Introduction to chronic lymphocytic leukemia

Description: Chronic lymphocytic leukemia (CLL) is a lymphoblastic proliferative neoplastic disease in which lymphocytes accumulate in bone marrow, lymph nodes, blood, spleen, liver and other organs. More than 95% of CLL is a clonal proliferation of B cells (ie, B-CLL), and less than 5% of cases are T cell phenotypes (ie, T-CLL). Etiology: (1) Causes of the disease The cause of CLL is unknown. There is no evidence that retrovirus and ionizing radiation can cause this type of leukemia; however, several factors are found to be closely related to the disease: hereditary (racial and familial) and gender. . 1. Genetic factors include CLL or other family history of lymphoid malignancies. The incidence of immediate family members is three times higher than that of the general population. The incidence of autoimmune diseases in relatives of CLL patients also increased significantly. 2. About 50% of CLL patients with chromosomal abnormalities have chromosomal abnormalities, often involving chromosomes 12 or 4, -8, i(7), i(2p), t(13;21), 18,6q-, 14q-, Abnormalities such as -X have been reported. Chromosomal abnormalities are related to the course of the disease. Early chromosomal abnormalities account for about 20%, and advanced cases can reach 70%. CLL-affected chromosomes often involve immunoglobulin-encoding genes (such as the heavy chain gene of chromosome 14) or oncogenes (such as c-ras-Harvey on chromosome 12 and c-ras-Kirsten on chromosome 11). (II) Pathogenesis The exact pathogenesis of CLL is unknown, and environmental factors are not significantly related to the incidence of CLL. Factors closely related to the onset of other types of leukemia, such as ionizing radiation, chemical carcinogens, and insecticides, have been reported to be unrelated to the pathogenesis of CLL. Viral infections such as HCV (hepatitis C virus) and Epstein-Barr virus are also unrelated to the pathogenesis of CLL. Although there were significantly more males than females in CLL patients, no correlation was found between sex hormones and the onset of CLL. Current research focuses on the relationship between CLL pathogenesis and genetic factors, chromosomes, cell oncogenes, and anticancer genes. 1. Genetic factors The incidence of CLL is higher in Caucasians and blacks, and lower in Asian yellows, and the incidence is not changed by ethnic migration. It is suggested that certain genetic factors of different races are associated with the pathogenesis of CLL. In addition, it has been reported that B-cell type CLL occurs in many people in the same family. The first-generation children of CLL have three times more risk of developing CLL or other malignant lymphoproliferative diseases than ordinary people, and most of them are young at the time of onset. It is suggested that genetic factors play an important role in the pathogenesis of familial CLL, but there is no significant correlation between HLA single phenotype and CLL. No genetic factors have been found with CLL, even in patients with single-oval twin CLL, no common genetic abnormalities have been found so far. 2. The cytogenetic study of chromosome CLL is difficult, because its lymphocytes are not easily stimulated by mitogens and proliferate, and it is difficult to obtain dividing cells. In recent years, by improving the stimulation of CLL cell division technology, chromosome R banding and in situ hybridization are applied. The (FISH) method improves the success rate of CLL chromosome research. About 50% of CLL patients were found to have cloned chromosomal abnormalities, while the remaining normal karyotypes may be normal T cell karyotypes and no CLL abnormal karyotypes were detected. (1) Chromosome 13 abnormality: Nearly 50% of CLL patients have a long arm loss of chromosome 13. Most of the missing sites were deleted in 13q12.3 and 13q14.3. 13q12.3, and the deletion site was breast cancer susceptibility gene (BRCA2). Deletion at 13q14.3, the deletion site can affect the tumor suppressor gene RB-1 (retinal gene), DBM (related to preventing lymphocyte malignant transformation), LEV1, LEV2 and LEV5 (related to the pathogenesis of CLL). (2) Chromosome 12 abnormality: The trisomy abnormality of chromosome 12 is rarely detected in CLL at the early stage, and CLL with chromosome 13 trisomy is found in the clinical progression of CLL or conversion to lymphoma (Richter syndrome). There are many complex changes in cells and atypical or young lymphocyte morphology. It is suggested that the trisomy 12 chromosome abnormality is related to the deterioration of CLL. The mechanism of the trisomy of chromosome 12 may be manifested by the influence of certain genes located between 12q13 and 12q22, such as the mdm gene. (3) Abnormal chromosome 11: Nearly 10% to 20% of CLL patients have chromosome 11 translocation or deletion, and those with abnormal chromosome 11 have a milder onset age (<55 years), and the course of disease often shows invasiveness. Abnormal chromosome 11 may affect 11q13, and it has been recognized that this site includes the tumor suppressor gene - MEN-1 (multiple