Endoscopic ultrasound–guided biopsy (EUS-guided biopsy) is a preferred minimally invasive method for histological verification of indeterminate focal splenic lesions, offering a high diagnostic yield with lower risk compared with surgical approaches. However, the spleen’s rich vascularization poses a significant risk of intraprocedural hemorrhage. This risk is compounded when dealing with locally advanced disease that might necessitate extensive surgical staging.

We report the case of a 53-year-old woman presenting with intermittent left upper-quadrant pain. Cross-sectional imaging identified a massive peritoneal lesion infiltrating multiple adjacent organs, including the greater curvature of the stomach, splenic flexure, spleen, and the left diaphragmatic dome, without distant lymphadenopathy. Despite comprehensive conventional endoscopic evaluation—where both upper endoscopy and colonoscopy confirmed the absence of any intraluminal mucosal pathology— the nature of the infiltrating peritoneal mass remained indeterminate. Given the multiorgan infiltration, a surgical approach for histological verification would have required a highly morbid multiorgan resection. To avert this extensive surgery, an EUS-guided fine-needle biopsy (FNB) was conducted using a 22G needle, with three passes taken to safely sample the accessible splenic component of the mass.

The patient was monitored for 24 hours with no post-procedural complications observed. Immunohistochemical analysis demonstrated findings consistent with follicular T-helper cell lymphoma. Following immediate hematologic evaluation, immunochemotherapy was initiated. Early follow-up PET-CT, performed three months after starting treatment, confirmed a complete metabolic response, with no evidence of residual disease.

This case highlights the indispensable diagnostic value of EUS-guided FNB in complex, locally advanced masses. Despite the technical challenges posed by the splenic location and the multiorgan engagement, EUS-guided biopsy provided crucial, non-operative histological data that directly influenced immediate management, successfully avoiding a major multiorgan resection and leading to an excellent patient outcome.