Langerhans cell histiocytosis in children

Introduction to pediatric Langerhans cell histiocytosis Langerhans cell histiocytosis (LCH) is a histiocytosis type I. Langerhans cell histiocytosis is a monoclonal-derived dendritic cell proliferative disease with diverse clinical manifestations. The lesions can be focal or disseminated. It is a group of urgency, clinical symptoms and differences in lesion range. A big syndrome, so far, the cause is not yet clear. With the advancement of chemotherapy methods, the prognosis of this disease has been significantly improved in recent years. basic knowledge Sickness ratio: 0.0001% Susceptible people: children Mode of infection: non-infectious Complications: respiratory failure, diabetes insipidus, superior vena cava syndrome

Causes of Langerhans cell histiocytosis in children

(1) Causes of the disease

The etiology and pathogenesis of LCH are still unclear. Possible etiology includes infection, immune dysfunction and tumors. It is generally believed that LCH has no genetic predisposition. At present, it is considered that this disease is an immune disease. Nature is still a hot issue of debate. Although a few cases eventually develop into malignant tumors, most studies consider it to be an immune disease. There is no research to confirm the correlation between bacteria and fungal infections and LCH. The virus was once suspected of being LCH. The cause is that LCH may be caused by human herpesvirus-6 (HHV-6) and human cytomegalovirus (HCMV), but there is still no strong evidence that the location of HHV-8 infection in the pathogenesis of LCH is also Not yet determined, in summary, ultrastructural studies of LCH did not reveal viral particles or virus-specific cell products.

(two) pathogenesis

1. Pathogenesis of normal LC originated from bone marrow CD34 stem cells, is an antigen-presenting-cell (APC), can secrete a variety of biologically active cytokines, pLCs produce IL-1, IL- Various cytokines such as 1, IL-4, TNF-, INF-, GM-CSF, TGF- and TGF-. This cytokine storm is an important component of the pathogenesis of LCH and is associated with LCH. Clinical features such as inflammatory hyperplasia, necrosis, fibrosis and osteolytic lesions, macrophages, eosinophils, giant cells, lymphocytes, especially lymphocytes, produce cytokines in LCH lesions It also plays a very important role. The proliferation of LCH is close to that of inflammatory tissue and lower than that of neoplastic tissue. Some scholars believe that clonal hyperplasia of pLCs is a response to inflammatory stimuli, similar to other inflammatory diseases when T, B or NK cells Clonal expansion, lesions are benign and can be repaired; while lesions are malignant, they can spread and have high risk factors leading to fatal outcomes, which can explain the variability of clinical symptoms and can also explain the lungs of adults. LCH is just Local infiltration of pLCs in the lungs has different opinions on whether LCH is an inflammatory response or a neoplastic hyperplasia, but it may reflect the fact that some cases of infection-reactive proliferation can develop into neoplastic diseases.

For example, Kaposis sarcoma caused by human herpesvirus 8 (HHV8) infection is one of the representatives. Yousem et al. analyzed the molecular cloning of adult lung LCH and found that only 29% of the diseased tissues showed clonality. Therefore, the LCH of the lung is not supported as a hypothesis of a neoplastic disease. The granuloma is considered to be a physiological response that prevents the spread of pathogens in the cell. In the case of granulomatosis, the balance between cell proliferation and apoptosis is highly reversal and network. Agglomeration plays a crucial role in inflammatory diseases such as benign lymphogranulomatosis, Crohn's disease and Wegeners granulomatosis. Swelling, this change has a protective effect on the tissue rather than a protective effect. Geissmann et al.'s studies have shown that the degree of differentiation of pLCs is different in different processes of the disease, and the expression of immature dendritic cells in pLCs in patients with chronic or bone infiltration Type (eg CD68, CD14), but not the cell membrane major histocompatibility complex (MHC) class II molecule or costimulatory molecule CD86, while IL-10 is positive, in adult lung LCH patients pLCs expressed CD86 and IL-10 negative. These results further suggest that adult lung LHC and chronic or bone infiltrating LHC may be different from clinical and pathophysiological processes. The former is a fibrous hyperplasia rather than a tumor process after inflammation, and it can also be speculated IL-10 produced by CD1-macrophages plays a crucial role in maintaining the immature properties of pLCs.

