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In patients presenting with intestinal symptoms who undergo colonoscopy with mucosal sampling, the pathologist plays a central role in identifying the underlying etiology in order to guide appropriate clinical management. However, common intestinal symptoms such as diarrhea are shared by a broad spectrum of conditions, including infectious diseases, functional disorders (e.g., irritable bowel syndrome), inflammatory bowel disease (IBD), drug-induced injury, and metabolic disorders (e.g., diabetes mellitus). Although serological biomarkers may support the diagnostic workup, they are frequently insufficient to establish a definitive diagnosis. Moreover, endoscopic examination may fail to detect significant mucosal abnormalities even when histology reveals disease-specific patterns, as occurs in lymphocytic and collagenous colitis (i.e., microscopic colitis). In this complex diagnostic landscape, histomorphological evaluation represents a crucial element, allowing integration of microscopic findings with clinical and endoscopic data to reach an accurate interpretation. In recent years, accumulating evidence has demonstrated that similar histological patterns of intestinal injury-such as IBD-like architectural and inflammatory changes or eosinophil-rich infiltrates-may be associated with different underlying etiologies. This overlap is particularly relevant in patients treated with novel oncologic therapies, including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and emerging treatments such as chimeric antigen receptor T-cell (CAR-T) therapy. In addition, in daily practice, pathology request forms often lack essential clinical, endoscopic, and laboratory information, further increasing the risk of diagnostic misinterpretation and inappropriate disease attribution. To address these challenges, the Italian Group of Digestive Disease Pathology (GIPAD) proposes a pattern-based histological approach for reporting mucosal damage in patients with colitis. In this first paper, we focus on non-chronic patterns of mucosal injury and discuss their principal differential diagnoses, with the aim of supporting standardized reporting and improving clinicopathological correlation.