The research team, led by investigators at the Affiliated Hospital of Putian University and Ganzhou People's Hospital, enrolled patients diagnosed between January 1, 2015 and December 31, 2025. To isolate true secondary intestinal involvement, the researchers applied the Dawson diagnostic criteria, which define primary intestinal lymphoma as disease confined to the gastrointestinal tract and regional mesenteric nodes without palpable superficial lymphadenopathy, mediastinal node involvement, normal peripheral white blood cell counts, and no evidence of hepatic or splenic infiltration. Patients who failed to meet these criteria—meaning their lymphoma originated in nodal or other extranodal sites and secondarily invaded the intestine—were classified as having SI-DLBCL.

The demographic profile that emerged is strikingly consistent: SI-DLBCL predominantly strikes middle-aged and elderly men. Of the 483 patients, 298 were male and 185 female, a ratio of 1.61 to 1, and the median age at onset was 60.5 years, with a range spanning 18 to 84. Nearly two-thirds of patients—64.39 percent—presented with advanced Lugano stage III or IV disease, and more than half carried high-risk International Prognostic Index scores of 3 to 5.

The molecular fingerprint of the tumors skewed toward the non-germinal center B-cell-like subtype in 57.76 percent of cases, and the Ki-67 proliferation index reached 80 percent or higher in nearly three-quarters of the cohort, underscoring the aggressive biology of this malignancy. What makes SI-DLBCL so dangerous, the study emphasizes, is how quietly it announces itself. Early symptoms—abdominal pain, low back pain, fatigue, fever, vomiting, weight loss—are nonspecific and easily mistaken for far more common gastrointestinal complaints.

Only 182 patients, or 37.68 percent, presented with abdominal pain as their chief complaint. The gold standard for diagnosis remains histopathological biopsy, supplemented by endoscopy, which allows direct visualization of intestinal lesions and immediate tissue sampling, and by PET-CT, which exploits fluorodeoxyglucose metabolism to pinpoint both intestinal and extraintestinal disease. The authors note that repeated biopsies should be pursued when clinical suspicion is high but initial pathology is negative, a practical point given how frequently the disease is misdiagnosed or overlooked.

Treatment across the five centers followed international and Chinese DLBCL guidelines, and the results reveal a system heavily weighted toward systemic therapy. Chemotherapy alone was the first-line approach for 322 patients, or 66.67 percent of the cohort. Within this group, the rituximab-based R-CHOP regimen—rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone—was the most common choice, given to 135 patients.

Other regimens included R2-CHOP in 58 cases, R-DA-EPOCH in 41, and a long tail of alternatives ranging from CHOP without rituximab to lenalidomide combinations and the BTK inhibitor zanubrutinib paired with temozolomide. Surgery alone was rare, performed in just 15 patients, while 146 patients received chemotherapy combined with surgical intervention, typically reserved for emergencies. When the researchers evaluated response after at least two treatment cycles using the 2014 Lugano criteria, they found significant differences among the three treatment groups.

The overall response rate—the sum of complete and partial remissions—was 78.47 percent across the full cohort, but reached 84.93 percent in the chemotherapy-plus-surgery group compared with 77.02 percent for chemotherapy alone and just 46.67 percent for surgery alone, a difference that was statistically significant. Safety profiles, by contrast, were remarkably similar: granulocytopenia affected roughly half of all patients, gastrointestinal disturbances nearly two-thirds, and rates of anemia, thrombocytopenia, hepatic and renal impairment, neurological and dermatological damage showed no significant differences across treatment groups. Survival statistics paint a sobering picture of the disease's trajectory.

With a median follow-up of 70 months, the one-, three-, and five-year progression-free survival rates were 75.36, 50.72, and 32.92 percent respectively, while overall survival rates were 78.47, 56.11, and 34.37 percent. In total, 116 of the 483 patients died during follow-up. Univariate analyses identified seven significant prognostic factors for both overall and progression-free survival: age, Lugano stage, IPI score, serum lactate dehydrogenase, albumin, beta-2 microglobulin, and first-line treatment modality.