2. Pathological changes The pathological changes of LCH are proliferative granuloma. The pLCs are mononuclear cells under light microscope, with a diameter of about 13 m. The cytoplasm is uniform pink, and the nucleus is curved like a coffee bean or a multilobular nucleus. Irregular chromatin, containing 1 to 3 basophilic nucleoli, nucleoli is obvious, under electron microscope, the cytoplasm is irregular, the pseudopod is easy to see, the cytoplasm is abundant, and there are a number of scattered organelles, such as coarse Endoplasmic reticulum, free polysomes, lysosomes and mitochondria, etc. The cytoplasm of pLCs contains a special organelle unique to LC - Langerhans cell pellets or Birbeck particles, which are long-plate shaped. It has a length of 190-360 nm and a width of 33 nm. It has a striatum in the center. Sometimes it can be seen as a saclike expansion at the end. It is a tennis racket or a rod. In addition to LC, lesions can also be seen in eosinophils, macrophages and lymphocytes. The cells proliferate to varying degrees.

In addition, there are also combined multinucleated giant cells, a few neutrophils and plasma cells. As the disease progresses, the lesions can be fibrotic or yellow tumor-like changes, and focal hemorrhage, necrosis and giant hemoglobin particles can be seen. In phagocytic cells, different stages of hyperplasia, necrosis or fibrosis can occur at the same time. The early stage of the lesion is only a single non-lipidated LC. The longer the lesion, the more easily the fat-filled cells (foam cells) are visible, and the longer the disease is visible. A large number of fat-filled LC and eosinophils, or eosinophils mainly form granuloma, the center of hyperplasia often has necrosis, through the frozen paraffin embedding of LCH specimens, pathological studies by immunoperoxidase staining found Langerhans cells and pLCs express MHC class I and class II proteins, CD1a, CD4, CD14, S-100, CD74 and vimentin, while also expressing CD25, IFN-, CD11b, CD35, CD21 and Fascin and adhesion molecules CD54 and CD58, these molecules can be detected in activated Langerhans cells, Langerhans cells are positive by immunohistochemical staining for ATPase, -mannose and S-100 protein The immunohistochemical staining has been used as one basis for the diagnosis of LCH.

Pediatric Langerhans cell histiocytosis prevention

The etiology and mechanism are not yet clear, and the focus is on actively preventing and treating infectious diseases.

1. Avoid contact with harmful factors to avoid exposure to harmful chemicals, especially drugs, pay attention to rational use of drugs, contact with poisons or radioactive substances, and strengthen various protective measures.

2. Vigorously carry out prevention and treatment of various infectious diseases, especially viral infections.

3. Strengthen physical exercise, pay attention to food hygiene, maintain a comfortable mood, work and rest, and enhance the body's resistance.

Pediatric Langerhans cell histiocytosis complications Complications, respiratory failure, diabetes insipidus, superior vena cava syndrome

Eczema-like, sebum-like rash, can leave white spots or pigmentation; extensive infiltration of the lungs, often complicated by respiratory infections, prone to pneumonia, and pneumothorax and subcutaneous emphysema, respiratory failure is the leading cause of death; bone lesions can occur Pathological fractures, but also osteolytic bone lesions; vertebral arch destruction, often accompanied by nerve compression symptoms, such as limb numbness, pain, weakness, paralysis, and even incontinence; can be complicated by digestive ulcers; liver, spleen Lymph node enlargement; ear pus, malnutrition, growth retardation, diarrhea and anemia; complicated with diabetes insipidus, biliary atresia and superior vena cava syndrome.

