Rare non-neoplastic gastrointestinal diseases–drugs and bugs

Rare diseases of the gastrointestinal (GI) tract present a significant diagnostic challenge. This paper focusses on two particular groups of conditions: drug-induced injuries and parasitic infections. With aging populations and increased use of complex pharmacologic regimens-including immunosuppressants and biologics-drug-related GI pathology is nowadays more frequently encountered. However, the histologic changes are often non-specific and overlap with more common conditions such as inflammatory bowel disease (IBD), ischemia, autoimmune diseases, or infections. Key patterns include lymphocytic or neutrophilic inflammation, crypt apoptosis, crypt abscesses, and architectural distortion. Certain agents, such as mycophenolate, olmesartan, immune checkpoint inhibitors, or ion exchange resins (e.g. sodium polystyrene sulfonate/kayexalate, sevelamer), have distinct but subtle histopathologic signatures. Parasitic infections, although less frequent in high-income countries, remain relevant due to global travel and migration. Organisms such as Schistosoma, Strongyloides, or Giardia can mimic IBD, neoplasia, or cause unexpected eosinophilic or granulomatous inflammation. Parasite ova may require special stains and careful morphologic assessment to be identified. Importantly, some helminths have been associated with chronic complications including cancer or fibrosis, thus underscoring the need for accurate recognition. For the practicing pathologist, these rare but impactful conditions demand a high index of suspicion, especially in cases with atypical histology or poor clinical correlation. Using some illustrative cases, this paper highlights diagnostic strategies and key morphologic features to improve recognition and avoid misdiagnosis of these underappreciated entities.