In October 2010, the Japanese Society of Gastric Cancer revised and published the 3rd edition of the Japanese Guidelines for the Treatment of Gastric Cancer, and published the first edition of the Guidelines for the Treatment of Gastric Malignant Lymphoma (hereinafter referred to as the Guidelines) in the form of an appendix. In view of the rapid progress of malignant lymphoma research in recent years, the classification has been refined, the diagnosis is accurate, the dominance of treatment has changed from surgical treatment to non-surgical treatment, and the treatment effect has been significantly improved. This guideline introduces the progress and status of gastric malignant lymphoma in a concise manner, focusing on the diagnosis and treatment of gastric malignant lymphoma. This article interprets the main contents of the guideline and discusses it briefly for the benefit of our clinical colleagues. Sun Zhiqiang, Department of Hematology, Affiliated Hospital of Guizhou Medical University
1 Overview
Gastric malignant lymphomas, mainly mucosa-associated lymphoid tissue (MALT) lymphomas, are indolent B-cell lymphomas and aggressive diffuse large B-cell lymphomas (DLBCL), as well as follicular There are also follicular lymphomas, B-cell lymphomas such as set cell lymphoma, and T-cell lymphomas such as adult leukemia lymphoma, but MALT lymphomas and DLBCL are rare. This guideline focuses on the first two, both of which are non-Hodgkin’s lymphomas.
2 Diagnosis
Gastric MALT lymphoma: It accounts for about 40% of malignant lymphomas of the stomach. The proportion of men and women is equal. It can occur from youth to old age, and the average age of onset is 60 years. There are mostly non-specific manifestations such as abdominal pain and indigestion. Gastroscopy reveals multiple erosions, ulcers, mucosal discoloration, similar to early gastric cancer; pavement-like mucosa, submucosal tumor-like elevation, crepitus hypertrophy and other diverse and multiple manifestations. Onset is mostly in the context of Helicobacter pylori (HP) infection follicular gastritis, with a slow clinical course and good prognosis, with 5- and 10-year survival rates of 86% and 80%.
Gastric DLBCL: It accounts for about 45%-50% of gastric lymphomas, with a median age of 60 years. The median age of onset is 60 years. Most of the patients have abdominal pain, vomiting and other stenosis symptoms and blood in the stool. Gastroscopy shows Borrmann type 1 and 2 ulcers and hypertrophy of folds. There was no clear association between the onset of disease and HP infection. Some of them have a mixed MALT lymphoma component. A purely high component malignant lymphoma, partly associated with EBV (epstein-barr virus, EBv).
2.1 Pathological and genetic diagnosis Malignant lymphoma is mainly diagnosed by pathological histology. HE staining of gastric low-grade malignant lymphoma reveals lymphoid cell infiltration and destruction of gastric glands (Figure 1); gastric high-grade malignant lymphoma is lamellar transitional type of mother cells (Figure 2). In addition, feasible immunohistochemical antibodies CD3, CD5, CD10, CD19
CD20, CD23, CD79a, cyclinD1, BCL2, etc. were detected. Cell surface markers kappa/lambda, CD14, CD20, CD5, CD23, CD10, MALT lymphoma-specific (t 11; 18) (q21; q21) chromosomal translocation, positive AP12-MALT1 fusion gene (stomach about 20%) and other tests were done by flow cytometry.
2.2 Clinical staging The clinical staging of malignant lymphoma of the alimentary canal as revised by the 1994 Lugano International Conference was applied (Table 1). Gastrointestinal endoscopy, CT of the neck, chest and whole abdomen, PET, abdominal ultrasonography, routine blood tests, biochemistry, s-IL2R, bone marrow aspiration, etc. should be performed. International prognostic factors (IPI) for DLBCL: age, stage of disease, serum LDH, performance status (PS), number of extra nodal lesions, it is also important to know the IPI.
3 Treatment
Firstly, we briefly review the research on surgical and nonsurgical treatment of gastric malignant lymphoma in the last 20 years or so. As early as 1984, Maor et al. reported 9 cases of stage I and II gastric lymphoma treated with chemotherapy and radiotherapy, with only 1 case of recurrence. In 1991, Avites et al. prospectively compared the results of 52 cases of stage I and II gastric lymphoma treated with chemotherapy or surgery + chemotherapy, and the differences in the relapse-free survival rate and the survival rate of the whole group were not statistically significant. A number of similar results have been reported in succession. It is concluded that chemotherapy and radiotherapy in early gastric lymphoma can achieve good results and additional surgical treatment is not necessary.
