Second Primary Malignancies After Primary Gastric Lymphoma: Incidence, Risk Factors, and Clinical Implications

Survivors of primary gastric lymphoma (PGL) face a significantly elevated and persistent risk of developing second primary malignancies (SPMs), with gastric adenocarcinoma representing the most frequent SPM and standardized incidence ratios reaching up to 16-fold above the general population. This excess risk persists for decades after initial treatment and is associated with increased cause-specific mortality compared to matched primary cancers. Among patients with PGL, approximately 5% develop gastric cancer (with two-thirds being metachronous), and nearly 15% harbor precancerous lesions including atrophic gastritis, intestinal metaplasia, and dysplasia. Beyond gastric malignancies, survivors also experience elevated rates of extra-gastric SPMs, particularly digestive system tumors (43%), respiratory cancers (21%), and urinary tract malignancies (13%). Key risk factors include treatment with immunochemotherapy or radiotherapy, advanced age, male sex, advanced stage at diagnosis, ulcerative-type lymphoma morphology, and persistent Helicobacter pylori (HP) infection. Patients receiving combined chemoradiotherapy demonstrate the highest SPM risk, particularly for gastric and pancreatic cancers. These findings underscore the critical importance of lifelong, risk-adapted surveillance strategies integrating both hematology and gastroenterology follow-up. Annual endoscopic surveillance is recommended for high-risk patients, with intervals adjusted according to lymphoma histology, HP status, and the presence of precancerous gastric lesions. Mandatory HP eradication with confirmation of response is essential for reducing gastric cancer risk. Future research priorities include prospective, standardized studies to better quantify SPM risk, validation of molecular and microbiological biomarkers for individualized risk stratification, and development of predictive models to enable personalized surveillance protocols and improve long-term outcomes in this vulnerable population.