SSAT - GASTRIC NEUROENDOCRINE TUMORS (NETS) ARISING FROM CHRONIC PPI USE: CHARACTERISTICS AND OUTCOMES OF A FOURTH SUBTYPE

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GASTRIC NEUROENDOCRINE TUMORS (NETS) ARISING FROM CHRONIC PPI USE: CHARACTERISTICS AND OUTCOMES OF A FOURTH SUBTYPE
Lena K. Egbert^*¹, Akash Kartik¹, Nabil Wasif¹, Katherine Poruk³, Thorvardur Halfdanarson², Travis E. Grotz²
¹Surgery, Mayo Clinic Arizona, Scottsdale, AZ; ²Mayo Clinic Minnesota, Rochester, MN; ³Mayo Clinic Florida, Jacksonville, FL

Introduction
There are classically three defined types of gastric neuroendocrine tumor (NET). Both Type I (chronic atrophic gastritis) and Type II (multiple endocrine neoplasia or Zollinger-Ellison syndrome related) are associated with hypergastrinemia, whereas Type III (sporadic) are not. The latter have higher malignant potential, and the recommended treatment is a formal gastrectomy with regional lymphadenectomy. However, the widespread use of chronic proton pump inhibitor (PPI) therapy resulting in hypergastrinemia has led to a distinct proposed fourth subtype, which may be amenable to more conservative management. Our study aimed to determine the characteristics and outcomes of this fourth subtype.

Methods
A multi-center cohort of patients with a diagnosis of gastric NET from 2012-2022 were included. Those with Type I and II gastric NETs were excluded, whereas patients with ?1 year of PPI use were classified as Type IV, and the rest as Type III. Descriptive statistics were reported as median and interquartile range (IQR) or number and percentage. Characteristics were compared between the two groups using Chi-squared, Fisher exact, and Mann-Whitney U tests. Time-to-event analysis was done with Kaplan-Meier and compared with Cox proportional hazards.

Results
A total of 79 patients with gastric NETs met our inclusion criteria, of whom 34 (43.0%) had Type III and 45 (57.0%) Type IV. Patients with Type IV were older (median age 65 vs 58, p=0.013). Type IV NETs were smaller (median 0.55 cm vs 1.10 cm, IQR 1 vs 2.79, p=0.02), more likely to be multifocal (22.2% vs 2.9%, p=0.01), located in the distal stomach (82.2% vs 67.6%, p<0.01) and had higher gastrin levels (median 99 vs 35, IQR 265 vs 152, p=0.025). They were less likely to be grade 3 (4.4% vs 23.5%, p=0.02), have nodal involvement (0% vs 23.5%, p<0.001), and have distant synchronous metastases (4.4% vs 26.5%, p<0.01) compared to Type III. Type IV NETs were more likely to undergo endoscopic resection (84.4% vs 52.9%, p=0.03). They were more likely to have local gastric recurrence (17.8% vs 0%, p=0.02) than Type III but less likely to have regional or distant metastasis (0% vs 5.9%, p=0.02). During a median follow up of 43 months, Type IV NETs had no distant metastasis or deaths due to disease (0% vs 11.8%, p<0.05) which compared favorably to Type III NETs.

Conclusion
In long term PPI users, Type IV gastric NETs represent a distinct phenotype which follows a more indolent course. The lack of regional and distant metastasis and excellent survival outcomes suggest that Type IV gastric NETs may be treated conservatively with endoscopic resection or wedge gastrectomy without lymphadenectomy. The frequent local recurrence highlights the importance of PPI cessation and long-term endoscopic follow up in these patients.

Table 1. Characteristics of patients with Type III and Type IV gastric NETs

Table 2. Outcomes of patients with Type III and Type IV gastric NETs

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