Follicular lymphoma accounts for the second highest incidence of non-Hodgkin’s lymphoma. The disease progression is clinically inert and mainly presents as painless lymph node enlargement. Prognostic factors include the Follicular Lymphoma International Prognostic Index (FLIPI), and the immune microenvironment of the tumor tissue. Immunochemotherapy has become the first-line treatment for follicular lymphoma, and treatment should be initiated as soon as follicular lymphoma is diagnosed, with a watchful waiting strategy limited to a few select cases. Hematopoietic stem cell transplantation is indicated for relapsed refractory cases. Follicular lymphoma (FL) has the second highest incidence in non-Ho lymphoma. WHO statistics show that follicular lymphoma accounts for 22.1% of non-Ho lymphoma, and FL in China is slightly lower than in Europe and the United States. t(14;18)(q32;q21) is characteristic of FL, forming an IgH-BCL2 gene rearrangement. Most patients are stage III-IV at diagnosis, often clinically inert and sensitive to conventional chemotherapy, but prone to recurrence and incurable disease, with increasingly shorter recurrence intervals with disease progression. The emergence of CD20 monoclonal antibodies has improved the prognosis of follicular lymphoma, and now immunochemotherapy has become the first-line treatment for follicular lymphoma. Clinical features: 1. Lymph node enlargement: It is the most common initial manifestation of follicular lymphoma, and often the only manifestation. It often presents as painless lymph node enlargement in the neck, axilla and groin, which may be solitary or in bunches, with a hard texture and poor mobility. In addition, ancillary examinations may reveal enlarged mediastinal, retroperitoneal, and abdominal lymph nodes. Huge lymph nodes in the neck and mediastinum may compress blood vessels and trachea leading to dyspnea and swelling of the face and neck. Generally primary mediastinal FL or single involvement of splenomegaly FL is rare. 2, B symptoms: Mostly seen in patients with progressive stage and large tumor load. They manifest as weight loss, fever, night sweats and skin scratching. 3.The corresponding end-organ involvement manifestation: primary extra-nodal involvement is rare. Depending on the site of lymphoma involvement, superior vena cava obstruction syndrome, pleural effusion, pericardial effusion, peritoneal effusion, dysphagia, intestinal obstruction and lower limb edema may occur. 50-60% of patients have bone marrow involvement. 4.Other manifestations: tumor may increase rapidly, local pain, elevated serum lactate dehydrogenase, anemia and hypoproteinemia may be associated with the progression of large cell transformation. (1) Primary gastrointestinal follicular lymphoma: It mainly occurs in duodenum and small intestine, commonly manifested as abdominal colic and abdominal mass, and in severe cases, there may be intestinal obstruction. Some patients may also present with dyspepsia and weight loss. Genetic studies have found that in addition to IgH/BCL2 rearrangement, some patients have the characteristic gene VH4 of mucosa-associated lymphoma, and the clinical course is similar, suggesting that duodenal follicular lymphoma and mucosa-associated lymphoma may have the same etiology. (2) Primary cutaneous follicular center cell lymphoma: It is more common in males, with a median age of 60 years. The lesions are confined to the skin and appear as limited papules, nodules or masses. Although the morphology and growth pattern are similar to follicular lymphoma, BCL2 expression is only 57% compared to 100% in secondary cutaneous follicular lymphoma; t is only 31% in primary compared to 77% in secondary; the prognosis is relatively good. (3) In situ confined follicular lymphoma: Cong et al. performed immunohistochemical analysis of 900 lymph nodes diagnosed with follicular reactive hyperplasia and found that 23 focal follicles were strongly positive for BCL-2, while other surrounding follicles were mostly negative; the affected follicles expressed CD10 and had a low proliferation rate (MIB1) compared with BCL-2(-) follicles in the same lymph nodes, and selected affected follicles were detected There was IgH/BCL-2 gene rearrangement. Three of the 13 cases (2-96 months, median 15.5 months) were diagnosed with FL after 3, 13, and 72 months of clinical follow-up, respectively, and Roulland also found a small number of BCL-2(+) cells in the peripheral blood of healthy subjects. Prognostic factors 1. Follicular lymphoma international prognostic index (FLIPI) (5): FL is classified as low risk, intermediate risk and high risk according to 5 single independent risk factors: Hb < 12g/dl, LDH > upper limit of normal, Ann Arbor clinical stage III-IV, lymph node area > 4 and age > 60 years. 