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The characteristic histologic findings in endoscopic esophageal biopsies include: multinucleated giant cells with nuclear molding and margination of the chromatin; large, eosinophilic, ground glass intranuclear inclusions with a halo (Cowdry A bodies); and a background of acute inflammation with ulceration. The viral inclusion bodies are present in viable squamous epithelial cells at the margins of the ulcer. They contain intact and fragmented virions. Biopsies taken from the center of the ulcer rather than the margins may lack viral cytopathic effects but stain positive with HSV immunostain.

Other diagnostic modalities that may be used on esophageal brushings or tissue include: isolation of HSV in tissue culture, detection of HSV DNA by PCR, or by demonstrating intranuclear viral inclusions by immunohistochemistry or in-situ hybridization (especially useful in cases that lack the characteristic morphologic changes).

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