Langerhans histiocytosis

Introduction to Langerhans' histiocytosis Langerhans' cellhistiocytosis (LCH) is a group of unexplained histiocytosis disorders. Langerhans cell (LC) hyperplasia is a common histopathological feature, but clinically It is a group of heterogeneous diseases. basic knowledge The proportion of illness: 0.0005% Susceptible people: no special people Mode of infection: non-infectious Complications: ascites edema, hypersplenism, diabetes insipidus, ataxia

Cause of Langerhans' histiocytosis

Infection theory (30%):

Acute cases of this disease, such as: LSD often have otitis media, sepsis, respiratory or digestive tract infections, a few cases are effective for antibiotic treatment, etc., seems to support this disease and infection, but the specific infection factor has not been confirmed, there are still people Study the relationship between this disease and certain viral infections.

Tumor (25%):

The prognosis of each type of this disease varies greatly. Whether the limitation of this disease is benign, and the acute type, especially the systemic type, is malignant. Some people are trying to solve the above by cell proliferation kinetics, DNA ploidy analysis or cloning. In doubt, after 1991, the International Organizational Cell Association registered 27 patients with LCH with malignant disease in 1 year, 4 with malignant lymphoma, 10 with other malignant solid tumors, and the remaining 13 cases occurred successively. Acute leukemia, including acute lymphoblastic leukemia in 5 cases, with acute myeloid leukemia in 8 cases, the exact nature of LCH associated with tumors remains to be further studied.

Immunobiological factors (20%):

In recent years, with the development of immunology and molecular biology, many people have made a lot of new explorations on the pathogenesis of this disease, in view of the important role of monocytes and macrophages in immune regulation and Langehans The cell line is differentiated from bone marrow mononuclear cells. In the past, efforts were made to find evidence of immune dysfunction in LCH patients. In 1981, Osband found that LCH patients had inhibitory T cell (T8, CD8) deficiency and peripheral blood helper T cells (T4). , CD4) and T8 ratio increased, and then the use of thymus extract to treat the disease to achieve efficacy, but did not get repeated verification of the posterity, Beijing Children's Hospital for 143 cases of various types of LCH patients, T cell subsets, and Continuous observation before treatment and 6 months to 9 years after treatment showed that the ratio of T4 and T4/T8 was significantly lower before treatment, and both values were improved after treatment. There was no statistical significance before and after treatment, suggesting immunological disorder. Not limited to the number of T4 and T8 changes.

(two) pathogenesis

The immune process plays an important role in the development of many benign and malignant diseases. It has been recognized that LC exists in the epidermis and shares the barriers and participates in immune responses with Thy-1+ cells and keratinocytes. These cells can produce certain Protein or glycoprotein as an immunoregulatory factor regulates cell growth and differentiation by specific receptors on target cells. Cytokines have strong effects on LC. These immune media may be closely related to LC proliferation of LCH. Although a specific pathway for cytokine-associated responses in LCH has not been found, the following results suggest a possible cause of LCH, in which cells in the LCH bone lesion spontaneously produce interleukin-1 (IL-1) and prostaglandin E2 ( PGE2), it is believed that LC in the bone lesion site acts by locally secreting IL-1 or directly causing bone absorption, or by generating PGE2 from neighboring cells, which may be the cause of multiple organ damage to the patient. Steiner By immunohistochemical study of 7 cases of LCH skin, it was found that LCH had an interleukin-2 (IL-2) receptor in LC, whereas LC in normal skin did not. It is proved that the LC of LCH has been activated, which may accelerate the process of its proliferation. In addition, Koch et al. demonstrated that tumor necrosis factor (TNF) released from keratinocytes and IL-1 and granulocyte-monocyte colony-stimulating factor (GM- CSF) may together constitute a signal for LC activation in the epidermis. The synergistic effect of GM-CSF and TNF plays a key role in the transformation of CD34 hematopoietic precursor cells into LC. Recently, it has been found that the content of certain cytokines in the lesions of LCH patients increases. These factors suggest that these factors play an important role in the induction of changes in LC phenotype. The changes in LC phenotype promote the development of LCH, which shows the close relationship between this disease and immunobiology.

