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Primary gastrointestinal mantle cell lymphoma is rare, and histopathological examination and specific immunohistochemical staining are still the gold standard for diagnosis. Therefore, it is necessary to find a new way to improve positive biopsy rates.A 58-year-old man was admitted to our hospital with epigastric pain, abdominal distension, nausea, and melena. Endoscopy identified submucosal neoplasms and diffuse gastrointestinal tract involvement including the esophagus.A false-negative diagnosis was first determined by ordinary endoscopy. However, a large tissue biopsy was subsequently performed using endoscopic mucosal resection based on endoscopic ultrasonography (EUS). Pathological examination of the biopsy specimens taken from the lesions of the duodenum and rectum revealed diffuse lymphocytic proliferation and obscure nodular and small cleaved cells with irregularly shaped nuclei. Immunohistochemistry showed that the cells were positive for CyclinD1, BCL-2, CD20, CD21, and CD5; however, they were negative for CD3, CD6, CD10, and CD43.The patient refused to receive further treatment.Mantle cell lymphoma was conclusively diagnosed.EUS has an important role in the diagnosis and management of gastrointestinal submucosal tumors. Performing a pathological biopsy including EUS may be useful for identifying the unknown nature of tumors of the digestive tract.