Primary Gastric Diffuse Large B-cell Lymphoma Research Articles

Bcl-6 expression and lactate dehydrogenase level predict prognosis of primary gastric diffuse large B-cell lymphoma

The gastrointestinal tract is the most common site of primary extranodal non-Hodgkin lymphoma, and the prognostic factors of primary gastric diffuse large B-cell lymphoma (PG-DLBCL) differ in various studies. We retrospectively searched for PG-DLBCL in a single institution, performed immunohistochemical analysis, classified tumor phenotype (Hans and Muris algorithms), reviewed medical records, and analyzed the clinical and immunophenotypic variables using Cox proportional hazard regression model. A total of 46 cases were identified including 25 males and 21 females with a median age of 63.5; 18 (39%) were at stage I and 28 (61%) at stage II. Seven (15%) patients underwent surgery as initial treatment including total (n=3, 7%) and subtotal (n=4, 9%) gastrectomy. Thirty-three patients (72%) received frontline chemotherapy treatment including ten with additional rituximab (MabThera) injection, and two (6%) of these patients developed perforation after chemotherapy. Four patients passed away shortly after diagnosis and the remaining three were lost to follow-up. The overall 2- and 5- year survival rates were 55% and 50%, respectively. The expression of various differentiation markers was CD10 (25%), bcl-2 (50%), bcl-6 (84%), and MUM1 (64%). Half of the cases studied (22/44) were classified as germinal center B-cell (GCB) phenotype and the remaining half as non-GCB according to Hans algorithm; 66% and 34% cases belonged to groups 1 and 2, respectively, according to Muris algorithm. Univariate analysis showed the expression of bcl-6 by the tumor cells as a favorable factor, while elevated serum lactate dehydrogenase (LDH) level, bcl-2 expression, and Muris group 2 were associated with poorer outcome. Multivariate analysis revealed that the two prognostic factors were bcl-6 expression and elevated LDH level, with hazard ratios of 0.09 (p=0.002) and 3.72 (p=0.024), respectively. In this retrospective study with heterogeneous treatment modality, we identified bcl-6 expression and elevated LDH level as two prognostic factors for PG-DLBCL.

Primary Gastric Diffuse B Cell Lymphoma in Association with Chronic Hepatitis C

Introduction: The association between chronic hepatitis C virus (HCV) infection and diffuse large B-cell lymphoma (DLBCL) is rare, but recent studies have demonstrated a modestly increased risk of DLBCL in HCV infection. We report a rare presentation of DLBCL in the setting of an underlying HCV infection. Case: A 64 year-old male presented with a one day history of epigastric pain associated with meals, hematemesis, dark stools, anorexia and a 20 pound weight loss in two months. He had a history of intravenous drug use but denied alcohol or NSAID use. On physical examination, he appeared cachectic and had right upper quadrant tenderness without rebound, Murphy's sign or palpable organomegaly. Rectal exam confirmed melena. Initial investigations demonstrated normocytic anemia, hemoglobin of 9 mg/dl and no evidence of hepatic synthetic dysfunction. Additionally, viral serology was positive for Anti-HCV antibodies. HBsAg and HIV-Ab were negative. Esophagogastroduodenoscopy revealed bulky, ulcerated masses in the gastric body with no stigmata of active bleeding. Biopsies showed heavy atypical lymphocytic infiltration into the submucosa without evidence of Helicobacter pylori infection. Immunohistochemistry demonstrated atypical lymphocytes positive for CD20 and BCL-6. An abdominal MRI illustrated a gallbladder mass extending into the hepatic parenchyma along with hepatic nodularity and para-aortic lymphadenopathy. A diagnosis of primary gastric DLBCL with gallbladder and hepatic metastasis was made. Discussion: We present a unique presentation of HCV associated DLBCL involving the gall bladder and presenting with hematemesis. HCV has major pathogenetic roles in several extra-hepatic dysplastic conditions. HCV is known to lower the activation threshold of B cells and initiates a multi-step cascade of malignant B cell transformation. Recent evidence suggests association of DLBCL and sero-positivity for HCV. Further, HCV positive patients have higher risk features of DLBCL at presentation; including being older and having more frequent splenic involvement and higher lactate dehydrogenase levels. A small retrospective study has demonstrated that antiviral treatment in HCV-positive non-Hodgkin's lymphoma is associated with a longer disease free survival and hence may reinforce the results of a successful chemotherapy regimen. In conclusion, we present a rare case of primary gastric DLBCL in a patient with HCV. The above observations illustrate the potential association between HCV infection and B-cell lymphoma, as well as provide some future prospects for therapeutic research.