The main pathological change of LCH is the presence of a number of tissue cells (ie, pathological LC) in the diseased tissue, stained with hematoxylin-eosin, which is a mononuclear cell under light microscopy with an average diameter of 12 m and medium cytoplasm. Amount, quality, fine pink particles, rare cytoplasmic vacuoles and phagocytosis, the nucleus often has folds or notches, or multi-lobed, nuclear chromatin irregular, containing 1 to 3 alkaloids Sexual nucleoli, fused tissue cells can form multinucleated giant cells, mitotic phase is absent, and a small amount of eosinophils, lymphocytes, plasma cells and neutrophils are visible in the diseased tissue, under TEM, cytoplasm Irregular edges, many pseudopods, abundant cytoplasm, and a number of scattered organelles, such as rough endoplasmic reticulum, free polysomes, lysosomes and mitochondria, etc. Slip surface endoplasmic reticulum is rare. Sometimes there are more Golgi devices, and the cytoplasm contains a special organelle. Langerhans cell particles or Birbeck particles are plate-shaped in the cytoplasm, ranging in length from 190 to 360 nm, but the width is relatively constant. 33nm, there is a striatum in the center, there is At the end, a cystic dilatation is seen, which is a tennis racket, often attached to the cytoplasmic membrane or a continuation thereof. Its function is not known. This Birbeck particle is unique to LC.

The main role of LC is to treat antigens and present this antigen to lymphocytes. The immunophenotype mainly shows FC-IgG receptors and C3 receptors. Its function is similar to that of mononuclear-macrophage system. In 1977, Elleder used immunization. Histochemical staining showed positive staining of LC-D mannosidase. Two years later: Nezelof confirmed that most of the LC cytoplasmic membrane was ATP-positive. In 1982, Nakajima found proliferating LC cytoplasm and nuclear S-100 protein positive. Response, the same year: Howard and Bastak reported that peanut agglutinin can be used as a marker of LC. In 1981, Murphy et al. first discovered that CD1a antigen was present in LC. These findings all constitute an important basis for the subsequent diagnosis of LCH.

Normal LC is mainly present in the epidermis of the skin, a few are found in the dermis, and a small amount of LC is also seen in the lungs and in the lymph nodes. From the existing pathological and immunophenotypic examination methods, it is difficult to normalize the normal and pathological LC. differentiate.

Langerhans Histiocytosis Prevention

LSD often has otitis media, sepsis, respiratory or digestive tract infections, and a few cases are effective for antibiotic treatment. It seems to support this disease and infection. It is recommended to actively prevent infection. It is recommended to pay more attention to eating more fruits and vegetables and drinking more water, and exercise to increase immunity. Pay attention to actively keep warm and prevent colds. Be careful to wear a mask and take care to prevent respiratory diseases. It is important to note that early prevention is important.

Langerhans histiocytosis complications Complications ascites edema, spleen function, hyperthyroidism, ataxia

1. Severe skin lesions often become secondary infections. Localized masses appear when soft tissue is involved. Most of them are found in the skull, neck, and bone lesions in the vicinity. The soft tissue of the external auditory canal is invaded. The external auditory canal can be overflowed, often with mastoid inflammation. , otitis media coexist.

2. Severe cases of cirrhosis with ascites and edema, and even liver failure, splenomegaly, can produce cytopenia caused by hypersplenism.

3. The combined skull destruction and exophthalmos accounted for 9.1%, similar to the results reported abroad. Patients with diabetes insipidus may be associated with developmental disorders, which are related to pituitary growth hormone deficiency. Late stage may be combined with other signs of CNS damage. Cerebellar lesions are LCH. The second most common site of CNS can cause ataxia and other manifestations. Some patients have found that cerebellar lesions have been discovered for many years after the disappearance of LCH. Patients may be associated with fever during the course of the disease, especially in young children, except by LCH itself. In addition, co-infection is an important cause of fever.