3.1 Treatment of gastric MALT lymphoma
3.1.1 Decontamination therapy
3.1.1.1 Indications and follow-up Sterilization is the standard treatment of choice for stage I and II gastric MALT lymphoma, with an efficiency of 70%-80% reported by Japanese authors and 80%-95% reported by Yoon et al (Table 2). The time to regression of MALT lymphoma after debridement therapy ranges from 2-3 months to several years. Regular endoscopy is required. In Japan, gastroscopy and CT examination of the chest and abdomen were performed at 6 weeks to determine the effect, and gastroscopy and CT examination were repeated every 3 months in the first year, every 4 months in the second year, every 6 months in the third year, and once a year after the fourth year.
3.1.1.2 Treatment is preferred for HP(+), and there is no consensus for HP(-). The effect of remission cases can be obtained, so most advocate debridement therapy. The standard treatment regimen is a three-dose combination of proton pump blocker, amoxicillin, and clarithromycin
The standard regimen is a three-dose combination of proton pump blocker, amoxicillin and clarithromycin for 1 week. Specific dosing regimen: clarithromycin 200mg, amoxicillin 750mg, lansoprazole 30mg (omeprazole is commonly used in China), 2 times/d, after breakfast and dinner, for 7d.
3.1.1.3 Debridement treatment resistant cases (1) submucosal mass type seen by gastroscopy; (2) deep to the lamina propria; (3) containing DLBCL component; (4) positive lymph node metastasis outside the region (progressive stage); (5) HP(-) cases; (6) t(11;18)(q21; q21) chromosomal translocation and fusion gene AP12-MALT1(+); (7) other chromosomal translocations, etc. . Most of the lymphoma cells remained after complete debulking treatment.
3.1.1.4 Second treatment for cases resistant to debridement There is no standard treatment. Radiotherapy or surgery (the same as radical surgery for gastric cancer) is used for limited stage cases, and chemotherapy is chosen for progressive cases. A combination chemotherapy (CHOP) regimen consisting of cyclophosphamide, adriamycin, vincristine and prednisone is used for MALT lymphoma in stage II or above, and Galactolysis (or melphalan rituximab) is used for B-cell malignant lymphoma.
3.1.2 Radiotherapy For MALT lymphoma stage I-II1 cases, 30 Gy/20 times for gastric and perigastric lymph nodes for those with residual lymphoma or HP(-) after treatment. There is no consensus on the timing of radiotherapy after sterilization. Radiotherapy should be administered if there is a tendency for malignant growth on gastroscopy or if symptoms recur. The US NCCN Guidelines state that radiotherapy should be administered if lymphoma is found to be residual and symptomatic after 3 months of debridement or after 6 months, with or without symptoms.
3.1.3 Chemotherapy and antibody therapy Gastric MALT lymphoma is low-grade malignant, slow-progressing, and mostly found in stage I and II. Debridement therapy is preferred, but low-grade malignant progressive lymphoma is usually difficult to cure with chemotherapy. For stage II or higher cases, systemic MALT lymphoma treatment is chosen, and the goal of treatment is to improve symptoms and prolong survival time.
Initial treatments are chemotherapy, antibody therapy, and antibody-combined chemotherapy.
Chemotherapy: The standard chemotherapy regimen has not been determined. CHOP regimens and cyclophosphamide, vincristine, and prednisolone (CVP) regimens are available. Recently, the CHOP regimen and CVP+rituximab regimen have been applied with good efficacy and are therefore mostly used.
CHOP regimen: cyclophosphamide 750mg/m2, adriamycin 50mg/m2, vincristine 1.4mg/m2 intravenously, only once on the first day; prednisolone 100mg orally, 1~5 times/d.
Antibody therapy and antibody combination chemotherapy: antibody refers to rituximab, a chimeric mouse/human monoclonal antibody that acts on CD20 antigen on pre-B cells and mature B cells, binding specifically and triggering an immune response of B cell lysis. The commonly used regimen is Rituxan combined with chemotherapy should (R-CHOP) regimen, which is the gold standard regimen for the treatment of DLBCL, with complete remission (CR) rates of 77% to 86%, 3-year survival rates of 67% to 93%, and 5-year survival rates of 47% to 79%.
