Step‐by‐Step Approach to the Incidental Diagnosis of Type I Gastric Neuroendocrine Tumors: Practical Insights

ABSTRACT

Objective

The incidental diagnosis of type I gastric neuroendocrine tumors (gNETs) has become increasingly frequent in clinical practice, largely due to the widespread use of upper gastrointestinal endoscopy and improved recognition of these lesions. Although typically indolent, type I gNETs require accurate assessment to ensure appropriate risk stratification, management, and follow‐up. This review provides a practical, evidence‐based guide specifically designed for gastroenterologists and clinicians managing patients with incidentally discovered type I gNETs.

Methods

Structured in a step‐by‐step format, the review outlines key aspects of diagnosis and management, including endoscopic recognition and differential diagnosis, histological confirmation with a focus on corpus‐restricted atrophic gastritis, initial risk assessment based on tumor characteristics and patient factors, and the use of additional imaging modalities such as endoscopic ultrasound, cross‐sectional imaging, and functional imaging.

Results

The review emphasizes the importance of referring patients to specialized centers for multidisciplinary evaluation, a strategy shown to improve clinical outcomes and adherence to best practices. Finally, practical recommendations for long‐term surveillance are provided, with clear indications tailored to individual patient risk profiles.

Conclusion

By integrating current guidelines with practical insights and highlighting critical decision points, this review serves as a concise, user‐friendly tool to support clinicians in optimizing the care of patients with type I gastric NETs. This stepwise approach aims to bridge the gap between complex guideline recommendations and daily clinical practice, offering actionable guidance to ensure safe, effective, and standardized management of these increasingly encountered lesions.

1. Introduction

Although considered rare neoplasms, neuroendocrine neoplasms (NENs) have shown a steady increase in incidence over the past few decades [1]. Among the various subtypes distinguished by the site of the primary tumor, gastric NENs (gNENs) occupy a particularly relevant position, with a significantly rising incidence attributable primarily to the widespread use of upper gastrointestinal endoscopy and to improved recognition by pathologists and endoscopists [1, 2, 3].

As with other NENs of the digestive tract, gastric NENs are classified according to the 2022 World Health Organization framework into well‐differentiated neuroendocrine tumors (NETs), graded based on the proliferative Ki‐67 index as G1 (Ki‐67 < 3%), G2 (Ki‐67 3%–20%), and G3 (Ki‐67 > 20%); and poorly differentiated neuroendocrine carcinomas, which are high‐grade by definition and characterized by an aggressive biological behavior [4].

In addition to this histopathological classification, gNETs have a unique clinical categorization based on their underlying pathophysiology [5]. Type I gNETs develop in the setting of corpus‐restricted atrophic gastritis (CAG) and are typically associated with hypergastrinemia. Type II gNETs arise within the context of Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1 syndrome, also under hypergastrinemic conditions. Type III gNETs, in contrast, are sporadic tumors that develop independently of any background gastric pathology or gastrin hypersecretion and are generally associated with a more aggressive biological behavior.

Importantly, the prognosis of gNETs is closely linked to the clinical type [5]. Type I gNETs are generally indolent lesions with a very low risk of metastatic spread and excellent long‐term survival, whereas type III tumors tend to behave more aggressively, with a significantly higher risk of metastasis and disease progression. However, the approach and management of these Type III gNETs are changing and evolving over time. Even within type I gNETs, however, clinical behavior is strongly influenced by tumor size: lesions smaller than 1 cm are associated with a negligible risk of progression, while larger lesions may carry an increased risk of metastasis and recurrence [6, 7].

Given this background, the incidental discovery of a gNET during endoscopy poses distinct challenges for gastroenterologists, who must rapidly and accurately assess the lesion's clinical relevance and decide on the most appropriate management strategy.

The aim of this review is to provide clinicians with practical tools to correctly approach and evaluate patients with an incidental diagnosis of a gNET. Throughout this review, the discussion will specifically refer to well‐differentiated type I tumors, ensuring a focused and evidence‐based clinical framework, and will be structured in a step‐by‐step format to support clinical decision‐making in routine practice.

2. Step 1: Recognizing a Gastric NET During Endoscopy

The accurate endoscopic recognition of a gNET is the essential first step in managing an incidental finding during upper gastrointestinal endoscopy. Type I gNETs typically arise in the context of CAG and are most often located in the gastric body or fundus [8, 9].

On conventional white‐light endoscopy, type I gNETs usually appear as small, sessile, or slightly raised nodules, with a smooth, sometimes glistening surface, often displaying a reddish or yellowish hue relative to the surrounding atrophic mucosa (Figure 1) [5, 8, 10, 11]. A critical clue to the diagnosis is the presence of multiple lesions on a background of evident atrophic changes, which is strongly suggestive of type I gNETs [5, 10].

FIGURE 1.

Multiple small sessile gastric neuroendocrine tumors (NETs) with a smooth reddish appearance, and central erosion (a). Narrow‐band imaging (NBI) showing regular circular mucosal pattern and central erosion (b).