Symptoms of pediatric Langerhans cell histiocytosis common symptoms rash papillary tissue cell hyperplasia diarrhea diarrhea panting urine collapse eyeball highlight high fever low heat scarring

The clinical manifestations vary greatly, and may be focal or systemic. The onset may be acute and slow, and the course of disease may be as short as several weeks or as long as several years. Each subtype has a relatively special clinical manifestation, but may be excessive or Overlapping performance.

1. Le-Ray syndrome (acute infant type) is mainly visceral lesions. This type of clinical manifestation is the most serious, and the most common, more than 1 year old, the onset is acute and serious, mainly affected by internal organs and skin. It is characterized by fever, rash, cough, pale, ear pus, liver, spleen is rapidly enlarged, the lungs are extensively infiltrated, the lymph nodes are slightly swollen, the heat type is irregular, and it is more common in periodic or persistent high fever. See the heat of queer, the rash is more special, mainly distributed in the trunk, neck, scalp and hairline, the limbs are rare, the beginning is a pale red maculopapular rash, diameter 1 ~ 3mm, followed by hemorrhagic or eczema-like, sebum-like rash, After the rash surface crusted, desquamation, leaving white spots or pigmentation after dislocation, rash can exist at the same time, often in batches, a batch of subsided, a batch of up, hand touch when there is a rough feeling, before the rash Often fever, rash accompanied by liver, spleen enlargement, rash fever, liver, spleen also shrink, often have a light cough, accompanied by respiratory infections, symptoms sharply aggravated, prone to pneumonia, asthma and cyanosis However, the signs of the lungs are not obvious, because of the interstitial lung Lesions can be complicated by pneumothorax and subcutaneous emphysema. Respiratory failure is the leading cause of death. In addition, common ear pus, malnutrition, diarrhea and anemia can also have osteolytic bone lesions, but compared with other types 2 Less, if not treated, often die within 6 months.

2. Han-Xue-Ke syndrome bone damage with moderate other organ invasion, also known as chronic xanthoma, occurs in children 3 to 4 years old, skull defect, exophthalmia, diabetes insipidus is the three characteristics of this type These three characteristics may appear one after another or only one or two in the course of the disease. The initial skull injury is a lumpy bulge, hard and mild tenderness. When the lesion penetrates the outer plate of the skull, the mass becomes soft. There is a sense of volatility, often touch the edge of the skull, tenderness is not obvious, after the lumps gradually absorbed, local depression, the defect can touch the brain, and with the pulse beat, the eyeball is mostly unilateral, for the destruction of the humerus As a result, diabetes insipidus is caused by pituitary or hypothalamic involvement, not necessarily saddle destruction, rash is isolated, sparse yellow papules, like half a millet or soy-like shape, protruding on the surface of the skin, if pressed by a slide On the above, it can be seen that the central rash of the rash is the cause of the chronic yellow tumor disease. After that, the rash begins to fade and become soft, shallow, and slowly absorbed. In addition, low fever, mild liver, spleen enlargement, anemia, and gum sulcus Swelling, inflammation, necrosis, atrophy, loose teeth, Fall is also common, severe lung involvement seen wheezing and cyanosis, prolonged course of this type, inter-face disease, most patients eventually recover.

3. Bone eosinophilic granuloma is a simple type of bone lesion, which is the best prognosis in this disease. It is usually caused by children aged 4 to 7 years old, but it can also be seen in infants or adults. Any bone can be affected, but with skull. The limbs, spine, and pelvis are the most common. The lesions are mostly single or multiple. The patient has no other symptoms or only low fever except for bone lesions. Many children are found by chance or pathological fracture. Only children with spinal lesions, especially those with vertebral arch destruction, often have symptoms of nerve compression, such as limb numbness, pain, weakness, paralysis, and even incontinence become the main complaint of the disease and seek medical treatment.

Examination of Langerhans cell histiocytosis in children

1. There are no characteristic changes in blood picture, generally positive cells are positive pigment anemia, severe cases may have thrombocytopenia or leukopenia.

