Eosinophilic and mastocytic gastrointestinal diseases: current knowledge and controversy in histopathologic diagnosis

Eosinophilic and mastocytic gastrointestinal (GI) diseases represent a spectrum of immune-mediated inflammatory disorders characterized by abnormal accumulation of eosinophils or mast cells in the GI tract. This review summarizes current knowledge on epidemiology, pathogenesis, histopathologic features, diagnostic challenges, and ongoing controversies across three major domains: eosinophilic esophagitis (EoE), non-EoE eosinophilic gastrointestinal diseases (EGID), and mastocytic GI diseases. Although these entities are increasingly recognized in clinical practice, their diagnosis remains challenging because clinical manifestations are often nonspecific and overlap with other inflammatory and functional GI disorders. Consequently, substantial uncertainties persist regarding diagnostic criteria and clinical relevance of certain histologic patterns. For non-EoE EGIDs, histologic diagnosis is particularly complicated by wide regional variation in normal eosinophil densities, the lack of universally accepted diagnostic cutoffs in adults, and limited correlation between tissue eosinophil burden and symptom severity. In mastocytic GI diseases, additional challenges include distinguishing reactive mast cell hyperplasia from clonal mastocytosis and interpreting proposed entities such as mastocytic enterocolitis, whose clinical significance remains controversial. Given these limitations, histopathologic evaluation of GI biopsies plays a central role in disease recognition and classification. This review emphasizes practical aspects of tissue interpretation, including site-specific reference ranges, proposed diagnostic thresholds, characteristic morphologic patterns, ancillary immunohistochemical and molecular studies, and common interpretive pitfalls encountered in routine practice. Recognizing these diseases ultimately requires careful clinicopathologic correlation, integrating histologic findings with clinical, endoscopic, and molecular data. Improved standardization of diagnostic criteria and clearer definition of histologic thresholds remain critical unmet needs for both pathologists and clinicians managing these complex disorders.