results. Specifically, the presence of histiocytic infiltration in the lesion detected through routine pathological examination confirms the diagnosis. The key to diagnosing this condition lies in identifying the tissue infiltration of Langerhans cells via pathological examination. Therefore, a biopsy should be performed whenever possible.

bubble_chart Treatment Measures

In recent years, advances in chemotherapy have significantly improved the prognosis of this disease. The specific treatment strategy depends on the disease stage, whether it is localized or systemic, the presence of functional impairment in major affected organs, and age factors, among others.

1. Treatment of bone and skin lesions For LCH presenting as localized bone lesions, the condition is often benign. Biopsy combined with curettage of the lesion can achieve therapeutic goals, and some patients may also experience spontaneous recovery over several months to years. The bone healing process takes approximately 10 weeks, with new trabeculae appearing in areas where trabeculae have disappeared. Sclerotic changes emerge around 13 weeks, the edges of the defect disappear around 24 weeks, and complete healing may occur between 36 to 40 weeks. About half of the patients require over a year for complete bone healing. Recent reports indicate that intralesional corticosteroid injections, either as local treatment or systemic adjuvant therapy, have yielded favorable results. Depending on the lesion size and the patient's age, the dose of methylprednisolone injected can range from 75 to 150 mg.

2. Treatment of systemic disease For patients with disseminated LCH, although spontaneous recovery without chemotherapy has been reported, systemic treatment should still be prioritized. For example, the efficacy of single-agent therapy with vincristine (VCR), vinblastine (VBL), or cyclophosphamide (CTX) is as follows: VCR 1.5–2 mg/(m²·W), VBL 5–6.5 mg/(m²·W), and CTX 2.5–5 mg/(kg·d), with response rates of 50%, 55%, and 65%, respectively. When using VCR + prednisone (Pred) 40–60 mg/(m²·d), or 6-mercaptopurine (6MP) + Pred, or chlorambucil + Pred, the remission rates range from 45% to 65%.