Management Strategies and Outcomes for Type 1 Gastric Neuroendocrine Tumors Measuring More Than 1 cm.

SCOPE: this guidance covers well-differentiated gastric NETs G1-G3. Type II gNETs and neuroendocrine carcinomas are explicitly EXCLUDED and referred to other ENETS guidance papers. WORKUP: OGD is the primary diagnostic tool. Take representative biopsies of the tumour AND separate biopsies of the surrounding mucosa from both antrum and body-fundus, as these establish aetiology, prognosis and treatment. NETs sit deep in the mucosa, not at the surface, so biopsy technique must account for this. Sampling of gastric juice for pH is strongly encouraged. Virtual chromoendoscopy (NBI, BLI, i-scan) may help identify field change or precancerous lesions in atrophic mucosa. EUS should be performed in all lesions >1 cm regardless of type AND in all type III lesions regardless of size, unless large or metastatic lesions are already found; report lesion size, infiltration depth and local nodes. Biomarkers: fasting gastrin (elevated in types I and II, normal in type III) and chromogranin A (useful as a tumour marker ONLY in type III); under ongoing PPI therapy gastrin and CgA are not diagnostic and are difficult to interpret, and CgA assays vary in accuracy. Where autoimmune gastritis is suspected, measure parietal cell and intrinsic factor antibodies, vitamin B12 and thyroid function. Type I does not usually require cross-sectional imaging unless there are metastases on EUS or high-risk features (G2, vessel invasion, suspected T2 on EUS); type III should have contrast-enhanced liver MRI and/or thoracoabdominal CT (with water ingested immediately before, to distend stomach and duodenum) plus functional imaging, preferentially 68Ga-SSA-PET/CT. TYPE I (chronic atrophic gastritis, ~80% of gNENs, indolent, metastatic risk <5%): all lesions <1 cm can be observed without any intervention, as metastatic risk is below 1% in tumours <10 mm. The observation OGD schedule is not defined; practice ranges from every 6 months to every 2 years, and the most widely used approach is first follow-up at 6 months then every 12 months. Routine rebiopsy is unnecessary unless atypical features appear (ulceration, erosion, pitting) suggesting invasive progression. Endoscopic resection should be proposed for type I gNETs larger than 1 cm and for lesions showing increased Ki-67, but the document states explicitly that NO Ki-67 cutoff has been defined for when excision should be performed. ESD and FTR achieve higher R0 rates than EMR, though no randomised trial has compared techniques head to head; for R1 resection of a NET >1 cm a step-up approach (EMR to ESD to FTR to surgery) is recommended, while smaller tumours may instead be managed by non-interventional endoscopic surveillance after R1. Somatostatin analogues are appropriate when resection is indicated but endoscopic or surgical techniques are not possible (difficult location, advanced age, comorbidity), and may be proposed for multiple or larger tumours or frequent relapse; complete response is 25-100% but relapse after discontinuation is frequent, so continuous therapy is the appropriate approach. Antrectomy should no longer be routinely offered, but may be an option for patients not tolerating or declining continuous SSA. Netazepide is not recommended pending larger randomised trials. Upfront surgery is recommended for tumours >20 mm or with suspected muscularis propria invasion (on axial imaging or EUS); surgery could ALSO be considered for high-risk biopsy features (high-grade G2, with the cutoff explicitly not established, or lymphovascular invasion), and Ki-67 above 10% should trigger evaluation for surgical treatment although the optimal Ki-67 cutoff is not determined. Limited resection with local nodal sampling is the preferred surgical strategy; gastrectomy with D2 lymphadenectomy (type of resection per tumour site) should be discussed in patients with known nodal metastases, or proposed as a completion procedure after final histology proves lymphatic spread following full cross-sectional staging, though no solid data support this. A G3 type I gNET should be managed primarily surgically given high metastatic risk. Endoscopic resection should NOT be attempted where there is muscularis propria invasion, suspected nodal metastases, or high-risk features of metastatic spread (high Ki-67, vascular invasion, size >20 mm); these patients need full staging including 68Ga-SSA-PET/CT and upfront surgery. FOLLOW-UP, type I: OGD every 12 months after complete endoscopic resection, with the interval discussed with the patient, potentially lengthened after prolonged relapse-free periods, or shortened for R1 resection or progression risk