Patients aged 60 or younger, those with stage I–II disease, low IPI scores, normal LDH, albumin of at least 35 grams per liter, beta-2 microglobulin at or below 3 micrograms per milliliter, and those treated with combined chemotherapy and surgery all fared significantly better in these initial analyses. But the multivariate modeling told a more disciplined story. When all significant variables were entered into Cox proportional hazards regression, only two factors retained independent prognostic power for both overall and progression-free survival: age and Lugano stage.

Advanced-stage disease carried a hazard ratio of roughly 4.7 to 4.8 for death, and age over 60 conferred a hazard ratio of about 1.02 per year of age. Notably, first-line treatment modality dropped out of significance in the multivariate models for both survival endpoints. The authors are explicit about why: surgical intervention was selectively reserved for patients with intestinal perforation, massive bleeding, complete obstruction, or bulky localized masses, creating confounding by indication.

The apparent survival advantage of the combined-modality group likely reflects a healthier, surgically eligible subgroup rather than a genuine therapeutic effect, and the researchers caution against generalizing it into a recommendation for upfront surgical debulking. A sensitivity analysis using mixed-effects Cox models with center as a random intercept confirmed the robustness of the age and stage findings, with between-center variance accounting for less than 2 percent of outcome variability. The study also situates SI-DLBCL within the broader biology of B-cell malignancy.

DLBCL cells typically express CD19, CD20, CD22, CD45, and CD79a, and rituximab's targeting of the CD20 surface protein—whose phosphorylation is elevated in malignant B cells—has anchored immunochemotherapy since the 1990s. The authors discuss emerging alternatives, including second-generation CD20 antibodies and Bruton's tyrosine kinase inhibitors that block B-cell receptor signaling, as well as the potential relevance of the ZCCHC7/PAX5 locus, where copy number gains and promoter mutations have been linked to lymphoma transformation. They also highlight the peril of intestinal perforation, a life-threatening complication of both tumor invasion and chemotherapy-induced necrosis, reported in roughly 9 percent of gastrointestinal lymphoma patients and more than six times as frequent in aggressive versus indolent subtypes.

The authors acknowledge important limitations. Molecular subtyping data, including cell-of-origin classification, double-hit status, and gene rearrangements, were incomplete for many patients because pathological testing varied across centers over the decade, precluding molecular subgroup analysis. Treatment protocols evolved during the eleven-year enrollment window, few patients received novel targeted agents or CAR-T therapy, and the retrospective, non-randomized design means treatment allocation was never balanced.

Even so, the scale of the cohort—nearly five hundred patients with complete follow-up, drawn from hospitals across multiple Chinese provinces—gives these findings a weight that single-center case series cannot match. For clinicians, the message is twofold: maintain suspicion of intestinal lymphoma in middle-aged and elderly men with vague abdominal complaints, and stratify prognosis primarily by age and stage, while awaiting prospective trials to settle the question of surgery's proper role.

Subject of Research: Clinical characteristics and prognostic factors of secondary intestinal diffuse large B-cell lymphoma in a multicenter retrospective cohort

Article Title: Clinical characteristics and prognosis analysis of secondary intestinal diffuse large B-cell lymphoma: a multi-center retrospective study over a decade

Article References: Chen, X., Yan, Z., Shen, J., Gan, D., Zeng, M., Yin, Y., Li, Z., Zhang, H., & Liu, Y. (2026). Clinical characteristics and prognosis analysis of secondary intestinal diffuse large B-cell lymphoma: a multi-center retrospective study over a decade. Frontiers in Oncology, 16, Article 1905087. https://doi.org/10.3389/fonc.2026.1905087

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1905087

Keywords: secondary intestinal DLBCL, diffuse large B-cell lymphoma, non-Hodgkin lymphoma, prognostic factors, Lugano stage, retrospective study, R-CHOP, rituximab, gastrointestinal lymphoma, overall survival, progression-free survival, confounding by indication