What's new in upper gastrointestinal pathology: Key updates and evolving challenges in 2026.

Diagnostic pathology of the upper gastrointestinal tract continues to evolve as molecular insights, clinical practices, and updated international standards improve our understanding of disease. The World Health Organization (WHO) classification of digestive system tumors, now in its 6th edition, includes several important changes, including incorporating esophageal epidermoid metaplasia as a separate section, and modifying the approach to metaplastic and dysplastic gastric lesions. These updates reflect a broader trend toward simplified terminology, clearer definitions of precursor lesions, and more consistent grading systems across the digestive tract. At the same time, increased use of immunotherapy has introduced new patterns of injury. Beyond immune checkpoint inhibitors, several agents, including rituximab and chimeric antigen receptor T-cell therapy have been associated with distinctive upper-GI mucosal alterations that can resemble infectious or immunologic diseases. Failure to recognize these patterns of injury can carry significant clinical implications, including treatment delay or discontinuation, and require careful histologic evaluation to avoid misclassification. This review summarizes select upper-GI updates from the 6th edition of the WHO classification and outlines emerging therapy-related injuries with a focus on rituximab- and CAR-T-associated changes. The aim is to provide a practical and contemporary guide for pathologists navigating these evolving diagnostic challenges.