I. Definition of LCH
Langerhans cell histiocytosis (LCH) refers to a group of disorders in which the mononuclear phagocyte system and the dendritic cell system are proliferating. In 1953 Lichtenstein first suggested the name histoplasmosis X. In 1973 Zelof et al. reported that the damage in histoplasmosis X was caused by abnormal proliferation and dissemination of Langerhans cells. In 1973, Zelof et al. reported that the damage in histiocytosis X was caused by abnormal proliferation and dissemination of Langerhans cells, so it was called Langerhans cell histiocytosis.
Clinical manifestations
The disease can occur in children at all ages, with a peak incidence between 1 and 4 years of age. The incidence of the disease in children is about 1 to 2 per 200,000 per year, and is slightly higher in males. According to the extent of the lesion, the disease can be divided into.
(1) Le-sue disease, fever, rash, hepatosplenomegaly, respiratory symptoms, otitis media, anemia, diarrhea, etc.
(2) Han-She-Co disease; bone defects, proptosis, uveitis, and rash.
(3) Eosinophilic granuloma of bone: mainly bone damage. Flat bones predominate and may be associated with fever and anemia.
(4) Mixed type: equivalent to the combined manifestation of Leucer’s disease and Han-She-Co disease.
(5) Single organ damage type, only a single organ damage, such as liver, spleen, lymph nodes, skin, etc. without the damage of other organs.
(1) Bone lesions: Almost all patients with limited or extensive LCH have bone damage, which manifests as painful swelling in the early stage. The skull is most susceptible, followed by the long bones of the upper extremities and flat bones (ribs, pelvis, spine). x-rays can clearly show single or multiple osteolytic defects with irregular margins. 1994 Kelly et al. reported that since Langerhans cells contain CDla antigen on their surface, intravenous administration of a murine monoclonal antibody against CDla antigen labeled with 111 indium is feasible for immunolocalization of LCH, and it has been shown that anti-CD1 monoclonal antibody nAI/nAI/nAI/nAI/nAI/nAI/nAI/nAI/nAI/nAI/nAI/nAI. CD1 monoclonal antibody nAI/34 has been shown to be delivered to active sites of disease, especially bone disease, in patients with LCH, a development that has attracted attention.
2. Skin: LCH often has skin lesions as the first or only symptom, manifesting as scaly, erythematous, seborrheic brownish-red papules.
3, lymph nodes: the cervical lymph nodes are most commonly involved, up to the extent of giant masses.
Bone marrow: normal bone marrow tissue can be seen with other dendritic cells, but no Langerhans cells. bone marrow dysfunction in LCH patients can lead to allogeneic cytopenia with marked hepatosplenomegaly and poor prognosis.
5. Liver and spleen: Hepatomegaly in LCH patients can be caused by LCH damage or obstructive lesions due to enlarged hilar lymph nodes. Hepatomegaly can also be caused by hypertrophy and hyperplasia of blastocytes (indicating general activation of the cellular immune system) without direct LCH damage or obstructive liver disease. Poor liver function is manifested by hypoproteinemia, ascites, hyperbilirubinemia, and prolonged prothrombin time. Pathological examination shows mild cholestasis to more severe histocytic infiltration of the hilar region with hepatocellular damage and bile duct involvement, which may eventually progress to sclerosing cholangitis, severe fibrosis, biliary cirrhosis, and liver failure. On histocytological examination CDla+ Langerhans cells can be found in the hilar infiltrate, which is an important marker of LCH, but Birbeck granules are rarely seen. Splenomegaly may be a cause of one or more of the hemocytopenias.
6. Lungs: pulmonary LCH can occur at any age and presents with cough, shortness or difficulty in breathing, bruising, fever and weight loss. Chest x-ray shows diffuse small nodule-like lesions. The cystic structures in the lungs are increasing, forming a “honeycomb lung”, and in advanced stages, large alveoli and even spontaneous pneumothorax are formed. In the end stage, emphysema and interstitial fibrosis were formed and expanded. Auerswald et al. reported that all patients with histologically confirmed LCH had >5% washout CD+1 cells (normal should be <1%).
7. Gastrointestinal tract: Gastrointestinal involvement manifests as vomiting, diarrhea and protein-losing enteropathy. Abdominal radiographs show alternating segmental dilatation and stenosis in the small and large intestine, but endoscopic biopsy is required to confirm the diagnosis.
8, thymus: chest X-ray may show significant enlargement of the thymus.