2, tumor immune response characteristics: (1) the number of lymphoma-associated macrophages: increased macrophages in tumor tissue suggests a poor prognosis for FL patients. In addition to participating in normal immune functions, normal human macrophages also mediate tissue repair and play a key role in the healing process through epithelial migration, plasticity and angiogenesis, while this normal function may be utilized by tumor tissue and contribute to tumor progression and metastasis.Farinha et al. analyzed the pre-treatment pathology of a group of FL patients receiving combination chemotherapy (BP-VACOP), and tumor tissue CD68+ cells <15/high magnification had a long survival (PFS 7.06m; OS 16.3m) and CD68+ cells >15/high magnification had a short survival (PFS 1.69m; OS 5.0m). Gene expression profiling studies also identified increased expression of genes associated with macrophages as a marker of poor prognosis in follicular lymphoma. (2) Lymphoma-associated T-lymphocyte count: Patients with increased T-cells often have a good prognosis. The number of T cells in the tumor tissue has an impact on limiting disease progression, especially regulatory T cells, which are more likely to be refractory to treatment in <5% of patients, and the lowest T cell content in patients who transform to diffuse large B-cell lymphoma (8, 9). (3) Mast cell count: Taskinen (10) et al. found that in patients receiving CD20 monoclonal antibody in combination with chemotherapy, those with increased mast cell count in tumor tissue had a poor prognosis, with only 34% disease-free survival at 4 years in patients with high mast cell count compared to 74% in patients with low mast cell count (P=0.002). The number of tumor-associated macrophages only had an effect on the prognosis of the low mast cell group. The treatment of follicular lymphoma 1. Indications for treatment: Since follicular lymphoma is inert and has a long natural course, it cannot be cured by chemotherapy alone, and radiotherapy failed to prolong patient survival in early studies in non-progressive patients, so what kind of patients should be treated and when to start treatment has been a clinical controversy. The NCI randomized clinical trial compared the effect of combination chemotherapy and watchful waiting on survival and found no statistically significant differences between the two groups; the GELF study randomly compared the efficacy of chemotherapy, watchful waiting and interferon and found no significant survival differences. Similar results were obtained in the UK BCLI study. These clinical studies were all completed before the introduction of rituximab (a CD20 monoclonal antibody) into the clinic, and as rituximab is used in a large number of clinical settings, more and more patients are achieving clinical and molecular complete remission (clinical cure), challenging the traditional concept of watchful waiting. The current preference for follicular lymphoma is to give immunochemotherapy ± local irradiation upon diagnosis in order to achieve clinical cure at an early stage. 2. Early-stage follicular lymphoma: The use of local radiotherapy has been the accepted treatment of choice for patients with stage I and II disease. There is no randomized clinical trial to compare the difference between local radiotherapy and radiotherapy combined with chemotherapy or chemotherapy alone. For patients with conditions, immunochemotherapy alone or combined with local radiotherapy can be used. 3. Advanced follicular lymphoma: The first-line treatment of choice for stage II patients with large masses or abdominal lesions and for patients with stages III and IV is immunochemotherapy. Several randomized clinical trials have demonstrated that rituximab (CD20 monoclonal antibody) in combination with chemotherapy significantly prolongs disease-free survival and overall survival in patients with follicular lymphoma.Schulz et al. (14) meta-analysis including 1480 FL cases showed that patients receiving immunochemotherapy had better overall efficiency, complete remission rate, event-free survival, disease-free survival, and overall survival than chemotherapy alone. The commonly used regimen, R-CHOP for 6-8 cycles, is also available as an anthracycline removal regimen (R-CVP) or a fodarabine-based regimen (R-FC/FND). Immunoradiotherapy (RIT) is the selective killing of CD20-positive lymphoma cells by conjugation of radionuclide 131I (Bexxar) or 90Y (Zevalin) on CD20 monoclonal antibody.The FIT (15) study investigating the efficacy of first-line administration of RIT after 6 cycles of CHOP regimen for follicular lymphoma enrolled 414 cases with a median follow-up of 2.9 years and a median of no progression Survival was 37 months in the Zevalin group and only 13.5 months in the control group (P < 0.0001); among them, PFS was 29.7 months in the PR patients after chemotherapy with Zevalin and 6.3 months in the control group (P < 0.0001), and 54.6 months in the Zevalin group and 29.9 months in the control group for those with CR (P = 0.01). It is suggested that immunochemotherapy is important for removing residual lesions and increasing the cure rate. In addition immunoradiotherapy can be used as pretreatment before hematopoietic stem cell transplantation to enhance the targeted clearance of tumor cells. 