This review reflects a collaboration between the American Registry of Pathology (the publisher of the Armed Forces Institute of Pathology Fascicles) and Annals of Diagnostic Pathology. It is part of a series of expert recommendations on topics encountered in daily practice. The authors, three pathologists with expertise in gastrointestinal tract pathology and immunohistochemistry, met on 30 July 2019 tasked with developing expert recommendations for evaluating poorly differentiated and undifferentiated malignant neoplasms encountered on mucosal biopsies of the gastrointestinal tract. We focused on esophageal, gastric, small intestinal, colorectal, and anal (i.e., tubal gut) samples. When faced with diagnostic uncertainty on the initial H&E, it is best to begin by trying to assign the broad tumor class with screening markers such as pankeratin, S100 protein or SOX10, and CD20 or CD45. Once a broad tumor class is established, more specific differentiation markers can be pursued (e.g., lineage-restricted transcription factors for adenocarcinoma; p40 for squamous cell carcinoma; chromogranin A and synaptophysin or INSM1 for neuroendocrine neoplasms). Every small biopsy containing tumor should be considered a potential molecular pathology sample; cutting extra unstained slides with this testing in mind is strongly encouraged.
Keywords: Differential diagnosis; Immunohistochemistry; Site of origin; Tumor classification.
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