9.Endocrine gland: DI is the most common endocrinopathy in LCH. It is commonly seen in patients with cranial involvement, and the diagnosis can be confirmed by water restriction test and urinary arginine pressin assay. Enhanced magnetic resonance imaging (MRI) may show thickening of the hypothalamic-pituitary stalk region (>2.5 mm) or lack of posterior pituitary “high signal” on T1-weighted images. Maghnie et al. found abnormal blood supply to the pituitary region of the hypothalamus, as evidenced by posterior pituitary strengthening >20 s and anterior pituitary strengthening >30 s. Growth retardation occurred in <1% of cases, mostly due to anterior pituitary involvement, growth hormone deficiency, impaired absorption, and corticosteroid treatment. However, most of the children with long-term follow-up in remission had no significant difference in height from the control group.
10. Central nervous system: acute manifestations such as intracranial hypertension or convulsions are rare. MRI shows high signal on T1-weighted images of the affected area, which helps in early diagnosis and follow-up. The lesions are usually symmetrical, often starting in the cerebellum and progressing to the paraventricular white matter. Biopsy shows histiocytic infiltration with yellow tumor changes, most of these histiocytes resemble the usual macrophages, and a few show typical Langerhans cells.
III. Diagnostic steps
In 1987, the Writing Group of the Histiocyte Society (WGHS) developed morphologic, immunohistochemical, and clinical criteria for the diagnosis of LCH and other histiocytic disorders in children by classifying them into 3 levels of confidence for the diagnosis of LCH.
(1) Proposed diagnosis: common pathomorphologic features.
(2) Diagnosis: ordinary pathomorphologic features plus ≥2 positive stains for the following
(i) adenosine triphosphatase.
②S-100 protein.
(iii) α-D mannosidase.
④Arachidonic phytohemagglutinin.
(3) Confirmation: general pathomorphological features, plus: electron microscopy showing Birbeck granules in lesioned cells, or positive staining for CDla antigen (T6) in damaged cells.
IV. Treatment
The treatment of patients with LCH depends on the extent of the lesion and the number of organs involved. Topical steroids are preferred for pure skin lesions, and if ineffective, low-dose systemic chemotherapy may be given. Bone damage alone may resolve spontaneously over months to years. In cases of severe pain or risk of disability or deformity such as impaired bone growth, fracture, hearing loss, or loss of permanent teeth, local corticosteroids may be administered to the lesion or localized lesions of the affected bone may be scraped to promote healing. If ineffective, low-dose radiotherapy at 150 cGy/d for 4 d. Lymph node involvement alone usually does not require treatment, and most cases resolve spontaneously.
Most advocate systemic chemotherapy for extensive LCH. Cyclophosphamide, cytarabine, pegylated glycosides (VP-16), and vincristine, with or without corticosteroids, have been shown to be effective in 50% to 60% of patients. 2-chlorodeoxyadenosine has been successfully used in patients with LCH resistant to conventional chemotherapy to exert specific cytotoxic effects and to control the release of immune-mediated cytokines. Those with DI symptoms can be treated with 1-desamino-8-D arginine pressor.
V. Follow-up and sequelae
The incidence of late sequelae of the disease is about 33% to 50%. They include intellectual problems, neurological symptoms, endocrine abnormalities, and disability requiring orthopedic surgery. It has not been demonstrated that extended treatment prevents these sequelae, with the possible exception of DI. McLelland et al. reported a 36% incidence of DI in patients receiving symptomatic treatment only, which is significantly higher than the incidence of DI in 106 children (15%) reported by Gadner et al. The latter treated all patients with multiple drugs and maintained them for 2 years. Except for 6 cases with DI at the time of diagnosis, only 10 of the remaining 100 children (10%) developed this complication later.
VI. Progress in basic research
Although the etiology of this disease is unknown, there has been some progress in the following three aspects.
1. Is LCH a neoplastic or reactive clonal disease? In the past, LCH was thought to be a reactive hyperplasia. Recently, experimental studies have confirmed that several types of LCH cells are clonally proliferating. It is also assumed that LCH is a neoplastic clonal disease, due to cell mutations that lead to clonal proliferation of Langerhans cells or their precursors in bone marrow and other organs. However, the response of a few progenitor cells attached to the lesion to cytokines can lead to non-tumorigenic clonal proliferation of tissue cells. Therefore, “clonality” does not necessarily mean malignant process, clonal cells have been found in several non-malignant diseases.
2. LCH is a cytokine-mediated disease. LCH patients have been found to have increased levels of certain cytokines in affected tissues. Another study showed that granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha can act together to induce hematopoietic stem cells (CD34 precursor cells) to produce Langerhans cells (20% containing Birbeck granules). Therefore, it can be inferred that the proliferation of Langerhans cells in LCH is related to the stimulation of these two factors.
3, It has also been proposed that LCH may be a reaction process after infection with a virus that can cause Langerhans cell proliferation (e.g. human herpesvirus-6).