factors (G2, size >20 mm). For lesions not requiring resection, first follow-up at 12 months then annual to every 1-2 years. Cross-sectional imaging is generally not required in follow-up, and CgA and gastrin should NOT be repeatedly measured, as they are elevated by the underlying atrophic gastritis and do not indicate relapse or progression. Separately, because chronic atrophic gastritis carries adenocarcinoma risk (yearly adenocarcinoma detection up to 1% in type I gNET patients), endoscopic follow-up every 12-24 MONTHS is recommended for patients with a previously diagnosed gNET, with specific timing per tumour size and histology, whereas the 3-YEAR interval applies to CAG patients WITHOUT gNETs. TYPE II (ZES, usually MEN-1, ~5%): outside the scope of this paper; treatment strictly depends on management of the MEN-1 syndrome. TYPE III (sporadic, 15-25%, higher metastatic risk, survival compromised except in early stages): characterise with endoscopy, biopsy, thoracoabdominal CT and liver MRI, often functional imaging (68Ga-SSA-PET/CT or FDG-PET/CT depending on grade), and EUS in most cases. Endoscopic resection may be considered for localised G1 type III gNETs <=10 mm, and occasionally for larger tumours with Ki-67 <10% and <15 mm diameter IF the risks of surgical resection are considered high and adequate staging is achieved (graded 3a-C, ie weak). Tumours above 10 mm are more likely to harbour nodal metastases even when imaging is negative. Current evidence does not support any particular endoscopic technique (EMR vs ESD); avulsion biopsy is not generally recommended. R1 margins should prompt additional endoscopic resection or surgical salvage. A limited gastric wedge resection with local nodal sampling and WITHOUT standard lymphadenectomy can be considered for localised G1-G2 type III gNETs with no lymphadenopathy on full preoperative staging including EUS; wedge resection can be safely proposed for G1 type III gNETs <20 mm limited to the submucosal layer with no lymphovascular invasion. The role of wedge resection in G2 type III remains debated, since grade strongly predicts aggressiveness, and the size cutoff for limited resection is not clearly defined, in practice <10 mm is usually endoscopic and >10 to <20 mm may have limited surgery as initial treatment. Radical surgery (total or subtotal gastrectomy with lymphadenectomy) is the procedure of choice for any type III gNET with at least one of: nodal or distant metastases on preoperative imaging, Ki-67 >20% (G3), or size >20 mm; where distant metastases are present, however, radical resection is the procedure of choice only if complete, curative-intent resection including the metastases seems feasible (per the METASTATIC DISEASE section, 4-B), and unresectable metastatic disease is instead managed by the systemic/palliative pathway. Radical surgery is recommended second-line when final histology after limited wedge resection reveals nodal metastases, higher grade than the original biopsy, lymphovascular invasion, or incomplete clearance (R1). FOLLOW-UP, type III: radiological follow-up by contrast-enhanced CT or MRI after surgical resection (graded 5-A); timing has never been clearly defined. After total gastrectomy with lymphadenectomy, apply the gastric adenocarcinoma follow-up schedule. Conservatively managed patients (endoscopic or local surgical excision) should have OGD at about 3 months to inspect the resection site, and if no macroscopic residual tumour, regular cross-sectional imaging plus endoscopy/EUS at a frequency driven by final tumour size, grade and patient fitness, usually reducing over time. Functional imaging and biopsies are performed for suspected relapse but are not routinely part of follow-up. METASTATIC DISEASE (the paper's section 3 covers gastric AND duodenal G2-G3 metastatic NETs jointly): surgery with curative intent should be performed for G1/G2/G3 if complete resection including metastases seems feasible (4-B); palliative surgery (primary resection, bypass) may be indicated to maintain quality of life (4-C). The choice of systemic therapy depends on tumour grading and includes biotherapy, everolimus, PRRT and chemotherapy (4-B). Specifically, somatostatin analogues are indicated for NETs G1-G2 with low Ki-67 (<10%) and positive somatostatin receptors, but can be given with higher Ki-67 if slow tumour growth or slow progression is seen; PRRT is a valid option depending on receptor status; everolimus is a therapeutic option but with limited evidence; in NET G3 chemotherapy should be administered. The document notes this systemic approach is extrapolated from advanced NETs of other primary sites owing to the lack of data in homogeneous gastric or duodenal NET series.