Gastric lymphoma is the most common extra nodal diffuse B-cell non-Hodgkin lymphoma (DLBCL) and accounts for 30% of cases of lymphoma in the stomach.1 According to the current WHO lymphoma classification criteria, gastric DLBCLs are classified with or without features of MALT.2 Recent studies revealed that Helicobacter pylori-related gastric DLBCL is a distinct less aggressive entity with greater chemosensitivity, thereby highlighting the heterogeneity of these lymphomas. The clinical presentation and course are also variable with clinical symptoms, laboratorial abnormalities and H. pylori, hepatitis B, and C infections, in addition to classical international prognostic index (IPI) factors having been related to prognosis.3 Different clinical behaviors may reflect distinct unidentified pathogenic mechanisms.4 A better characterization of prognostic factors is required in order to discover new potential disease mechanisms, improve outcomes and individualize treatment approaches. The present study aims to identify prognostic factors in patients with gastric DLBCL diagnosed and treated in different countries by analyzing demographic and clinical characteristics, response to treatment and outcome.

A retrospective study of 104 consecutive patients with DLBCL diagnosed and treated in hematology centers in Brazil, Italy and Portugal between February 2008 and December 2014 was performed. The inclusion criteria were age >18 years old, lymphoma primarily located in the stomach, with or without the involvement of other intra-abdominal structures and with a confirmed DLBCL histology. All cases were diagnosed according to World Health Organization (WHO) classification criteria.2 Patients with transformation from another type of lymphoma to DLBCL were excluded. Patients were considered H. pylori positive when their histology results were positive.

Data were retrieved from patient's charts with all patients having signed a consent form submitted to the local ethics committee in the diagnosis period. All patients were subjected to a detailed physical evaluation including an investigation of B symptoms (pain, nausea, dysphagia, bleeding, obstruction), routine blood exams (hemoglobin, total and differential leukocyte counts, platelet count and peripheral smear for abnormal/blast cells), biochemical exams [liver function tests, serum lactate dehydrogenase (LDH), β2 microglobulin, albumin, urea, creatinine and uric acid] and serologic investigations for hepatitis B and C and HIV. Upper gastrointestinal endoscopic examinations were performed in 95% of the patients. Imaging studies included chest radiographs and/or computed tomography scans and abdominal and pelvic computed tomography scans or ultrasonography. Bulky disease was defined as lesions with a diameter >10cm. All patients underwent bone marrow aspiration and biopsy as part of the staging procedure. The international prognostic index (IPI), age-adjusted IPI (aaIPI)5 and Ann Arbor stage6,7 were calculated for each patient.

All patients were treated by systemic chemotherapy mostly consisting of six cycles of the rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) regimen with the intention to cure.8 Patients with residual disease received local radiotherapy. Imaging studies and endoscopic examinations were used to evaluate response.

The influence of the following parameters were evaluated in the response to treatment and survival: LDH, β2 microglobulin, albumin, presence of bulky disease, B symptoms (fever, weight loss, pain, nausea, vomiting), aaIPI, type of treatment (surgery plus chemotherapy, chemotherapy alone), anemia, dysphagia, bleeding, obstruction and presence of H. Pylori at diagnosis. Anemia was defined as hemoglobin <12.0g/dL and elevated LDH levels as >240U/L.

All patients underwent imaging and follow-up endoscopic examinations (with a biopsy of suspicious lesions) to document treatment response. At the end of chemotherapy, response was classified as complete remission (CR), partial response (PR), stable disease (SD) or progressive disease (PD) according to the International Working Group criteria.6 Patients who failed initial therapy with R-CHOP (PR, SD and PD) received high-dose chemotherapy together with autologous stem cell transplant. Patients with H. pylori at diagnosis also received antibiotic therapy.

Survival was estimated using the Kaplan–Meier method and compared using the log-rank test. The prognostic value of the different variables for clinical outcome was estimated by univariate and multivariate analyses, applying the Cox proportional hazards regression model. Two-sided p-value <0.05 was considered significant. The Statistical Package for the Social Sciences (SPSS version 15.0) software (Chicago, IL, USA) was used for data analysis.

An unexpected high incidence of primary gastric DLBCL was found in this multicenter series of patients treated at tertiary care centers. Advanced stage was present in half of the patients and one third had high-risk aaIPI. Regardless of the prevalence of factors considered to be associated with poor prognosis (advanced stage, B symptoms, bulky disease, elevated LDH and high-risk aaIPI), the outcomes compared favorably with registry data.9

The majority of the published data showed that primary gastric DLBCL predominates in men.10,11 Interestingly, in this cohort of Brazilian and European patients, a slightly higher incidence was observed in women. Most patients had advanced stage disease and a high-risk aaIPI at diagnosis. The median age was 69 years old, ranging between 28 and 88 years, which is in agreement with others studies.12,13 In nodal DLBCL, an age higher than 60 years is a confirmed poor prognostic factor. Similar to another study, no relationship was found between age and survival.14

The main clinical presentations of the disease were non-specific gastrointestinal symptoms, including abdominal pain, nausea, vomiting and weight loss. Some authors identified abdominal pain, gastrointestinal bleeding and nausea/vomiting as the most common symptoms in large cohorts of patients.12,15 The results of this study were similar with 85% of evaluable patients developing abdominal pain, 75% had weight loss and 51% had nausea. Anemia, detected in 43% of the evaluable patients, was also common. In general, the clinical manifestations of gastric lymphoma are non-specific which may result in a delayed diagnosis.

Low albumin levels have been suggested as an important predictor of survival in elderly lymphoma patients and particularly in gastric DLBCL.16 In this study, 31% of the patients had hypoalbuminemia, nevertheless, this hypothesis was not confirmed in the multivariate analysis.

Thirteen of the 45 patients who were tested for H. pylori were positive. This is not a high incidence, but H. pylori infection plays a role in DLBCL.17 Hence, these patients were also treated for H. pylori infection.

Univariate analysis confirmed published data regarding the prognostic impact of the aaIPI, ECOG, elevated DHL, advanced stage, B symptoms, anemia, bulky disease and albumin levels.10,15 Nevertheless, multivariate analysis showed that only aaIPI retained its significance as an independent predictor of outcome. Almost one quarter of the patients had bulky disease at diagnosis and this turned out to be a negative impact factor, and although rituximab decreased the adverse prognostic value of bulky disease, it did not eliminate the effect completely.18

One of the limitations of this study is its retrospective design however this was the best way to get a relevant number of the patients with similar clinical features. The aaIPI was identified as a predictor of survival in patients treated with conventional immunochemotherapy.

M.T. Delamain, M.G. Da Silva, J. Desterro and S. Luminari conceived and designed all study. M.G. Da Silva, J. Desterro, E.C.M. Miranda, A. Fedina, and C.S. Chiattone were responsible for the data acquisition. E.C.M. Miranda applied all analyses. M.T. Delamain, M.G. Da Silva, J. Desterro, and S. Luminari, F. Merli, C.S. Chiattone, K.B. Pagnano, M. Federico, C.A. De Souza were responsible for interpretation, manuscript drafting and critical revision. All authors approved the manuscript.

The authors declare no conflicts of interest.