Indications: The main targets of MALT lymphoma treatment with chemotherapy and antibody therapy are progressive (stage III and IV) cases, restricted stage MALT lymphoma with failed debulking therapy, unsuitable for radiotherapy or relapsed cases, and those who are not suitable for surgery or do not want surgery.
Also available is the fludarabine (fludarabine) + rituximab regimen.
For treatment-resistant and multiple recurrent progressive MALT lymphoma, high-dose chemotherapy with autologous hematopoietic stem cell transplantation is used. Allogeneic hematopoietic stem cell transplantation is being studied on a trial basis, and its efficacy is not confirmed, so it is advisable to choose carefully.
3.1.4 Surgical treatment Gastric MALT lymphoma has been treated with surgical treatment. Because of the multiple and extensive lesions, total gastrectomy was performed and lymph node dissection was performed according to the standard of gastric cancer treatment. The rate of lymph node metastasis is not very low and sometimes contains N2 metastasis in No.10 lymph nodes (+). Those without DLBCL component on pathological examination have excellent treatment results. In recent years, HP debulking therapy is preferred. Attention should be paid to the mixed presence of DLBCL components in the lesion, those who were originally HP(-), and those for whom debridement therapy is not indicated should be treated with non-debridement therapy. The use of radiotherapy and chemotherapy may be effective. Surgery should be considered only for those who are not amenable to radiotherapy and chemotherapy, but MALT lymphoma is rarely likely to cause severe bleeding and perforation. There is one exception to this rule, which is to perform an appropriate extent of gastrectomy in combination with nonsurgical treatment for gastric cancer if total gastrectomy is not necessary. Total gastrectomy should be an option.
3.2 Treatment of gastric DLBCL
3.2.1 Chemotherapy and radiotherapy Initial case of progressive stage (stage II or above): single local therapy is not recommended. R-CHOP therapy for adults for 6~8 cycles is the standard treatment. Poor International Prognostic Index (IPI) factors (>61 years, stage III or higher, pS2 score or higher, elevated serum lactate dehydrogenase (LDH), more than 2 extra-nodal lesions), of which 3 or more (+) have a poor prognosis. Current clinical trial protocols include autologous hematopoietic stem cell transplantation combined with high-dose chemotherapy (HD-SCT) and new drug trials.
Initial case-limited stage (below stage II): Binn et al. reported no statistically significant difference between surgery + chemotherapy for 3-4 cycles compared to chemotherapy-only group. German and Japanese scholars reported no statistically significant difference in survival rates between surgery and chemotherapy and radiotherapy combination therapy. The current indications for surgery are only perforation and hemorrhage.
The standard treatment regimen for limited DLBCL: R-CHOP therapy after 3 cycles + radiotherapy at 40 Gy. However, there is an increased tendency for late recurrence at long-term follow-up. The NCCN guidelines recommend 6-8 cycles of R-CHOP therapy + chemotherapy for large tumors over 10 cm in diameter.
In conclusion, the standard treatment regimen for initial DLBCL cases is 3 cycles of R-CHOP therapy + 40 Gy of radiotherapy in the limited stage, and 8 cycles of R-CHOP therapy in the progressive stage, one cycle every 3 weeks.
Treatment of relapsed cases: more intensive chemotherapy except in advanced age, with a recommended regimen of autologous hematopoietic stem cell transplantation combined with high-dose chemotherapy. More intensive chemotherapy regimens are: etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP); dexamethasone, etoposide, isocyclophosphamide, carboplatin (DeVIC); etoposide, prednisone, vincristine, cyclophosphamide, adriamycin (EPOCH).
3.2.2 Surgical treatment After gastrectomy D2 for stage I-II1 DLBCL, the 5-year survival rate is up to 90%, with recurrence seen after 5 years. DLBCL is usually treated with a combination of radiotherapy and chemotherapy, and surgery is a local therapy. If surgery is not suitable for radiotherapy, additional chemotherapy is necessary. On the contrary, radical surgery without chemotherapy according to the standard of gastric cancer can still be cured.
Indications for surgery: It is limited to cases with complications such as hemorrhage and perforation caused during non-surgical treatment and a few cases of salvage surgical treatment. Cases with complications often have severe bone marrow suppression and are performed urgently as high-risk surgery. In consideration of future treatment, the residual gastric lesions should be removed as much as possible without systemic lymph node dissection, and a gastrectomy of the necessary extent should be performed. In addition, for those who are not suitable for chemotherapy or radiotherapy, standard radical surgery for gastric cancer can be performed, and total gastrectomy is often performed according to the tumor site and size.