4. Post-remission maintenance therapy: Since follicular lymphoma has a high recurrence rate after remission, post-remission maintenance therapy has been an issue of clinical discussion. Early studies have shown that maintenance chemotherapy or interferon maintenance therapy may prolong the duration of remission or disease-free survival, but neither prolonged overall survival with increased adverse effects, and maintenance chemotherapy may also increase the risk of secondary tumors. the SAKK35/98 study investigated the effect of continued rituximab maintenance after 4 courses of rituximab monotherapy induction therapy on survival with event-free survival (23.2 months vs. 11.8 months), and duration of remission (primary: not reached median time vs. 20.4 months; repeat: 24.7 months vs. 12.7 months) were significantly improved, but no effect on overall survival was seen. No difference in OS was seen in patients treated with rituximab maintenance compared with those treated again with rituximab after relapse without maintenance therapy, although PFS was prolonged (31.7 months vs 7.4 months). These results suggest that chemotherapy alone and rituximab maintenance therapy alone only delayed relapse and did not achieve disease clearance. To investigate whether increasing the intensity of treatment or maintenance therapy after combination of chemotherapy and immunotherapy could increase the cure rate, the EORTC20891 study investigated the effect of R-CHOP6 course induction therapy followed by rituximab maintenance therapy on survival in patients with relapsed follicular lymphoma, which resulted in not only increased disease-free survival but also significantly improved overall survival (3yOS 85.1% vs 77.1%, P= 0.0111), suggesting that maintenance treatment with rituximab after immunochemotherapy prolongs survival in patients with refractory relapsed follicular lymphoma. A meta-analysis of 985 evaluable patients showed that rituximab maintenance therapy significantly prolonged overall survival compared with control, with a major benefit in relapsed refractory cases and a nonsignificant benefit in primary patients. The GELF-94 study showed no difference in progression-free survival or overall survival between autologous HSCT after CHOP chemotherapy and chemotherapy alone plus interferon. 54% of patients relapsed at a median time of 1.5 years after transplantation, and progression-free survival was 44% and 31% at 5 and 10 years, respectively. Therefore, autologous HSCT is not recommended as first-line treatment for follicular lymphoma and is limited to relapsed refractory cases. Allogeneic HSCT has a graft-versus-lymphoma effect, resulting in a significant reduction in relapse rates, but this effect on survival is offset by an increase in transplant-related deaths. The low relapse rate did not translate into a high survival rate (51% for Allo-SCT and 55% for Auto-SCT), although allogeneic HSCT had a transplant-related death rate of 30% compared to 8% for autologous HSCT. Therefore, allogeneic HSCT is not suitable for conventional first-line treatment of follicular lymphoma and should only be used as a clinical trial for refractory drug-resistant cases. The reduced-intensity pretreatment regimen of allogeneic HSCT has shown better efficacy in follicular lymphoma. Khouri et al. initially treated 20 patients with FL using a non-cleared marrow regimen with a 2-year survival rate of 80%, which sparked interest in RIC-Allo-SCT for FL. 47 non-cleared marrow transplants were completed in the following 8 years with a 5-year PFS of 83% and OS of 85%. Vigouroux et al. reported 73 cases of RIC-AlloSCT for low-grade malignant lymphoma with 51% EFS and 56% OS at 3 years. The choice of different pretreatment regimens and intensities, patient selection, and the place of RIC-AlloSCT in the treatment of follicular lymphoma require further large-scale clinical studies. IV. CONCLUSIONS Follicular lymphoma is characterized by t(q32;q21), formation of IgH/BCL2 gene rearrangement, and inert clinical presentation. In addition to the Follicular Lymphoma International Prognostic Index (FLIPI), the immune environment of the pathological tumor tissue is of great value in determining prognosis, and macrophage and mast cell infiltration is often a sign of poor prognosis, while adjuvant T-cell increase reflects good prognosis. As a result, follicular lymphoma is no longer an incurable disease. In view of this, treatment of follicular lymphoma should be initiated upon diagnosis, with a watchful waiting strategy limited to a select few cases. The combination of CD20 monoclonal antibody with radionuclides (immunoradiotherapy) increases the chance of cure in follicular lymphoma, and its use in combination with chemotherapy or stem cell transplantation will benefit more patients. The combination with chemotherapy or stem cell transplantation will benefit more patients. Hematopoietic stem cell transplantation is not used for first-line treatment of follicular lymphoma and is only used for rescue therapy in relapsed refractory cases. Non-cleared allogeneic hematopoietic stem cell transplantation is a hot topic for further research and its place in the treatment of follicular lymphoma needs to be further investigated.