The comparison between CHOP and R-CHOP in primary gastric diffuse large B cell lymphoma

The combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) plus rituximab is the standard treatment for patients with primary gastric diffuse large B cell lymphoma (DLBCL). However, a few trials comparing CHOP plus rituximab (R-CHOP) with CHOP have been conducted in primary gastric DLBCL. Among 93 consecutive patients receiving CHOP or R-CHOP as a first-line chemotherapy at our institution, 38 patients received CHOP and 55 patients received R-CHOP. With a median follow-up time of 48 months, the complete response (CR) rate, event-free survival (EFS), and overall survival (OS) did not differ between two treatment groups (P = 1.000, P = 0.744, and P = 0.213, respectively). The CR rates were 93.9% for patients receiving CHOP and 92.5% for patients receiving R-CHOP. The 3-year EFS rates were 86.0% for patients receiving CHOP and 81.7% for patients receiving R-CHOP; the 3-year OS rates were 94.7 and 84.7%, respectively. In a multivariate analysis, The CR rate was affected by the number of extranodal involvements (P = 0.011). The EFS and OS rates were affected by the Lugano stage (P = 0.067 and P = 0.008, respectively). High serum level of β₂-microglobulin was associated with worse EFS and OS in patients receiving R-CHOP (P = 0.018 and P = 0.015, respectively). In conclusion, the addition of rituximab was not found to have an impact on patients' outcomes with primary gastric DLBCL. The β₂-microglobulin in primary gastric DLBCL might be able to discriminate the patients' prognosis who are treated with R-CHOP chemotherapy.

Rituximab in treatment of primary gastric diffuse large B-cell lymphoma

In the rituximab era, the optimal treatment modality for primary gastric diffuse large B-cell lymphoma (PG-DLBCL) still remains unclear. We performed a retrospective, multicenter analysis of 65 patients with PG-DLBCL to assess the efficacy and toxicity of the addition of rituximab to conventional chemotherapy. When compared with conventional chemotherapy, there was a trend that rituximab plus chemotherapy yielded a higher complete response rate, 5-year event-free survival (EFS) rate and 5-year overall survival (OS) rate, but this was not statistically significant. In subgroup analysis, better OS was observed only for patients with advanced-stage disease when rituximab was added. When involved-field radiotherapy (IFRT) was included, EFS and OS were significantly prolonged in the conventional chemotherapy group, but not in the immunochemotherapy group. If focusing on patients with localized-stage disease receiving immunochemotherapy, the efficacies of short-course rituximab (R)-chemotherapy plus IFRT and 6–8 courses of R-chemotherapy without IFRT were comparable. In conclusion, it is necessary to carry out prospective randomized trials to help further illuminate the role of rituximab in the PG-DLBCL treatment landscape. If a patient has been treated with a non-rituximab-containing regimen, additional IFRT should be considered, and for patients with advanced-stage disease, rituximab should be considered.

Long-term follow-up of localized, primary gastric diffuse large B-cell lymphoma treated with rituximab and CHOP

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP (i.e., R-CHOP)] is considered to be the standard regimen for treating localized, primary gastric diffuse large B-cell lymphoma (PG-DLBCL). However, few studies have reported the long-term efficacy of R-CHOP therapy in the management of localized PG-DLBCL. In the present study, we performed a retrospective analysis of 11 patients with localized PG-DLBCL, who were treated with R-CHOP at Nihon University Itabashi Hospital and Kasukabe Municipal Hospital (Japan) from 2001 to 2008. Limited stage cancer was defined as stage I/II according to the Lugano staging system for gastrointestinal (GI) lymphomas. The relative dose intensity (RDI) of CHOP therapy was calculated for each patient. The median age of the patients was 68 years (range, 48-82). Gastralgia and anemia were common symptoms at initial presentation. All patients except 1 received 6 cycles of R-CHOP treatment without consolidative radiation therapy or prior surgery. RDI was maintained at over 80% in 9 out of 11 patients. All patients achieved complete remission and the estimated overall survival with a median follow-up of 54 months (range, 39-103) was 100%, without relapse or significant GI adverse effects, such as perforation or bleeding during R-CHOP treatment. No long-term adverse effects of rituximab were recorded during the observation period. Helicobacter pylori infection was diagnosed in 72.7% (8 cases) of the patients, but was eradicated in a limited number of patients. Our data suggest the feasibility and effectiveness of the addition of rituximab to conventional CHOP therapy in the management of localized PG-DLBCL.