Langerhans histiocytosis symptoms common symptoms maculopapular dry cough, dyspnea, gums, swelling, urine collapse, low heat, wheezing, diarrhea, polydipsia

The clinical signs of LCH are obviously heterogeneous, and the onset can be concealed or sudden. The disease range can be damaged from the local involvement of an organ to multiple parts of the organ, and can also affect multiple organs, ie, multiple systems. The incidence, the severity of the disease and the age are closely related, the younger age has a wide range of lesions, the disease is heavy, with age, the lesion range is correspondingly reduced, the condition is often lighter, clinically, bone, skin, soft tissue lesions are the most common, followed by the liver, The spleen, lymph nodes and lungs are again the hypothalamus-pituitary and other parts of the central nervous system (CNS).

1. Skeletal lesions: mainly flat bones, but can also involve long bones. The lesions are isolated or multiple, and can be affected at the same time as other organs. The bones of the lesions are mostly without any symptoms, and local pain can also occur. Eyelid lesions can be One-sided or bilateral ocular protrusion is one of the characteristic clinical manifestations, which is caused by the formation of granuloma after the eyeball. The skull is involved in the first position. When the large area is destroyed, the induration often forms an indurated mass, which then becomes soft and fluctuating. After absorption, the scalp is concave, sometimes touching the edge of the bone defect. When the pedicle or vertebral body is involved, limb numbness, pain, weakness, and even spinal cord or spinal cord compression symptoms such as paralysis and incontinence may occur. Clinically, mastoid inflammation, otitis media, and maxillary involvement can cause swelling of the gums, loose or floating teeth, and less involvement of the hands and feet.

2. Skin and soft tissue damage: Eczema-like rash is the most common, especially in infants and young children, followed by skin lesions similar to seborrheic dermatitis, papules or nodules, with lesions at the folds and scalp. There are two types of skin lesions: 1 acute type: acute onset, mostly infants, skin lesions are mainly distributed in the limbs, starting from rash, and soon turned into exudative eczema and seborrheic dermatitis, may be associated with bleeding, knot, desquamation, often leave white spots after quiescence, rash can exist at the same time, one after another; 2 chronic type: slow onset, scattered in all parts of the pale red maculopapular rash, can be converted to brown red, brown Yellow or yellow, forming papules or verrucous nodules, when the depression subsides, the central depression subsides, resembles crusted chickenpox, and finally the skin becomes thin and slightly concave, slightly shiny, or slightly desquamate, sometimes the skin lesions can subside .

3. Liver, spleen, lymph node enlargement: more common, the degree of swelling is different, mostly mild to moderate swelling, isolated or systemic lymphadenopathy, more common in adults than in children, liver involvement can cause intrahepatic cholestasis , there is jaundice.

4. Pulmonary lesions: more common in childhood than in infancy, lesions can be limited, but more part of the systemic lesions, adult LCH lung involvement is more common, the incidence is more than children, sometimes the only lesions in the body, the lungs Affected by dry cough, chest pain, shortness of breath, wheezing, etc., a small number of patients with pneumothorax, mediastinal emphysema and subcutaneous emphysema, make breathing difficulties worse, more than 5% of CDla positive cells can be found in bronchoalveolar lavage fluid, lung lesions People, especially adults with lung cancer, may be significantly higher than the normal population.

5. Diabetes insipidus and nervous system damage: Skull lesions spread to the brain parenchyma, or intracranial granuloma infiltration can cause CNS lesions, CNS lesions are often confined to the hypothalamus - pituitary, polydipsia, polyuria, but very Less is the first performance of LCH, the incidence of diabetes insipidus is 5% to 30%. At this time, there are often signs of multiple organ involvement. The positive water limitation test is an important basis for diagnosis. It is necessary to detect blood antidiuretic hormone ( ADH) and blood, urine osmotic pressure, while the head CT rarely shows lesions, only a few patients with abnormal findings of magnetic resonance imaging (MRI).

Langerhans Histiocytosis

1. Peripheral blood: Systemic diffuse LCH often has moderate to severe anemia, reticulocytes and white blood cells can be slightly increased, platelets are often reduced, and in a few cases there may be leukopenia.

