Diagnosis and treatment of diffuse large B-cell lymphoma

  Diffuse large B cell lymphoma (DLBCL) is the most common subtype of adult lymphoma and is a group of malignant tumors with great heterogeneity in terms of clinical presentation, histomorphology and prognosis. In China, DLBCL accounts for about 45,8% of all non-Hodgkin’s lymphomas (NHL) and 40,1% of B-cell lymphomas [1].DLBCL occurs mainly in middle-aged and elderly people, and is rare in children, with a median age of onset of 60-70 years. It is more frequent in men than in women. In recent years, the incidence of DLBCL has continued to rise, and there have been some changes in the diagnosis and treatment of DLBCL. The diagnosis of DLBCL is mainly based on histopathological biopsy and immunohistochemical analysis, and the general pathological manifestation of DLBCL is that most or all of the lymph node structures are replaced by homogeneous fish flesh-like tumor tissue, with local hemorrhage and necrosis; microscopically, the normal follicles in the lymph nodes disappear and are replaced by diffusely distributed large cells, with obvious cell heterogeneity and visible The cells were clearly heterogeneous and had a splitting appearance. The typical immunophenotype of these cells is: CD45(+), CD20(+), CD19(+), CD79α(+), CD3(-). Other immunomarkers can provide biological and prognostic information about DLBCL. For example, Ki-67 indicates an index of the degree of cell proliferation; a higher index indicates more rapid proliferation and a worse prognosis. Lymph nodes with lesions should be excised as completely as possible for pathological examination, and fine-needle or coarse-needle aspiration biopsy is not suitable for the diagnosis of DLBCL. In specific cases where pathological examination of the suspected lesion is not possible, fine or coarse needle aspiration biopsy combined with immunohistochemistry, flow cytometry, PCR, Fish and other techniques can be applied for diagnosis [2]. If the tissue and its findings at one time are not diagnostic, another biopsy should be performed for clarification.  In recent years DNA microarray (DNA microarray) technology has been applied in the diagnosis of DLBCL, which can be classified into germinal center B-cell lymphoma [3-4], activated B-cell lymphoma and type III DLBCL according to different gene expression patterns [5].  DLBCL can be classified into GCB subtypes and non-GCB subtypes by detecting biochemical central B-cell markers (CD10, BCL-6, GCET1) and post-growth center B-cell markers (FOXP1, MUM1), and these typing by applying immunohistochemistry may have some significance for patient prognosis.  2. Staging and prognosis The staging of DLBCL is still using the Ann Arbor/Costswolds staging system. Through a comprehensive staging examination, the scope of lesion invasion and the organism condition of patients can be accurately understood. However, the clinical value of the above staging for patient prognosis is less than that of the International Prognostic Index (IPI), and therefore it is not recommended as a major reference factor when formulating the best treatment plan. The introduction of PET-CT into the disease assessment system, however, can more accurately guide clinical treatment and determine the prognosis of the disease.  IPI is currently recognized as a prognostic indicator for DLBCL (see Tables 1 – 3). Poor prognostic factors include age > 60 years, stage III and IV lesions, LDH > upper limit of normal value, ECOG physical status score R2 and extra-nodal invasion site at R2. The 5-year overall survival of patients was 70%-80% in the low-risk group (score 0-1), 50%-60% in the low-intermediate risk group (score 2), 40%-50% in the {intermediate risk group (score 3), and 20%-30% in the high-risk group (score 4-5), respectively. The age-adjusted IPI (aaIPI) was scored with lesions of stage III/IV, LDH > upper limit of normal, and ECOG physical status score R2 for patients <60 years of age.  Table 1, International Lymphoma Prognostic Index (IPI) Associated factors Good prognosis Poor prognosis Age <60 years or >60 years Stage I, II or III, IV Number of extra-nodal invasion sites 0, 1 or >1 Physical fitness grading (EGCO criteria) 0, 1 or 2, 3, 4 LDH normal or abnormal Table 2, Lymphoma prognosis grading Prognosis grading Poor factors Low risk 0, 1 Low intermediate risk 2 High intermediate risk 3 High risk 4, 5 Table 3, ECOG physical fitness grading criteria (PS) level physical fitness status 0 normal life 1 symptomatic, do not need to be bedridden, living on their own 250% of the time do not need to be bedridden, occasionally need care 350% of the time need to be bedridden, need special care 4 bedridden II. Treatment In recent years, the treatment of DLBCL has made great progress, and currently the conventional radical chemotherapy regimen based on the CHOP regimen treats The cure rate of DLBCL is about 30%-40% [6], and the treatment of rituximab combined with CHOP regimen has further improved the cure rate of DLBCL patients.  