Retrospective analysis of primary gastric diffuse large B cell lymphoma in the rituximab era: a multicenter study of 95 patients in Japan

Primary gastric diffuse large B cell lymphoma (PG-DLBCL) is common subtype of extranodal non-Hodgkin lymphoma. The optimal treatment strategy for PG-DLBCL in the rituximab era still remains unknown. To evaluate clinical outcomes of PG-DLBCL in the rituximab era, we conducted a retrospective, multicenter analysis of 95 patients with PG-DLBCL. In 58 patients with localized disease, 3-year progression-free survival (PFS) and overall survival (OS) were 91% and 91% for patients with six cycles of rituximab plus CHOP (R-CHOP) and 92% and 95% for patients with three to four cycles of R-CHOP plus radiotherapy (Log-rank test, P = 0.595 and P = 0.278, respectively). In 37 patients with advanced disease, 3-year PFS and 3-year OS were 43% and 64% for patients with R-CHOP chemotherapy with or without radiotherapy. On multivariate analysis, advanced stage and elevated serum LDH levels were independent predictors of survival in patients with PG-DLBCL. One patient with localized disease relapsed in lymph node, and eight patients with advanced disease relapsed in lymph node (n = 3), stomach (n = 2), central nervous system (CNS; n = 2), and duodenum (n = 1). Intriguingly, CNS relapse developed within 6months after initial series of treatment (4.9 and 5.8months, respectively), and stomach relapse developed in later phase (27.2 and 32.9months, respectively). Clinical outcomes of PG-DLBCL were extremely favorable for localized-stage patients in the rituximab era, although these might be poor for advanced-stage patients even in the rituximab era. Further prospective analyses are warranted.

Clinical analysis of primary gastric diffuse large B-cell lymphoma

To analyze the clinical features and prognostic factors of primary gastric diffuse large B-cell lymphoma (PG-DLBCL) and to evaluate the staging system and treatment modality of PG-DLBCL. The clinicopathological data of 69 patients with PG-DLBCL were retrospectively analyzed. Event-free survival (EFS) and overall survival (OS) were the primary endpoints. The EFS rates at 1, 3, and 5 years were 83.8%, 71.1%, and 69.0%, respectively, with a mean EFS of 91.3 months. The 1-, 3-, and 5-year OS rates were 91.3%, 80.3%, and 72.4%, respectively, with a mean OS of 98.8 months. Univariate analysis revealed that either EFS or OS was significantly prolonged by the following factors (P < 0.05): modified Ann Arbor stage I(E) or II(E1) disease; normal lactate dehydrogenase (LDH) level; normal hemoglobin level; normal albumin level; International Prognostic Index (IPI) of 0 or 1; tumor size < 5 cm; and less depth of invasion. While gender, age, B symptoms at presentation, performance status and treatment modality were not significantly associated with the prognosis (P > 0.05). Cox regression model revealed that only modified Ann Arbor stage and albumin level were independent prognostic factors for EFS and OS. The most accurate staging system and the exact role of different therapeutic options for PG-DLBCL are still debated. Further randomized prospective studies with a large number of patients are still needed to establish an optimal management for this disease.

Primary gastric diffuse large B‐cell Lymphoma (DLBCL): analyses of prognostic factors and value of pretreatment FDG‐PET scan

We report a single institution experience with gastric diffuse large B-cell lymphoma (DLBCL) in an attempt to evaluate the roles of different treatment modalities, to assess the value of pretreatment positron emission tomography (PET) scan, and to identify potential prognostic factors. Among 384 patients diagnosed with DLBCL between 1995 and 2008, 75 patients had primary gastric DLBCL and were reviewed and analyzed. The median age was 66. International prognostic index (IPI) risk was low in 52%, low-intermediate in 23%, high-intermediate in 9%, and high in 16%. Pretreatment PET scan was highly sensitive in detecting gastric lesions except stage I gastric DLBCL without detectable mass by CT or gastroscopy. As a general rule, patients with limited-stage disease were treated with three times of CHOP (with or without rituximab) and radiotherapy, and those with advanced-stage disease were treated with eight cycles of CHOP (with or without rituximab), and radiotherapy was given to residual diseases after chemotherapy. Three-year overall survival (OS) rate was 78%. Multivariate analysis revealed that low albumin, hemoglobin <12.0 g/dL, and treatment without rituximab were independently associated with shorter OS. Low albumin, hemoglobin <12.0 g/dL,and advanced stage were independently associated with shorter progression-free survival. We showed the survival benefit of rituximab and potential prognostic value of pretreatment hemoglobin and serum albumin levels in gastric DLBCL.

