Introduction to malignant lymphoma

Disease Name: Introduction to Malignant Lymphoma: Malignant lymphoma (ML) is an immune cell tumor that occurs in lymph nodes and/or extranodal lymphoid tissues. It is derived from the malignant transformation of lymphocytes or tissue cells. A solid tumor that is cured. Etiology: (1) Causes of the disease It has been proven that many animals such as chicken, mouse, cat and cow malignant lymphoma can be caused by viruses. In humans, although it has been considered for many years that certain clinical manifestations of lymphoma such as fever, hyperhidrosis, and increased white blood cells are very similar to infections in many respects, it has not been proven in recent years that some lymphomas are caused by viruses. Most of the etiology of lymphoma studies began in high-incidence areas or high-risk groups. 1. Viral Human lymphoma was first confirmed to be associated with EBV infection in Burkitt's lymphoma. In Central Africa, the disease mainly occurs in children aged 3 to 12 years old. It is related to certain climatic conditions and can account for more than half of the local children's tumors. Only 5% of the patients are over 20 years old. Although there are scattered patients in other parts of the world, they are rare cases. The genome of Epstein-Barr virus has been found in 98% of Burkitt's lymphoma by cell biology techniques, but only 15% to 20% of Burkitt's lymphomas contain Epstein-Barr virus. The shell antigen antibodies of EB virus in patients in the endemic area were all positive and the titer was high. The risk of developing this tumor in children with positive shell antigen was 30 times that of the control group. Infection with certain mites with Epstein-Barr virus can cause malignant lymphoproliferative lesions similar to Burkitt's lymphoma. Therefore, it is currently believed that this disease is a serious and persistent EB virus infection in children in Africa, the immune function is inhibited, and the oncogene is activated, resulting in the malignant proliferation of B lymphocytes. It is currently believed that malaria transmitted by mosquitoes is only a cofactor, and malaria infection changes the lymphatic network and is susceptible to the triggering of the virus. B cell infection is controlled by T lymphocytes, and viral nuclear proteins (such as EBNA-2, EBNA-3) and membrane proteins (such as LMP-1) can induce B cell proliferation. Epstein-Barr virus infection is also common in HD patients, but the relationship between the two is still unclear. Epstein-Barr virus infection is associated with nasopharyngeal carcinoma and infectious mononucleosis. There have been many reports in the literature that HD can coexist with the latter or occur in patients who have previously had infectious mononucleosis. Recent studies have found that 50% of RS cells have EBV genes on their surface to form their shell RNA, which is the most common type in mixed cell types. Because of the relationship between lymphoma and EB virus in China, it is also highly valued. Due to the high infection area of Epstein-Barr virus in China, the infection rate of Epstein-Barr virus in the normal population is very high. Another important finding is the viral cause of adult T-cell lymphoma. As early as 1987, Gallo et al isolated a type C RNA virus from a tumor tissue of a mycosis fungus, called T cell leukemia lymphoma virus (HTLV-1). This is a very special retrovirus with a single-stranded RNA and an outer envelope. The virus has three structural proteins: core protein, envelope protein and enzyme protein (including viral polymerase and reverse transcriptase). It was proved by Gall et al. that the AIDS virus was isolated from the French scholar Montagnier (human acquired immunodeficiency virus, HIV). To date, this virus (HTLV) has been isolated from tumor specimens from nearly 10 patients with T-cell lymphoma and is considered to be a highly specific virus. At the same time, according to the epidemiological survey of adult T-cell lymphoma, Japanese scholars found that the high incidence occurred in the southern part of the four countries and Kyushu. The peak incidence was in the summer, and the patients were mostly engaged in agriculture, fisheries and forestry, and often had poor nutrition in the past. Factors such as tropical disease infections are likely to be associated with viral and/or filariasis infections. They also isolated RNA viruses independently, called ATLV. After studying ATLV and HTLV, it is also a causative factor of adult T-cell lymphoma/leukemia. However, through a large number of serological studies, there is no positive relationship between T cell lymphoma and HTLV-1 (or ATLV) in China. To date, there have been only 4 cases reported in China related to HTLV-1 (or ATLV). The detailed mechanism of the virus causing lymphoma is not fully understood. Viral replication is associated with the production of a retro-acting factor (tax) that induces expression of the REL gene and allows cells to proliferate. There are other factors that require the malignant transformation of cells. Many people in the high-incidence area are infected with HTLV-1, but only a small number of T-cell lymphomas occur. Thus supporting host factors including genetic factors may have an important position. 