2. Bone marrow examination LCH patients with more common bone marrow hyperplasia, a small number of hyperplasia can be found, pLCs are rarely found in the bone marrow, so bone marrow cytology examination lacks specificity, generally as a routine examination in the case of abnormal blood.

3. Hepatic and renal function abnormalities of liver and kidney function indicate poor prognosis. Liver function tests include SAST, SALT, alkaline phosphatase and blood bilirubin increase, plasma protein decrease, prothrombin time prolonged, fibrinogen content decreased, etc. Renal function tests include urea nitrogen, creatinine, urinary osmotic pressure, etc. If there are symptoms of diabetes insipidus, urine relative density and water restriction test should also be tested.

4. Pulmonary function such as blood gas analysis showed obvious hypoxemia, suggesting impaired lung function, and pulmonary dysfunction often indicates poor prognosis.

5. Immunological examination routine immunological examination is more normal, T cell subsets can be reduced T4, T8 can be reduced, lymphocyte transformation function can be reduced, T lymphocytes lack of histamine receptors.

6. Pathological biopsy or rash print biopsy shows typical Langerhans cells as the basis for diagnosis. Skin lesions, lymph nodes, bone lesions, local punctures or scrapings can be pathologically examined, which is characterized by better differentiation. Tissue cell proliferation, foam-like cells, eosinophils, lymphocytes, plasma cells and multinucleated giant cells can also be seen. Different types can have different cell components. In severe cases, the original tissue can be destroyed, but the differentiation is poor. In malignant tissue cells, a large number of multi-lipid tissue cells and eosinophils are seen in chronic lesions, forming eosinophilic granuloma, which may have hemorrhage and necrosis.

7. Immunohistochemical staining S-100 protein staining positive, CD1a positive, in addition to -D-mannosidase, ATPase and peanut agglutinase can also be positive.

8. Electron microscopy The Langerhans giant cells, which are large mononuclear cells with irregular cell bodies, up to 13 m in diameter, with scattered organelles in the cytoplasm, and special organelles called Langerhans particles or Birbeck particles, can be seen in the lesions. Support the diagnosis of this disease, the particle length is 190-360nm, the width is 33nm, the end can be foam-like expansion, the shape is like a tennis racket, the nucleus is irregular, twisted, and the nucleolus is obvious, mostly 1~3.

9. Skeletal X-ray examination of the whole body bone film can be found, the lesion features osteolytic destruction, flat bone and long bone osteolytic bone destruction, flat bone lesions are worm-like to huge defects, irregular shape, edge can be It is jagged, the skull has a huge defect and can be a map. The vertebrae are compressed with flat vertebrae, but the intervertebral space is not narrow. The long bones are mostly cystic defects. The single or interfacial fusion is atrial, the cortical bone is thin, and there is no dead bone. Formation, destruction can be obvious at the layer of periosteal hyperplasia, the destruction of the upper and lower jaw can cause tooth loss, the above typical bone X-ray changes suggest Langerhans cell histiocytosis.

10. X-ray examination of the lungs may have diffuse reticular or dot-net shadows, showing localized or granular shadows, which need to be differentiated from miliary tuberculosis. In severe cases, emphysema or honeycomb lung cysts, mediastinal gas can be seen. Swollen, pneumothorax or subcutaneous emphysema.

Diagnosis and diagnosis of Langerhans cell histiocytosis in children

diagnosis

Need clinical, radiation and pathology in combination with diagnosis, fever, anemia, hepatosplenomegaly, ear sputum with typical rash, consider Langerhans cell histiocytosis type I, exophthalmos, diabetes insipidus, skull Defect is a typical manifestation of type II syndrome, suspected and this disease, typical bone X-ray changes, rash print or biopsy, pathological examination of bone lesions to see typical Langerhans cells is the basis for diagnosis, laboratory examination S-100 protein staining was positive, and the Birbeck particles were found by electron microscopy to support the diagnosis of this disease. In 1987, the Tissue Cell Association writing group proposed a three-level standard for the diagnosis of LCH. This standard has been widely adopted internationally and it helps LCH. Identification with other histiocytosis is also conducive to international exchanges.

