Patterns of Expression in the Upper Gastrointestinal Tract and Utility as a Marker of Gastric Origin in Neuroendocrine Tumors

center dot Context.-Claudin-18 is expressed in some gastric cancers. Clinical trials are evaluating it as a therapeutic target.Objectives.-To evaluate claudin-18 expression in in-testinal metaplasia, dysplasia, and adenocarcinoma of the distal esophagus/gastroesophageal junction and stomach and to evaluate claudin-18 expression in gastric and nongastric neuroendocrine tumors as a marker of gastric origin.Design.-Samples included gastroesophageal junction with intestinal metaplasia (n = 40), dysplasia (n = 54), and adenocarcinoma (n = 20) and stomach with intestinal metaplasia (n = 79), dysplasia (n = 43), and adenocarci-noma (n = 25). Additionally, gastric (n =40) and nongastric (n = 322) neuroendocrine tumors were included. Claudin-18 expression was evaluated for any staining as positive and by meeting clinical trial inclusion criteria (>2+ intensity in >50% of tumor).Results.-Claudin-18 staining was not significantly different across dysplasia categories in the gastroesopha-geal junction (P = .11) or stomach (P = .12). The rate of positive staining was higher in gastroesophageal junction than stomach for intestinal metaplasia (37 of 40 [92.5%] versus 37 of 79 [46.8%]; P < .001) and high-grade dysplasia (33 of 38 [86.8%] versus 9 of 16 [56.3%]; P = .03). Intestinal metaplasia showed staining in 7 of 37 autoimmune gastritis samples (18.9%) compared with 30 of 42 samples without autoimmune gastritis (71.4%) (P < .001). Adenocarcinoma showed similar staining in gastro-esophageal junction (15 of 20; 75.0%) and stomach (17 of 25; 68.0%) (P = .85). Eighty percent (32 of 40) of gastric neuroendocrine tumors were positive for claudin-18 expression, with 57.5% (23 of 40) meeting clinical trial inclusion criteria. Comparatively, 0.62% (2 of 322) of nongastric neuroendocrine tumors showed staining (P < .001).Conclusions.-Claudin-18 staining was similar in intes-tinal metaplasia, dysplasia, and adenocarcinoma. Claudin-18 was negative in most cases of intestinal metaplasia in autoimmune gastritis, indicating that intestinal metaplasia in this setting may differ from other forms. Claudin-18 was sensitive and specific for gastric origin in neuroendocrine tumors.(Arch Pathol Lab Med. 2023;147:559-567; doi: 10.5858/ arpa.2021-0428-OA)