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Microscopic

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As none of the histologic features are specific for GERD, other etiologies such as infection, eosinophilic esophagitis, iatrogenic injuries, Crohn's disease, and inflammatory skin disorders involving the esophagus may enter into the differential diagnosis.

The presence of large numbers of neutrophils in the superficial epithelium should suggest the possibility of fungal infection or superinfection, and special stains (PAS‐diastase, GMS) should be performed to exclude Candida organisms. Large numbers of intraepithelial eosinophils raising the possibility of eosinophilic esophagitis and correlation with clinical findings and PPI treatment status are required (see Section “Eosinophilic Esophagitis”). Numerous intraepithelial lymphocytes, if predominant, may suggest an alternative diagnosis such as lymphocytic esophagitis or lichen planus‐associated esophagitis (see Sections “Lymphocytic Esophagitis” and “Dermatological Diseases Involving the Esophagus”).

Ulceration with regenerative squamous epithelial atypia may be difficult to distinguish from in situ‐squamous cell carcinoma and dysplasia. The regenerating epithelial cells have round nuclei with minimally thickened nuclear membranes; fine chromatin; and large, irregular nucleoli, and generally have abundant cytoplasm. Further, maturation toward the epithelial surface can usually be found. In difficult cases, additional biopsies should be requested after medical treatment of the esophagitis. However, in some cases, inflammatory pseudotumors with marked atypia of the reactive stromal cells will need to be differentiated from poorly differentiated carcinoma or sarcoma. Cytokeratin immunohistochemistry (IHC) may be helpful when trying to distinguish between reparative reactions and malignancy.

Less commonly, activated lymphocytes in areas of ulceration may appear atypical and raise the suspicion for lymphoma. In some cases, immunohistochemistry and/or flow cytometry may be necessary to assess for clonality.

Gastrointestinal Pathology

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