2. Bone marrow examination: Most patients with LCH have normal bone marrow hyperplasia, and a few can be active or decreased. A total of 59 cases of LCH reported by Beijing Children's Hospital have different degrees of myeloproliferative and/or megakaryocyte reduction. Bone marrow dysfunction, most of the reticular cells in the bone marrow are normal, only a few have a slight increase. In 470 cases of comprehensive domestic reports, only 4 cases of abnormal reticular cells were seen, and 1 case of phagocytic erythrocyte reticulocytes, indicating a few LCH bone marrow is infringed, so this test is only done when abnormal peripheral blood is found.

3. ESR: In some cases, ESR increases.

4. Liver and kidney function: Some cases have abnormal liver function, which indicates poor prognosis, including SAST, SALT, alkaline phosphatase and blood bilirubin increase, plasma protein decrease, prothrombin time prolongation, fibrinogen content and Partial thromboplastin production test is reduced, renal function includes urine osmotic pressure, and those with diabetes insipidus should measure urine relative density and conduct water restriction test.

5. Blood gas analysis: If there is obvious hypoxemia, it indicates impaired lung function.

6. Pathological examination: The key to the diagnosis of this disease is the pathological examination of the tissue infiltration of Langerhans cells. Therefore, biopsy should be done as much as possible. If there is a new rash, it should be rashed, such as a rash. Skin biopsy is more reliable; lymph node enlargement, lymph node biopsy, bone destruction, tumor scraping, scraping for pathological examination, or thick needle at bone destruction Puncture drainage for smear examination, conditional units, the above specimens should be sent for ultrastructural examination under fluoroscopy, in order to find positive Langerhans cell particles (Birbeck particles).

7. Immunohistochemical staining: As mentioned above, Langerhans cells have been found to have an immunophenotype of CD1a in recent years, and anti-CD1a monoclonal antibody is specifically positive for immunohistochemical staining, and the following four enzymes are also available. Positive reaction, namely S-100 neuroprotein, -D-mannosidase, ATPase and peanut agglutinin, can be used to confirm the diagnosis if there are conditions.

8. X-ray examination: Chest X-ray examination can be seen in the lungs with dot-like shadows, severe cystic emphysema, honeycomb-like lungs, emphysema, pneumothorax, etc., bone X-ray visible single or multiple bones Quality defect, manifesting osteolytic damage. If a part of the lesion is found, the bone image of other parts should be taken, followed by the skull, spine, pelvis and proximal limbs.

9. Pulmonary function test: Patients with severe lung disease may have different degrees of pulmonary dysfunction, which may indicate poor prognosis.

10. Immunological examination: In view of the fact that this syndrome often involves immune regulation dysfunction, such as the abnormal number of T cell subsets and the imbalance of T-assisted and T-suppressed cells, the conditioned condition should be phenotypic analysis of T cell subsets. , lymphoblastic transformation test and serum immunoglobulin quantification.

Diagnosis and differentiation of Langerhans histiocytosis

Diagnostic criteria

The traditional diagnosis method of this disease is based on clinical, X-ray and pathological examination results, that is, the pathological examination of the lesion can be confirmed by tissue infiltration in the lesion, in view of Langerhans cells have a special immunophenotype and super Microstructure, the International Organizational Cell Association recommended in 1987 that the credibility of the diagnosis of this disease is divided into three levels, to improve the credibility of the diagnosis, first of all to facilitate the identification of this disease and other types of histiocytosis, conducive to international The harmonization of diagnostic criteria is also necessary to strengthen international exchanges and further in-depth research, which puts higher demands on the diagnostic level of hematologists.

1. Traditional classification This disease is traditionally divided into three types.

(1) Lettler-West's disease (LSD): more common in infants and young children, the peak incidence within 1 year old, the most common symptoms are rash and fever, followed by cough, pale, poor nutrition, diarrhea and hepatosplenomegaly.

(2) Han-Xu-Ke disease (HSCD): The head mass, fever, exophthalmos and urine collapse are common symptoms, but also may be accompanied by rash, liver spleen and anemia.

(3) Bone eosinophilic granuloma (EGB): more manifested as single or multiple bone damage, or accompanied by hypothermia and secondary symptoms (such as neurological symptoms and pain).

"Practical Pediatrics" has added three types on the basis of the above classification, namely: intermediate type: refers to the transition type of ISD and HSCD; single organ type: refers to the disease alone invading an organ; difficult to type: refers to difficult to column Enter the above categories.