Differential diagnosis

1. The disease should be differentiated from the following histiocytosis

(1) sinus histiocytosis with massive lymphadenopathy (SHML): often manifested as painless swelling of bilateral cervical lymph nodes, other parts of enlarged lymph nodes and extranodal lesions such as skin, Soft tissue and bone damage can be seen in nearly half of patients, skin lesions are yellow or yellow tumor-like, bone lesions are osteolytic lesions, so clinical manifestations and X-ray findings are difficult to distinguish from LCH, histological changes of SHML are tissue cells Sexual hyperplasia, often mixed with other lymphoid cells and plasma cells, the diseased cells have no typical nuclear depression characteristics of LC cells, negative for CD1a antigen, and no Birbeck particles under electron microscope.

(2) Hemophagocytic lymphohistiocytosis (HLH) including familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hematopoietic cells Viral associated hemophagocytic syndrome (VAHS) is also known as secondary hemophagocytic syndrome. HLH is an autosomal recessive disorder. It is a group of clinical syndrome characterized by fever, complete cytopenia and liver and splenomegaly. The natural course is short and the prognosis is poor. About 10% of cases in FHL have chromosome 9q21.3-22 abnormalities, 20% to 30% of cases have chromosome 10q21-22 abnormalities, and most of the cases are infants within 6 months. 50% of cases have a positive family history, nearly 30% of parents have a history of close relatives, high triglyceride (>2.0nmol/L), low fibrinogenemia and lymphocytosis in cerebrospinal fluid are typical changes of FHL There is no rash in the child, no bone infiltration, no eosinophil infiltration in the lesion can be differentiated from LCH, but if there is a lack of positive family history, it is difficult to identify with VAHS clinically. This should be noted in the diagnosis, the clinical characteristics of VAHS is complete blood cell reduction, mononuclear macrophages in the bone marrow, and the phenomenon of phagocytosis of blood cells, children with high fever, hepatosplenomegaly, abnormal liver function and coagulopathy It is believed that in addition to viral infection, VAHs can be secondary to bacterial or fungal infections, also known as LAHS (infection associated hemophagocytic syndrome), which can be self-healing after removal of infectious agents.

(3) malignant histiocytic disorders: rare tumor diseases derived from tissue macrophages or histiocytes, which are difficult to distinguish from diseases such as HLH or SHML, clinically more common in adults, and children of any age. Can be onset, often manifested as high fever, weight loss, failure, skin mucosal hemorrhage, hepatosplenomegaly and lymphadenopathy, splenomegaly is particularly obvious, early bloody abnormalities of the disease are not obvious, with the progress of the disease can appear complete blood cell reduction, the disease progresses rapidly The prognosis is poor, and the course of disease is no more than 6 months. The main pathological features are malignant tissue cells or high-differentiated tissue cells in the liver, spleen, lymph nodes and bone marrow, and extensive focal infiltration in organs. Blood cells are phagocytized, and typical abnormal tissue cells found in bone marrow smears are an important basis for diagnosis and can be differentiated from LCH.

2. Identification with other diseases

(1) Diseases causing bone lesions: clinical osteomyelitis, Ewing sarcoma, osteosarcoma, bone giant cell sarcoma and other bone tumors and bone metastases of neuroblastoma can cause irregular bone destruction, sclerosis and periosteal reaction. When diagnosing LCH, care should be taken to distinguish these diseases that can cause bone lesions.

(2) Skin diseases: LCH has various skin changes and no specificity, and should be differentiated from seborrheic dermatitis, pyoderma, thrombocytopenic purpura and the like.

(3) Respiratory diseases: The lung manifestations of LCH are often confused with miliary tuberculosis, and attention should be paid to identification.

(4) Lymphatic network disease Liver, spleen and lymphadenopathy should be differentiated from Hodgkin's disease, acute leukemia, chronic granulomatosis, Niemann-Pick disease.

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