1, The following items must be examined before evaluating DLBCL patients to receive treatment: (1) Medical history including B symptoms:fever >38,0°C for more than 3 consecutive days without infectious causes; a kind of reduction of more than 10% within 6 months; night sweats; (2) Physical examination: including general condition, general skin, superficial lymph nodes (especially Wechsler’s ring), liver, spleen and abdominal pack fast. (3) Physical status. (4) Laboratory examination: three major routine, liver and kidney function, EKG, LDH, β2 microglobulin. (5) In addition to routine examination, patients with DLBCL should undergo bone marrow cytology and bone marrow biopsy examination before treatment to clarify the presence of bone marrow infiltration. (6) Monitoring of hepatitis B virus surface antigen/antibody and core antigen/antibody. HBV DNA copy number and HIV.(7) Imaging examinations: CT of neck, chest, abdomen and pelvis; PET-CT is recommended; cardiac ultrasound; gastroscopy should be performed in case of gastrointestinal tract involvement; lumbar puncture and cranial MRI should be performed in case of central nervous system symptoms. Pre-treatment system evaluation is important for the selection of treatment plan.  2, the choice of treatment plan is currently recommended according to the age and risk decomposition of different treatment plans: (1) young (< 60 years old) low-risk (aaIPI 0-1 score) patients: the standard treatment is 6-8 courses of R-CHOP. aaIPI scores can be further selected according to the different chemotherapy regimens, aaIPI score of 0 patients can be applied to 6 courses of R-CHOP21 Patients with aaIPI score of 1 can be treated with 8 courses of R-CHOP21, and if there is also a large mass (R7, 5 cm), local radiotherapy can be added to the 8 courses of R-CHOP21, or the high-intensity R-ACVBP regimen can be applied directly.  (2) Young (<60 years old) high-risk patients (aaIPIR2 score): there is no standard regimen, and it is recommended to increase the drug dose or dosing density on top of R-CHOP to improve the efficacy. Autologous hematopoietic stem cell transplantation (AHSCT) is also recommended for patients with poor treatment outcome.  (3) Elderly patients (>60 years old):8R-6/8CHOP21 treatment can be applied. For those who are ultra-advanced (>80 years old), a 6-course R-minCHOP21 regimen can be applied if there is no cardiac insufficiency; if cardiac insufficiency is present, adriamycin should be used with caution. In the case of diffuse large B-cell lymphoma of the testis, radiotherapy of this testis is recommended after the application of chemotherapy. For some elderly patients who cannot tolerate high-dose chemotherapy or rituximab, some low-toxicity and high-efficiency second-line treatment regimens can be used, and supportive therapy can be enhanced.  For relapsed/refractory patients, some second-line chemotherapy regimens without crossover with CHOP can be used in combination with rituximab, or individualized regimens can be applied. Post-chemotherapy hematopoietic stem cell transplantation ± local radiotherapy may be performed in some eligible patients or enter clinical trials. Patients with DLBCL who have negative PET-CT results prior to transplantation have a better prognosis [7]. If patients are not eligible for transplantation or the disease status is still stable or progressive after treatment, they enter clinical trials or perform supportive therapy, or screen out some suitable targeted therapeutic drugs through gene expression analysis and give gene targeted therapy [8].  4, treatment of complications (1) Prevention and treatment of central system invasion: some patients at moderate to high risk or high risk, especially those with more than one site of extra-nodal accumulation, elevated LDH, sinus involvement and bone marrow involvement should be alerted to the risk of central nerve invasion and must be treated prophylactically by giving 4-8 intrathecal injections of MTX±Ara-C or 3-3, 5 g/m2 systemic MTX as prophylaxis. If the patient already has CNS involvement then MTX should be added to conventional chemotherapy.  (2) Prevention of adverse cardiac reactions: Patients applying anthracyclines, especially elderly patients, should be alert to cardiotoxicity and can be cardioprotected when applying chemotherapy.  (3) Hepatitis B virus reactivation: Both chemotherapeutic drugs and rituximab may cause HBV reactivation, leading to the development of fulminant hepatitis. Therefore, all patients planning to receive chemotherapy or rituximab should first be tested for hepatitis B virus surface antigen, and if positive, the hepatitis B virus DNA copy number should be tested and appropriate antiviral therapy should be administered.  III. Regular follow-up is required after the treatment of DLBCL patients, and the time and content are as follows: 1.  2. Contents: blood routine, liver and kidney function, LDH, β2 microglobulin, EKG, abdominal ultrasound, chest X-ray or CT, and other necessary examinations.  Conclusion Although great progress has been made in the treatment of DLBCL in recent years, the outcome of high-risk aggressive DLBCL and relapsed/refractory DLBCL is still unsatisfactory, and there is still a lot of research to be done. Molecular targeted therapy, hematopoietic stem cell transplantation, and an integrated treatment model combined with conventional radiotherapy may further improve the cure rate of DLBCL patients.