Classification of gastric neuroendocrine tumors and associations with survival.
Authors: Song Yun , Chen Eunise , Chiang Y. Sabrina , Yao James C. , Halperin Daniel M. , Chatterjee Deyali , Badgwell Brian D. 
Published: January 2024

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Background: The World Health Organization (WHO) classification of gastric body neuroendocrine tumors (GNETs) includes type 1 tumors characterized by hypergastrinemia and arising in a background of atrophic gastritis, type 2 tumors associated with gastrinomas, and type 3 tumors with low serum gastrin level and no background mucosal pathology. However, certain tumors remain unclassified, and the prognostic significance of these tumors is currently unknown. The purpose of this study was to better characterize GNET types and to determine associations with distant metastasis and disease-specific survival (DSS). Methods: Patients diagnosed with GNET (1986-2021) were retrospectively identified and tumors classified as type 1, 2, or 3. Unclassified tumors were reviewed for background gastric mucosal changes associated with chronic proton pump inhibitor (PPI) use. Tumors were categorized as PPI-associated if there were prominent parietal and neuroendocrine cell hyperplasia in the background mucosa, in the absence of a gastrinoma and a positive history of chronic PPI use. WHO grade was determined using mitotic index or Ki-67 proliferative index when available. Characteristics by tumor type, associations with distant metastasis at initial diagnosis, and DSS were determined using standard statistical methods. Results: Of 246 patients, 164 (66.7%) had type 1, 5 (2.0%) had type 2, 52 (21.1%) had type 3, 18 (7.3%) were PPI-associated, and 7 (2.8%) remained unclassified. Multifocal disease was more common for types 1 (56.1%) and 2 (40.0%) than type 3 (13.5%) and PPI-associated tumors (27.8%, P<0.001). Patients with type 3 GNET were also less likely to have WHO grade 1 tumors (26.9%) compared to other GNETs (type 1 37.2%, type 2 40.0%, PPI-associated 50.0%, P<0.001). Additionally, distant metastases at presentation occurred more frequently with type 3 (38.5%) than type 1 (1.2%), type 2 (20.0%), and PPI-associated tumors (11.1%, P<0.001). GNET type (type 1 vs 3, odds ratio [OR] 0.005 [95% confidence interval [CI] 0.001-0.050; PPI-associated vs type 3, OR 0.040 [95% CI 0.004-0.45]), race (non-white vs white, OR 0.17 [95% CI 0.040-0.73]), and WHO grade (2/3 vs 1, OR 10.5 [95% CI 1.93-57.2]) were associated with distant metastasis at presentation. Five-year DSS rates were 100.0% for type 1, 59.7% (95% CI 42.7-73.2%) for type 3, and 90.9% (95% CI 50.8-98.7%) for PPI-associated (log-rank P<0.001). By multivariable analysis, multifocality of primary tumors (hazard ratio [HR] 0.070 [95% CI 0.010-0.46]) and distant metastasis at diagnosis (HR 44.9, 95% CI 6.21-324.8) were independently associated with DSS, while tumor type was not (type 1 vs 3, HR 0.18 [95% CI 0.010-2.44); PPI-associated vs type 3, HR 0.13 [95% CI 0.010-1.33]). Conclusions: PPI-associated tumors may represent a distinct GNET type with intermediate outcomes compared to type 1 and type 3 tumors. However, factors other than tumor type must be considered in determining survival.