2. The occurrence of immunosuppressive lymphoma is closely related to immunosuppression. Because of the long-term use of drugs to inhibit the immune mechanism in organ transplantation, the incidence of lymphoma is significantly higher than the general population, and the original is more than the extra-outer, a group of reports can be as high as 69%. In addition, central nervous system invasion is also very high (28%) in patients with general lymphoma (1%). The immunosuppressive drugs used also have an effect on the occurrence of lymphoma. In the cyclophosphamide-based regimen, lymphoma accounts for 26% of primary cancer and occurs earlier. The application of Imari (Azathioprine) only accounts for 11%. In patients with anti-CD3 monoclonal antibodies, lymphoma accounts for 64% of the second primary cancer. Another fact that has received widespread attention is that many patients with primary immunodeficiency and acquired immunodeficiency (AIDS) are also prone to lymphoma and other tumors. Especially in patients with EB virus infection, the incidence of lymphoma is higher. 3. Bacterial infection In recent years, it has been reported that Helicobacter pylori (Hp) can cause chronic gastritis and gastric cancer, and can also cause high incidence of gastric lymphoma. In some patients, lymphoma can be reduced after antibiotic treatment. Some authoritative organizations in the United States, such as NC-CN in recent years, have adopted antibiotic therapy as the preferred method of mucosa-associated lymphoma (MALT). This is the first example of the use of antibiotics to treat tumors. 4. Environmental factors In the early years, the United States reported that the incidence of lymphoma was several times higher than that of the normal population due to the use of pesticides and pesticides in the midwestern farmers. The US Navy has been involved in the development of lymphoma in paint vessels and veterans who have been exposed to fluoride. High, but it is difficult to explain its mechanism. More definitely, the atomic bomb victims, the Hiroshima residents who have received radiation above 1Gy and those who have been treated with spondylitis, have a higher incidence of lymphoma than the normal population. Patients with HD who have undergone radiation and chemotherapy have a significant increase in the second primary cancer, especially large cell lymphoma, and often invade the digestive tract. 5. Some other congenital immunodeficiency diseases, such as telangiectasia ataxia, Wiscott-Aldreich syndrome, Chediak-Hig syndrome, etc. are often complicated by malignant lymphoma. Other so-called "immunoinflammatory" diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sj?gren syndrome (sjogren's syndrome), and immunological hemolytic anemia may be concurrently treated with other long-term immunosuppressive drugs. Malignant lymphoma. The long arm (q) translocation of chromosome 14 is also associated with the development of malignant lymphoma. In addition, long-term use of certain drugs (such as phenytoin, methamphetamine, etc.) can also induce lymphoma. The etiology of malignant lymphoma has shown that many factors are related to the occurrence of this disease, and its specific process and detailed mechanism need to be further clarified. (B) the pathogenesis 1. The pathogenesis of non-Hodgkin's lymphoma Due to the different stages of lymphocyte differentiation, different stages of tumor cells can occur in the affected lymph nodes or lymphoid tissues. In the same lesion, there may be poorly differentiated tumor cells or cells with more mature differentiation. As the lesion progresses, the histological type of malignant lymphoma may change, such as nodular type can be transformed into diffuse type. The proliferating tumor tissue may be a single cell component, but since the original pluripotent stem cells may differentiate in different directions, sometimes the cellular components may be more than two or more. In recent years, due to the widespread use of monoclonal antibodies and immunohistochemistry, it has been possible to distinguish T and B lymphocytes at different stages of differentiation. Tumors that occur in subcapsular cortical thymocytes are usually T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma. All other T-cell lymphomas are derived from more mature T cells, positive for CD4, including adult T-cell lymphoma (ATL), mycosis fungoides, Sezary syndrome, and most so-called peripheral T-cell lymphoma (international work) Diffuse large cells, immunoblasts, and mixed lymphoma in the classification) and more than half of T cell chronic lymphocytic leukemia. There are some peripheral T-cell