Endoscopic Treatment of Gastric Neuroendocrine Tumors: What’s Next?

Gastric neuroendocrine tumors (G-NETs) occur in 5% to 15% of cases of neuroendocrine neoplasms in the gastrointestinal tract.¹ According to recent data, G-NETs account for less than 2% of all gastric neoplasms.² In Europe, the prevalence of G-NETs is estimated to be 0.32 per 10,000 inhabitants, while in the United States, it is 0.17 per 10,000, and in Japan, it is 0.05 per 10,000.² G-NETs represent 0.6% to 2% of gastric polyp cases discovered during upper gastrointestinal endoscopies.² It is important to note that many G-NETs are discovered incidentally during routine endoscopic examinations. In a single-center study in Korea, the prevalence rates of G-NET and duodenal neuroendocrine tumor were 0.77 and 1.35 per 100,000 individuals, respectively.³

G-NETs are classified according to their pathophysiology, clinical features, and histological characteristics. In the pathophysiological classification, type 1 G-NETs account for 70% to 80% of all G-NETs and are associated with chronic atrophic gastritis and hypergastrinemia. Type 1 G-NETs are typically small, multiple and confined to mucosa or submucosa. It is indolent and has an excellent prognosis (5-year survival rate: 90% to 95%). Type 2 G-NETs are rare (5% of cases). It is associated with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1. Type 2 G-NETs are caused by ectopic gastrin production from gastrinomas, leading to hypergastrinemia. Type 2 G-NETs may metastasize up to 30% of cases but generally have a favorable prognosis (5-year survival rate: 70% to 90%). Type 3 G-NETs occur sporadically and are not associated with hypergastrinemia or chronic atrophic gastritis. They are typically single, large lesions with high malignant potential and early metastasis. It has a poorer prognosis than types 1 and 2, and surgical resection is often required. Type 4 G-NETs are poorly differentiated neuroendocrine carcinomas (NECs), including small cell and large cell NECs. These are highly aggressive with frequent lymph node and liver metastases and are associated with a poor prognosis,^1,4 More recently, general atrophy in chronic Helicobacter pylori associated gastritis, parietal cell dysfunction due to mutations or proton pump inhibitor use have also been reported to be associated with NETs, These newly described gastric NETs are similar to the originally described type 1 G-NETs in that they are secondary to failed acid secretion. G-NETs in long-term proton pump inhibitor users are likely to be less aggressive and have an indolent course compared with sporadic type 3 G-NETs.⁵ The World Health Organization (WHO) classifies G-NETs based on the Ki-67 proliferation index and mitotic count:⁶ grade 1 G-NETs are low-grade, well-differentiated tumors. Grade 2 NETs are medium-grade, well-differentiated tumors. Grade 3 NETs are high-grade tumors, further subdivided into well-differentiated G-NETs and poorly differentiated NECs.⁶ The main differences between these subtypes lie in their etiology, clinical presentation, prognosis, and treatment approaches. Types 1 and 2 are generally more indolent and associated with specific conditions, while types 3 and 4 are more aggressive and have a poorer prognosis. The classification is crucial for determining the appropriate management strategy. For example, type 1 and type 2 G-NETs are often treated conservatively or endoscopically, while type 3 and type 4 typically require more aggressive surgical or systemic therapy.

According to several guidelines,^4,7 tumors smaller than 1 cm are either endoscopically resected or endoscopically observed. Endoscopic surveillance should be tailored to the size and number of prominent lesions, annually or every 2 years with biopsy of the polyps.^4,7 Endoscopic resection should be considered for type I G-NETs larger than 1 cm. Endoscopic mucosal resection or endoscopic submucosal dissection are acceptable endoscopic techniques with a good safety profile.⁸ Surgical resection is recommended in all tumors that are greater than 20 mm in size or with suspected muscularis propria invasion, either on axial imaging or endoscopic ultrasound. In addition, surgery could be considered in tumors showing high-risk features on biopsy (e.g., high grade 2 NET or lymphovascular invasion). A limited resection with sampling of local lymph nodes is the preferred approach. Total gastrectomy with D2 lymphadenectomy should be discussed in patients with known lymph node metastases or might be proposed as a completion procedure after final histology has proven lymphatic spread.⁷

The prognosis of G-NETs is determined by several factors: tumor type, type 1 and type 2 G-NETs generally have a more favorable prognosis with lower metastatic potential. The WHO grading system, based on the Ki-67 proliferation index and mitotic count, is crucial for determining prognosis. The TNM stage, presence of liver metastasis, and multiple concurrent NETs are also poor prognostic factors. There are limited data on the cutoff value of tumor size predicting the risk of metastases in the subgroup of type 1 G-NETs. Also, the optimal cutoff value for Ki-67 for determining surgical treatment has not been defined yet. High fasting serum gastrin at follow-up is known to be associated with recurrence. Patients with disease progression had significantly higher serum gastrin levels than patients without progression. Fifty percent of patients with disease progression required reinterventions with a median follow-up of 22 months after the first intervention.⁴ Another study followed 84 patients with type 1 G-NET after initial endoscopic or surgical intervention. Fifty-two percent of patients developed local recurrence requiring reintervention during a mean follow-up period of 45 months. No metastasis or death was reported during this period, with a median recurrence-free survival of 31 months.⁹ These factors may help in treatment decisions, surveillance intensity, and overall management of patients with neuroendocrine tumors.

Zheng et al.¹⁰ present a single-center retrospective data of 69 patients with G-NETs. Their work highlighted three important themes: (1) the continued predominance of type I and grade 1 G-NETs; (2) the critical role of deep invasion and resection margin status in predicting recurrence; and (3) the generally favorable long-term survival of patients with early detected tumors. The authors found that, in addition to the known risk factors such as lesion size and tumor grade, margin positivity and invasion deeper than the submucosal layer are the principal drivers of recurrence. The authors also highlighted that there is ongoing debate about whether tumor size, Ki-67 index or serum gastrin levels can reliably predict recurrence. Zheng et al. did not find these markers to be significant predictors of recurrence in their patient population, emphasizing that multiple variables are likely to interact, including the gastric mucosal environment, genetic alterations, and host-specific factors.

Zheng et al.¹⁰ have provided important data emphasizing margin status and local invasion depth as pivotal prognostic markers. These findings suggest that if endoscopically resected lesions have positive margins, clinicians should consider further treatment, such as surgical resection or alternative local excision, or at least short-term monitoring to reduce the likelihood of residual disease. Grade 1 lesions confined to the mucosa or submucosa can be managed safely with endoscopic resection if the endoscopic resection margins are clear. It also suggests that surveillance endoscopy appears to play an important role in detecting G-NETs before they become locally extensive. These findings should encourage clinicians to maintain diligent follow-up protocols, particularly for patients with high-risk features.