2. Lavin and Osband grading authors proposed a new grading method in 1987: summarizing the age, the number of affected organs and their functional status, three main factors affecting prognosis. Through our clinical practice, we realized that this grading method is Grading the disease as a whole can avoid the cumbersome and overlapping of traditional classification, reduce the difficulty of diagnosis and classification, and directly relate to the prognosis according to different grades, and take corresponding treatment strategies.

3. International Histocytic Society (Histolocyte Society) classification: The International Organization of Cellular Association in the LCH international treatment program started in 1983, the LCH is divided into two types of single system disease and multi-system disease.

(1) Single system disease:

1 single site type: A. single bone damage; B. isolated skin lesions; C. isolated lymph node involvement.

2 multi-site type: A. multiple site bone damage; B. multiple site lymph node involvement.

(2) Multi-system disease: refers to multiple organ involvement.

It has been reported that multi-site and multi-system diseases in single-system diseases are collectively referred to as diffuse LCH, and a comparative chemotherapy regimen is adopted.

Differential diagnosis

(1) skeletal system: bone lesions of this disease such as irregular destruction, soft tissue swelling, sclerosis and periosteal reaction, can also be seen in osteomyelitis, Ewing sarcoma, osteosarcoma, giant cell tumor of bone and other neuroblastomas Bone marrow metastasis should be distinguished from it.

(2) Lymphatic network: liver, spleen and lymph node enlargement must be differentiated from tuberculosis, Hodgkin's disease, leukemia, chronic granulomatosis, Niemann-Pick disease, Gaucher disease and blue cell histiocytosis.

(3) Skin diseases: It should be differentiated from seborrheic dermatitis, atopic eczema, pyoderma, thrombocytopenic purpura, etc. Skin candida infection may be confused with the scaly rash of this disease, but after the lesion is healed The formation of small scars and pigmentation is characteristic.

(4) Respiratory system: Special attention should be paid to the identification of miliary tuberculosis. There have been many cases in which LCH was misdiagnosed as tuberculosis.

2. Identification with other histiocytosis

(1) sinus histiocytosis with massive lymphadenopathy (SHML): SHML often presents as a painless enlargement of bilateral cervical lymph nodes, the incidence of which is much lower than LCH, except In addition to cervical lymph node involvement, the remaining lymph nodes or extranodal lesions such as skin, soft tissue and bone damage can be seen in more than 40% of patients, skin lesions are often yellow or yellow tumor-like, bone lesions are also osteolytic lesions, X-ray is difficult Different from LCH, the histological features of SHML are sinus hyperplasia of tissue cell population, and mixed with other lymphoid cells and plasma cells. The diseased cells lack typical LC nuclear sag characteristics, and CDla antigen is negative, and ultrastructural examination is lacking. Birbeck particles are thus different from LC.

(2) Hemophagocytic lymphohistiocytosis: familial hemophagocytic lymphoidhistiocytosis (FHLH) is a group of clinical syndrome characterized by fever, complete cytopenia and liver and splenomegaly. The diagnosis is based on bone marrow, lymph nodes, liver and spleen and meningeal lesions, hypertriglyceridemia, low fibrinogen and cerebrospinal fluid. Lymphocytosis is a typical change of the disease. FHL is autosomal recessive, sometimes diagnosed. It is extremely difficult to distinguish from secondary hemophagocytic syndrome in children. The latter is also called virus-associated hemophagocytic syndrome (VAHS). Later, VAHS is expanded to be applied to other similar factors induced by other infectious factors. Signs, even cases of hemophagocytic syndrome in which children have not received any immunosuppressive therapy or have not been significantly infected, are currently lacking laboratory or histopathological methods to distinguish these syndromes, such as lack of family history, identification of families Sexual or secondary will be quite difficult, for this reason, the Tissue Cell Association FHL Study Group will FH L and VAHS are collectively named hemophagocytic lymphoidhistiocytosis (HLH).

(3) This disease should also be distinguished from malignant histiocytosis, acute monocytic leukemia and true histiocytic lymphoma.

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