lymphoma, nearly half of T-cell chronic lymphocytic leukemia and some Tγ lymphoproliferative diseases, CD8 positive. B cell lymphomas have fewer specific antibodies but surface immunoglobulin expression. The earliest B cells have the expression of CD10 and CD19 on the surface, and there are terminal transferases in the cells and recombination of the heavy bond genes. Later, the cells express CD20, the μ heavy bond is generated in the cytoplasm, the recombination of the K light bond gene, the recombination of the λ light bond gene, and the terminal transferase loss. These represent the developing pre-B cell stage. After the cell loses the expression of CD10, it becomes an immature B cell with IgM expression on its surface. IgD and IgM are produced on the surface of the cell surface expressing CD21 receptor (C3d). The developmental stage of all B cells occurs under antigenic stimulation, and the immunoglobulin genes are activated and secreted after being stimulated by the antigen. Thereafter, the cells lose CD21, CD20 and surface immunoglobulin, and the markers PC-1 and PC-2 of the plasma cells are secreted to secrete immunoglobulin. This is the development process of B cells in the cell follicle center, which becomes lymphocytic lymphoma after malignant transformation. The maturation of the B-cells in the follicular center and the initiation of the immunoglobulin genes are regulated by T helper cells, but there are also some unknown B lymphocytes. The B cells in the mantle cell area appear to be relatively less affected by T cells, which are CD5 positive, which is a full T cell marker and appears to be independent of immunoglobulin. Most acute lymphocytic leukemias are derived from pre-B cells, Burkitt lymphomas and leukemias are derived from surface IgM-positive immature B cells, and most follicular and diffuse B-cell lymphomas are derived from mature or activated B cells. Macroglobulinemia (Waldenstrom syndrome) and multiple myeloma are derived from the terminal stage of differentiation. Chronic lymphocytic leukemia expresses CD5, and diffuse moderately differentiated lymphoma expresses CD5 and CD10, suggesting that these are from the mantle cell region. B cells that are not follicular centers. The immunophenoty and clinical manifestations of some lymphomas are still very confusing. Diffuse large cell lymphoma may be the most heterogeneous, and may be derived from B cells, T cells, and tissue cells. Therefore, the prognosis of these patients does not depend entirely on clinical stage. Adult T-cell lymphoma is derived from mature T cells from an immunophenotype, but clinical manifestations are very dangerous, lymphoblastic lymphoma from immature T cells. These are for further study, especially the role of different genes in them. 2. The pathogenesis of Hodgkin's lymphoma Most patients with classic Hodgkin's lymphoma have clonal cytogenetic abnormalities, which vary with different cases, and the abnormalities within the clones are also heterogeneous, suggesting chromosomes Unstable. Many cases show 14q abnormalities, similar to B-cell lymphoma, but t(14;18) abnormalities rarely occur. Two groups used fluorescence in situ hybridization (with or without fluorescent immunophenotyping) and found that RS cells in all Hodgkin's lymphoma cases showed abnormal clone values. In the early reports, Bcl-2 rearrangements were found in about one-third of Hodgkin's lymphoma, but no Bcl-2 rearrangements were detected in other laboratories. Moreover, Bcl-2 rearrangement is also found in highly reactive tissues such as reactive tonsils. The EBV-associated transforming protein is capable of upregulating Bcl-2 in cultured cells, and this evidence further indicates the relationship between Bcl-2 expression and Hodgkin's lymphoma. The conclusions obtained from immunohistochemical studies of Bcl-2 overexpression are not consistent. However, Bcl-2 expression appears to be unrelated to histology, EBV( ) or t(14;18) translocation, and enhancement of Bcl-2 expression may be present in background cells and does not play an important role in the pathogenesis of Hodgkin's lymphoma. . However, a group of researchers applied cytogenetic analysis to clearly confirm the presence of Bcl-2 rearrangement in tumor cells without t(14;18). Recently, a novel inhibitor of apoptosis, Bcl-X(L), was found in Hodgkin's lymphoma, and Bcl-X(L) was positive in 94% of Hodgkin's lymphoma, and most RS cells were highly expressed. . The rate of expression in non-Hodgkin's lymphoma is low (<20%), except for reticular central lymphoma. Therefore, it is speculated that the abnormal expression of Bcl-X(L) in RS may be the cause of Hodgkin's lymphoma. No correlation was found between Bcl-X (L) and EBV expression. By immunohistochemical analysis, P53 tumor suppressor gene expression has been detected in Hodgkin and other lymphomas of CD30. However, recent studies have found that there are no P53 mutations in Hodgkin and RS cells in 8 Hodgkin's