Outcomes in patients with primary gastric diffuse large B-cell lymphoma after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy

e19543 Background: The optimal therapy for primary gastric diffuse large B- cell lymphoma (DLBCL) still needs to be defined. The aim of this study was to investigate the patient's outcomes after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) treatment in primary gastric DLBCL in a single institution. Methods: We searched AMC Registry for Non-Hodgkin's Lymphoma and found 26 patients with primary gastric DLBCL, who received R-CHOP as first-line chemotherapy. Ten of 26 patients had localized disease. Remaining patients had disseminated disease. R-CHOP was repeated every 21 days in all patients. Results: Overall, complete response (CR) was observed in 20 of 26 patients (76.9%). Three-year event free survival (EFS) and overall survival (OS) was 76.5% and 75.0%, respectively. After analyses of 10 patients with localized disease, we found that these patients had received a total 38 cycles, with a median of 3 cycles per patient. Of 10 patients, one patient had 2 cycles of R-CHOP, 4 had 3 cycles, and one had 4 cycles, all 6 patients above followed by consolidation radiotherapy. Remaining one patient and 4 patients had 5 cycles and 6 cycles of R-CHOP, respectively. In patients with localized disease, CR was observed in 10 of 10 patients (100%), and both 3-year EFS and OS was 100% (10 of 10 patients). In analyses with 16 patients with disseminated disease, all patients had received a total 91 cycles, with a median of 6 cycles per patient. In these patients, two patients had radiation therapy after R-CHOP, one patient had CR before consolidation radiation therapy, and another had partial response before radiation therapy. CR after R-CHOP treatment was observed in 10 of 16 patients (62.5%), partial response in 3 patients, stable disease in 1 patient, and progressive disease in 1 patient. Three-year EFS and OS was 61.1% and 57.8% in patients with disseminated disease. Conclusions: R-CHOP regimen showed a promising result in primary gastric DLBCL. Combination with rituximab in CHOP regimen showed excellent prognosis especially in patients with localized disease. In localized disease, CR was 100%, 3-year EFS and OS was 100%. In disseminated disease, CR was 62.5%, 3-year EFS and OS was 61.1% and 57.8%. No significant financial relationships to disclose.

Translocations Involving the Immunoglobulin Heavy Chain Gene Locus Predict Better Survival in Gastric Diffuse Large B-Cell Lymphoma

The pathogenesis and clinical heterogeneity of gastric diffuse large B-cell lymphoma (DLBCL) are poorly understood. We have comprehensively investigated the incidence and clinical significance of lymphoma-associated chromosomal translocations, particularly those involving the immunoglobulin heavy chain (IGH) gene locus, in a large series of gastric DLBCL. One hundred forty-one cases of primary gastric DLBCL [58 with mucosa-associated lymphoid tissue (MALT) lymphoma and 83 without MALT lymphoma] were enrolled. Translocations involving BCL6, c-MYC, FOXP1, MALT1, and IGH were investigated using interphase fluorescence in situ hybridization. In positive cases, additional fluorescence in situ hybridization was done with appropriate probes for potential partner genes. Cases were classified into germinal center B-cell-like (GCB) or non-GCB subgroups by immunophenotyping with CD10, BCL6, and MUM1. Translocations involving IGH were detected in 36 (32%) of 111 cases; their partner genes included BCL6 (n = 10), c-MYC (n = 5), and FOXP1 (n = 3) but remained unknown in the remaining 18 cases. t(14;18)/IGH-BCL2, t(14;18)/IGH-MALT1, and t(1;14)/BCL10-IGH were not detected in any case. t(11;18)/API2-MALT1 was detected in none of the cases, except for one case of DLBCL with MALT lymphoma, which showed positive signals only in MALT lymphoma cells. IGH-involved translocation was associated with younger age but not with any other clinicopathologic factors including GCB or non-GCB immunophenotypes. Cox multivariate analysis revealed that IGH-involved translocation, in addition to younger age and early stage, was an independent prognostic factor for better overall and EFSs. IGH-involved translocations are frequent in gastric DLBCL and seem to identify cases with favorable prognosis.

