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Genetic alterations hidden in tumors: why are they so critical for DLBCL?
Diffuse large B-cell lymphoma (DLBCL) is a cancer that begins in B cells, the cells responsible for producing antibodies. DLBCL is the most common type of non-Hodgkin lymphoma in adults, with an annual incidence of 7-8 cases per 100,000 people in the United States and the United Kingdom. This cancer occurs primarily in older people, with a median age of diagnosis of about 70, although it can occur in younger adults and, less commonly, children. DLBCL can arise in almost any part of the body and, depending on a number of factors, tends to be a very aggressive malignancy. The first sign of the disease is usually the observation of a rapidly enlarging mass or tissue infiltrate, sometimes accompanied by systemic B symptoms such as fever, weight loss, and night sweats.
The pathogenesis of DLBCL is not fully understood. Generally, DLBCL arises from normal B cells, but it can also be a malignant transformation of other lymphomas (particularly marginal zone lymphoma) or, in rare cases, called Richter's transformation, from chronic lymphocytic leukemia. Immunodeficiency is an important risk factor for the development of the disease and is associated with infection with certain viruses (such as Epstein-Barr virus, Kaposi sarcoma-associated herpes virus, and human immunodeficiency virus HIV) as well as Helicobacter pylori. However, most cases are associated with unexplained increases in genetic mutations and changes in gene expression that promote the malignant behavior of specific B cell types.
The diagnosis of DLBCL is usually made by removing part of the tumor for a biopsy and examining the tissue under a microscope.
Multiple subtypes of DLBCL have been identified that differ in clinical features, biopsy findings, aggressiveness, and prognosis. Conventional treatment for most subtypes is chemotherapy plus a monoclonal antibody drug that targets cancer cells, usually rituximab. With these treatments, more than half of DLBCL patients can be cured; however, the overall cure rate is lower in older adults, whose five-year survival rate is approximately 58%.
Subtypes of DLBCL
Diffuse large B-cell lymphoma comprises a biologically and clinically diverse group of disease subtypes, many of which are difficult to distinguish using well-defined and widely accepted criteria. According to the 2016 World Health Organization reclassification, DLBCL can be divided into the most common subtype, diffuse large B-cell lymphoma not otherwise specified (DLBCL, NOS), which accounts for 80% to 85% of all DLBCL cases. The remaining cases consist of relatively rare subtypes that differ in their morphology (microscopic appearance), immunophenotype (i.e., expression of specific marker proteins), clinical features, and association with certain pathogens.
DLBCL, NOS, although not part of the 2016 World Health Organization classification, is clearly associated with persistent infection with Helicobacter pylori.
DLBCL, not otherwise specified
DLBCL cases that do not meet the characteristic clinical, histological, tumor cell phenotype, and pathogen-related criteria of other DLBCL subtypes are referred to as DLBCL, NOS. Typically, the disease is aggressive, with long-term survival rates of about 65 percent for patients who receive standard chemotherapy. However, there are many variants of the disease that differ significantly in parameters such as their aggressiveness and response to treatment.
Clinical manifestations and prognostic indicators
Approximately 70% of DLBCL, NOS cases present primarily with nodal disease. In these cases, the most typical clinical presentation is a rapidly enlarging mass located in an area with multiple lymph nodes, such as the groin, axilla, or neck. The remaining approximately 30% begin as extranodal lymphoma, most commonly in the stomach or, less commonly, in other organs such as the testicles, breast, uterus, ovaries, kidneys, adrenal glands, thyroid, or bones.
Patients may experience systemic B symptoms such as weight loss, night sweats, and fever.
In addition, it is also common for patients with DLBCL to have abnormally elevated levels of lactate dehydrogenase and beta-2 microglobulin in their blood, and 10% to 20% of cases may heal to the bone marrow.
The impact of genetic variation
In most cases of DLBCL, NOS, the pathological process results, at least in part, from a stepwise progression of genetic changes, such as mutations, altered expression, and amplification and translocation of genes. These changes often lead to increased or decreased function of gene products, thereby affecting the activity of cell signaling pathways. Many genes are altered in DLBCL, and some of these changes are bizarre and not fully understood.
For example, the BCL2 gene and its product Bcl-2 protein regulate the cell apoptosis process, while MYC is an important transcription factor that controls cell proliferation and spread.
Diagnostic Methods
Microscopic examination of the affected tissue may reveal large masses of malignant cells that would normally be classified as B cells. These cells are arranged in a diffuse pattern and often disrupt the architecture of normal tissue. The cell morphology shows a large number of central cell types, immunoblastic cell types or atypical cell types.
Treatment and prognosis
The first-line treatment for DLBCL usually includes the R-CHOP regimen, which is a combination of chemotherapy drugs and monoclonal antibodies. For GBC type, the overall response rate of the R-CHOP regimen can reach 60-70%. However, for certain mutations, such as changes in the MYC gene, this approach is less effective. For these high-risk cases, clinical studies have also brought new hope to the DA-R-EPOCH regimen.
Although treatment has achieved certain success, the deep correlation between DLBCL mutations and genetic changes remains an area worth exploring. How will future studies reveal the potential role of these genetic changes in the development and treatment of DLBCL, and what new insights will they bring us?