lymphomas. Recently, Humboldt et al reported that IκBα mRNA was overexpressed in HRS cells from lymph node biopsy samples from patients with HL, and IκBα gene mutation was detected, resulting in a C-terminal truncated protein, suggesting that this protein could not inhibit NF-κB-DNA binding activity. It prevents the apoptosis of HRS cells and triggers proliferation. Therefore it is related to the pathogenesis of HL. The cytogenetic data of NLPHL is scarce, and the results of cytogenetic abnormalities are also inconsistent. Of the large series of HLs reported by Tilly et al, there is only one NLPHL, which has a 46XY karyotype. Hansmann et al. reported a case of high diploid NLPHL, 6q-, 2l, and several unclear markers. The study found that the DEV cell line originating from NLPHL has the following karyotype abnormalities: 48, XXY, t (3; 14) (3; 22), t (3; 7), del3, -2, 12, mar. Analysis of ploidy of HL, 3 of 5 NLPHL were aneuploid, no tetraploid was detected, and tetraploid was common in classical HL. Bcl-2 gene rearrangement was detected in only a small number of cases, and immunohistochemistry was used to detect Bcl-2 protein expression, and the number of positive cases was small. Based on this, it is speculated that Bcl-2 translocation may not play an important role in the onset of NLPHL. The origin of tumor cells, it has long been believed that different histological types in HL represent morphological variations of the same disease, with HRS cells in a reactive background, and each tissue subtype has a characteristic cellular composition. In the past 20 years, people have gradually found that the above concepts are only partially correct. For example, nodular lymphocyte-based HL is different from other types of HL and is a different biological disease. (1) Cellular origin of HRS in classical HL: The earliest immunohistochemical study on Ig expression of IRS, such as Garvin et al in 1974 and subsequent Taylor, etc., their study confirmed that HRS expression of IgG was obtained in HL biopsy specimens, indicating HRS Originated from Ig-producing B cells, but other immunohistochemical studies have shown that HRS originates from non-lymphoid cells. Subsequent to the application of monoclonal antibody technology, CD30 molecules were discovered. It was demonstrated that HRS of classical HL selectively expressed CD30, whereas normal individuals were only expressed in some activated lymphoblasts. This data demonstrates for the first time that HRS is the origin of lymphocytes. Gene level studies showed that clonal Ig gene rearrangement occurred in HRS, and 12 cases were detected in 13 cases of HL in the Rajewsk series. stein also reported that 24 cases were rearranged in 25 cases, which proved that 95% of HLs are B cell origin. . Sequence analysis demonstrated a high load of somatic mutations in the rearranged V region. Since some classical HLs of HRS cells express one or more T cell antigens and 40% of the cell lines in HL have T cell phenotypes and genotypes, it is speculated that the remaining 5% of classical HL originates from transformed T cells. However, this speculation cannot be confirmed because the rearranged TCR gene has not been detected in HRS cells. Recent studies have found that classical HL originates from germinal center B cells rather than germinal center B cells; B cell line progeny can undergo two independent transformations, one forming HRS cells and the other forming NHL; producing HL transformation Cells that completely altered the morphological and immunophenotype of normal progenitor cells (not expressing CD20, CD10, Bcl-6, and IgM and down-regulating the mutational machinery, expressing CD30 and CD15) and converting to NHL retained more or less B cell lines. The characteristics of the ancestors. The population of HRS cells in a particular case is completely derived from a single transformed cell and clones proliferate. In the WHO (2001) classification, nodular lymphocyte-based Hodgkin's lymphoma is derived from the B cell of the germinal center of the germinal center, while 98% of the classical Hodgkin's lymphoma is in the differentiation stage of the germinal center. Mature B cells. (2) Cell origin of lymphocytes and/or histiocytes (H and L) in NLPH: lymphocyte-based HL, a characteristic tumor cell [lymphocytes and/or tissue cells (H and L)] The subtype is related to the huge nodule of the germinal center for progressive transformation. Immunohistochemical studies have shown that H and L cells are a series of B cells. Because they express a large number of B cell markers including CD19, CD20, CD22, CD79a and J chain, and recent molecular studies have also suggested: H and L. Cells are central cells of transformation. In the major clonal populations, immunoglobulin heavy chains continue to undergo somatic hypermutation. In developed countries, EBV is rarely associated with H and L cells and may not be associated with the disease. H and L cells are often used by CD3, CD4 Read more...