P058 Modified NHL-BFM-90 program in primary gastric diffuse large B-cell lymphoma (PGDLBCL) with adverse prognostic factors

P058 Modified NHL-BFM-90 program in primary gastric diffuse large B-cell lymphoma (PGDLBCL) with adverse prognostic factors

CHOP followed by involved field radiotherapy for localized primary gastric diffuse large B-cell lymphoma: Results of a multi center phase II study and quality of life evaluation

We aimed to define the role of cyclophosphamide, vincristine, doxorubicin, prednisone (CHOP) followed by involved field radiotherapy (IFRT) for treating localized primary gastric diffuse large B-cell lymphoma (DLBCL). Newly diagnosed patients with localized primary gastric DLBCL were to receive four cycles of CHOP followed by IFRT of 40.0 Gy. At 1 year after the completion of treatment, patients filled out the EORTC Quality of Life Questionnaire specified for stomach cancer (QLQ-C30-STO22). Fifty evaluable patients (25 men, 25 women) were included. The median age was 54.5 years (range, 21 – 73 years. The overall response rate to the CHOP was 94% (95% confidence interval [CI], 87 – 100) in the intent-to-treat population. Forty-one of the 50 patients (82%; 95% CI, 71 – 93) achieved complete remission (CR). After the completion of radiotherapy, five patients who were in PR following chemotherapy eventually attained CR. The overall complete response rate was thus 92% (95% confidence interval, 84 – 99). With a median follow-up period of 30 months, the 2-year progression-free and overall survival rate was 92% and 92%, respectively. The gastric function was well preserved with negligible stomach-related symptoms at 1 year after the completion of treatment. This organ-preserving combined treatment is highly effective and well tolerated for the patients with localized gastric DLBCL.

Point mutation of 5’ noncoding region ofBCL-6gene in primary gastric lymphomas

To investigate the mutations of the 5' noncoding region of BCL-6 gene in Chinese patients with primary gastric lymphomas. PCR and direct DNA sequencing were used to identify BCL-6 gene mutations in the 5' noncoding region in 29 cases of gastric diffuse large B-cell lymphoma (DLBCL) and 18 cases of gastric mucosa-associated lymphoid tissue (MALT) lymphoma as well as 10 cases of reactive hyperplasia of lymph node (LRH). Six of 29 gastric DLBCLs (20.7%), 4 of 18 gastric MALT lymphomas (22.2%) and 1 of 10 LRHs(10%) were found to have mutations. All mutations were single-base substitutions and the frequency of single-base changes was 0.20 x 10(-2) -1.02 x 10(-2) per bp. Point mutations in the 5' noncoding region of BCL-6 gene are found in Chinese patients with primary gastric DLBCLs and MALT lymphomas, suggesting that they may, in some extent, participate in the pathogenesis of primary gastric DLBCLs and MALT lymphomas.

Primary intestinal diffuse large B-cell non-Hodgkin's lymphoma: Clinical features, management, and prognosis of 66 patients

In Saudi Arabia, primary gastrointestinal non-Hodgkin's lymphoma (NHL) is common. Recently we have reported one of the largest series of primary gastric (PG) diffuse large B-cell lymphoma (DLCL). This has prompted the analysis of another series of patients with primary intestinal DLCL to depict the clinical features and the outcome of that disease and to compare those with that for PG involvement. The data of 66 adult patients with primary intestinal NHL having DLCL histology were retrospectively reviewed. Patients had a median age of 45 years. Of 64 treated patients, 16% and 84%, received single and multiple modality treatment, respectively. Seventy-six percent, ten percent, and fourteen percent attained complete remission (CR), partial remission (PR), and no response/progressive disease, respectively. Multivariate analysis failed to identify any variable that predict the likelihood of attaining CR. Over a median follow-up of 81 months for all 66 patients, 32 (48%) were alive and disease-free, 5 (8%) were alive with evidence of disease, and the remaining 29 (44%) were dead. The median overall survival (OS) was 101 months and it was 58% (+/- 6%) and 48% (+/- 7%) at 5- and 10-year, respectively. Of the 54 patients who achieved CR or PR, the median event-free survival (EFS) was not reached, but the predicted 5- and 10-year EFS was 61% (+/- 7%) and 52% (+/- 7%), respectively. Only low serum albumin (<30 g/l) was associated with adverse OS and EFS in a univariate analysis, however, multivariate analysis was not possible. Our analysis showed that compared with single-modality management, multi-modality strategy attained significantly higher CR, and advantageous EFS, but without a significant superior effect on OS. In comparison with patients with PG DLCL, those with primary intestinal disease demonstrated more adverse prognostic features, but had an equivalent survival. This series characterized the clinico-pathologic features and outcome of patients with primary intestinal DLCL. While surgical resection in primary intestinal NHL seems beneficial, only prospective randomized studies can ascertain its precise role. Compared with patients with PG NHL, patients with primary intestinal disease had more prevalence of adverse prognostic features.