endocrine neoplasia syndrome type I). The most common chromosome 11 deletion is between 11q14-24, especially between 11q22.3-23.1, where there may be a tumor suppressor gene RDX (multiple neurofibromatosis type II tumor suppressor gene congener) and AIM (hereditary ataxia - hair cell vasodilator mutant gene), the function of these two genes is related to the activation of the tumor suppressor gene p53. The p53 gene regulates the cell cycle and maintains gene stabilization. Its expression products can block abnormal cells from entering the cell cycle, which is convenient for abnormal cells to repair DNA. For example, cells cannot repair damaged cells by themselves. DNA will self-apoptosis. (4) Chromosome 6 abnormality: including the short arm of the chromosome 6 and the abnormality of the long arm. Short-arm abnormalities of chromosome 6 have not yet been found to have specific gene function changes. Patients with abnormal 6q21-q24 often show a clinical progression of juvenile lymphocytosis and invasive disease. In addition, TNF-α (tumor necrosis factor α), and LY-α (lymph) are located on the long arm of chromosome 6, and these two factors are involved in promoting proliferation of CLL cells and inhibiting proliferation of normal lymphocytes and bone marrow cells. (5) Abnormal chromosome 14: often expressed as a translocation. It is rare in CLL patients, and t(11;14)(q13;q32) translocation is more common in lymphoma patients: rare in CLL. 14 q32 contains the immunoglobulin a heavy chain isoform switch gene, while 11q13 has the cyclin D1 gene (cyclic D1) t (11; 14), which is common in coat-type non-Hodgkin's lymphoma. T (14:18) CLL patients are rare, common in low-grade follicular lymphoma. 3. Special gene alterations (1) p53 gene: The p53 gene is an important tumor suppressor gene located at the 17p13.1 site and encodes a 53-kD nucleic acid phosphoprotein. The mutation or defect may be the cause of the disease in nearly half of the tumor patients. Short arm loss on chromosome 17 is only seen in 10% to 15% of CLL patients. In addition, 10% to 15% of CLL patients have p53 gene mutations, patients with p53 gene mutations are mostly progressive, with high proliferation rate of leukemia cells, short survival time, clinical characteristics of resistance to first-line treatment drugs, seen in half of Richter Syndrome and B cell lymphocytic leukemia suggest that p53 gene mutation may be acquired in the course of certain CLL patients. (2) Multiple drug resistance gene (MDR): MDR-1 gene expression is increased in about 40% of CLL patients, and MDR-1 is located in 7q21.1, encoding a 170kD transmembrane glycoprotein. The expression of MDR-1 is increased in B cells of CLL patients but not in normal B cells. In addition, the expression of MDR-1 gene is also increased due to treatment or other factors. The abnormal expression of MDR gene is more likely to promote the progression of CLL patients. Not the primary cause of CLL. (3) bcl-2: The bcl-2 gene is located on chromosome 18q21, and most CLL patients have increased expression due to bcl-2 gene rearrangement. About 5% of CLL patients with bcl-2 gene rearrangement are IGk or lambda light chain genes located on chromosomes 2 and 8, and bcl gene translocations on chromosome 18. However, in addition to gene rearrangement, increased expression of bcl-2 in CLL leukemia cells is associated with hypomethylation of its gene locus. There may be some genes that are not yet known to be involved in the action of CLL cells against apoptosis. 4. Cytokine CLL cells have the ability to secrete a variety of cytokines, such as TNF-α, TGF-β (transfer growth factor β), IL-7 (interleukin-7), IL-5, IL-2, etc. It has the effect of directly or indirectly stimulating CLL leukemia cell proliferation or preventing apoptosis of CLL cells, and inhibiting the proliferation of normal lymphocytes and bone marrow hematopoietic cells. Therefore, cytokines are associated with the pathogenesis and disease progression of CLL patients. Cellular dynamics studies showed that the number of 3H-labeled white blood cells in the peripheral blood of CLL patients was small, suggesting that most white blood cells were in the resting phase (G0 phase) without proliferation, and that almost all CLL leukocytes expressed high levels of anti-aging. The death protein bcl-2, and the low level of apoptotic protein bax, the imbalance of bcl-2/bax ratio, resulting in impaired apoptosis, consistent with the accumulation of a large number of mature small lymphocytes in clinical, constitute the main pathological basis of CLL. Symptoms: 1. About 1/4 of the patients with general symptoms are asymptomatic and accidentally found due to blood tests. Fatigue, decreased physical activity and weakness are common symptoms. It occurs more often before the patient develops anemia or lymph nodes and hepatosplenomegaly. Other rare symptoms include chronic rhinitis caused by infiltration of nasal mucosa in CLL cells, multiple neuropathy in sensorimotor nerves, and allergies to mosquito bites. During the progression of the disease, the patient may have symptoms of weight loss, recurrent infection, bleeding, or severe anemia. In addition, CLL patients are mostly elderly, and can be combined with lung, heart and cerebrovascular disease. 2. CLL patients with 80% lymph node enlargement have a painful lymphadenopathy at the time of diagnosis. The most common sites are the neck, supraclavicular and axillary lymph nodes. Typical CLL lymph nodes are hypertonic, but may be tender when combined. High lymphadenopathy can cause local compression symptoms and affect organ function. For example, oropharyngeal lymph node enlargement can cause upper airway obstruction. Abdominal lymphadenopathy can cause urinary tract obstruction and hydronephrosis, and obstructive bile duct causes obstructive jaundice. However, mediastinal lymphadenopathy in CLL patients rarely causes superior vena cava syndrome. If this syndrome occurs, it is highly suspected to have a lung tumor. 3. Hepatosplenomegaly About half of CLL patients have mild or moderate hepatosplenomegaly at diagnosis, often accompanied by fullness and bloating. In some patients, the spleen may exceed the umbilical level and even extend to the pelvic cavity. A small number of splenomegaly may be associated with hypersplenism, resulting in anemia and thrombocytopenia. Some CLL patients may have hepatomegaly. Hepatic dysfunction in the liver is mostly mild, mostly without jaundice. However, if the abdominal lymph nodes enlarge the biliary tract, obstructive jaundice can be produced. 4. Extranodal involvement in organ examination of CLL patients often found organ infiltration, but abnormalities in organ function are rare. For example, more than half of patients had autoimmune findings of leukemia cell infiltration in the renal interstitial, but rare renal failure. In some organs and tissues accompanied by leukemia cell infiltration can produce symptoms, such as in the back of the eye, pharynx, epidermis, prostate, gonads and lymphoid tissue, leukemia cell infiltration can cause exophthalmos, upper airway obstruction, scalp nodules, urethra Obstruction and other symptoms. Pulmonary X-rays of pulmonary interstitial infiltrates show nodular or miliary changes that can cause pulmonary dysfunction. Pleural infiltration can produce bloody or chyle-like pleural effusions. Leukemia cell infiltration can cause thickening of the digestive tract mucosa, resulting in ulcers, bleeding, and malabsorption. CLL central nervous system infiltration is rare, can produce headache, meningitis, cranial nerve palsy, unresponsiveness, coma and other symptoms. 5. Rare clinical manifestations (1) Conversion to invasive lymphoma/leukemia: 10% to 15% of patients converted to invasive lymphoma/leukemia. The most common conversion to Richter syndrome is manifested as progressive liver, spleen, lymph node enlargement, fever, abdominal pain, weight loss, progressive anemia and thrombocytopenia, and peripheral blood lymphocytes rapidly increase. Lymph node biopsy pathology is large B cells or immunoblastic lymphoma. Through immunophenotypic, cytogenetics, immunoglobulin heavy chain gene rearrangement, DNA sequence analysis and other studies, it is proved that the large lymphocytes of patients with 1/2 Richter syndrome are derived from a single clone of CLL. Patients with Richter syndrome have a poor response to systemic chemotherapy and generally have a survival period of 4 to 5 months. CLL can also be converted to young lymphocytic leukemia, acute lymphocytic leukemia, plasma cell leukemia, multiple myeloma, Hodgkin's lymphoma and the like. (2) Autoimmune diseases: About 20% of CLL patients can be combined with autoimmune hemolytic anemia with positive Coombs test, and half of them have obvious clinical manifestations. 2% CLL patients with immunological thrombocytopenia. The severity of clinical CLL was not associated with a combination of immunological anemia and thrombocytopenia. Patients with autoimmune hemolysis and thrombocytopenia generally respond well to adrenocortical hormone. If the adrenal cortex hormone is ineffective, try a large dose of intravenous gamma globulin, splenectomy or spleen area irradiation. (3) pure red blood cell aplastic anemia: it has been reported that CLL combined with pure red blood cell aplastic anemia can be as high as 6%, the clinical manifestations are severe anemia, bone marrow erythrocytes and peripheral blood reticulocytes are reduced, but without granulocyte and thrombocytopenia . Adrenal cortex hormones have a short-term effect. Most patients are effective for chemotherapy, which increases hemoglobin values and is associated with a reduction in CLL. Cyclosporin A is also effective with or without adrenocortical hormone in CLL patients with pure red blood cell aplastic anemia, but often only the amount of hemoglobin is elevated, and the condition of CLL is not improved. 6. Patients with secondary malignant tumors may develop secondary malignancies due to autoimmune deficiency or chemotherapy. The most common are lung cancer and malignant melanoma. Other tumors include Hodgkin's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and multiple myeloma. diagnosis: Read more...