Advanced imaging techniques, particularly narrow‐band imaging (NBI), have proven extremely useful in refining the endoscopic diagnosis. On NBI, type I gNETs may show a regular circular mucosal pattern and frequently demonstrate a central erosion with or without a demarcation line (Figure 1). These features help differentiate them from other polypoid lesions, such as hyperplastic polyps or adenomas [8]. In a prospective study, central erosion was identified in 77.8% of type I gNETs [11]. The vascular pattern tends to remain regular, although slight vascular irregularity can occasionally be detected. Virtual chromoendoscopy (VCE), including NBI and blue‐light imaging (BLI), is now strongly recommended for evaluating gastric mucosal abnormalities, as it enhances visualization of the lesion margins and mucosal patterns and is superior to WLE alone [8, 9, 10, 11]. In fact, the updated MAPS III guidelines recommend the use of VCE to guide targeted biopsies whenever neoplastic lesions are suspected [9]. Differential diagnosis at endoscopy includes hyperplastic polyps, fundic gland polyps, and subepithelial tumors such as gastrointestinal stromal tumors. However, certain clues—such as multiplicity of lesions, small lesion size, and typical NBI patterns—strongly favor the diagnosis of type I gNET [8, 10, 12].

Thus, during any diagnostic upper gastrointestinal endoscopy, when small, sessile, or nodular lesions are identified, particularly in the body or fundus, the endoscopist should systematically suspect a type I gNET, utilize virtual chromoendoscopy to characterize the lesion, and proceed with targeted biopsies of both the lesion and the surrounding mucosa to confirm the clinical suspicion and guide subsequent management.

3. Step 2: Biopsy, Histopathological Confirmation, and Serological Assessment

Corpus‐restricted atrophic gastritis is defined histologically by the irreversible loss of specialized gastric glands, with replacement by fibrous tissue or intestinal metaplasia, leading to mucosal thinning and functional impairment of the stomach [13]. The condition is strongly associated with an increased risk of gastric adenocarcinoma and type I gNETs, making its early identification a critical component of gastric cancer prevention strategies [14, 15].

At endoscopy, CAG typically presents with pale, thinned mucosa, increased visibility of submucosal vessels, loss of normal gastric rugal folds, and patchy mucosal atrophy, particularly within the corpus and fundus. However, relying solely on endoscopic appearance can be misleading. High‐definition white‐light endoscopy, enhanced by virtual chromoendoscopy techniques, is recommended to improve visualization and facilitate early recognition of subtle mucosal changes [9, 12, 15, 16].

Confirmation of CAG requires systematic and extensive histological sampling. Following international best practices, biopsies should be obtained separately from the antrum, incisura angularis, and corpus [9, 15]. A minimum of five biopsies is advised, with careful placement of antral and corpus samples in separately labeled vials, thus permitting topographical staging according to OLGA and OLGIM classification systems [13, 14, 15]. This approach is vital not only to confirm the diagnosis but also to stratify the patient's risk for gastric neoplasia and guide future surveillance. Random biopsies remain necessary even in the absence of obvious endoscopic atrophic changes, especially when assessing individuals at risk or when chromoendoscopy is unavailable [9]. However, when VCE highlights suspicious areas, targeted biopsies should be prioritized as they improve diagnostic accuracy and efficiency.

The clinical relevance of recognizing CAG is underscored by the substantial risk of neoplastic progression documented in the literature. Data from recent multicentric studies confirm that patients with autoimmune gastritis (AIG) are at increased risk of developing gastric polyps and neoplastic lesions, including NETs and adenocarcinomas [17]. Nevertheless, the frequency reported across various studies in the literature is highly variable, ranging from 2.4% to 35.4% in similar populations, reflecting differences in diagnostic criteria, population characteristics, and surveillance practices [17, 18].

Older age and elevated serum gastrin have been identified as potential risk factors associated with the development of both neuroendocrine and non‐neuroendocrine lesions [17, 19]. Given this elevated risk profile, endoscopic surveillance combined with systematic and targeted biopsies is critical. Biopsies not only serve to confirm the presence of atrophy and intestinal metaplasia but also enable the detection of early neoplastic transformation, which may not be evident during initial endoscopic evaluation [9, 15]. A comprehensive endoscopic examination employing enhanced imaging, strategic biopsy protocols, and careful histological assessment constitutes the cornerstone for the optimal diagnosis and risk stratification of patients with CAG, facilitating early identification of type I gNETs [20]. As with all other NENs, the pathological report for type I gNETs should incorporate, at minimum, information regarding tumor differentiation, the presence or absence of necrosis, the mitotic count, the Ki‐67 index, and immunohistochemical positivity for chromogranin A and synaptophysin. In addition, the presence or absence of CAG must be clearly stated to accurately classify the tumor as either type I (CAG‐associated) or type III (sporadic) [10, 20].

In addition to the histological assessment, selected serological tests can provide valuable diagnostic information. Serum pepsinogens reflect both the functional and structural status of the gastric mucosa and are useful indicators of advanced atrophy. Measurement of parietal cell antibodies (PCAs) and intrinsic factor antibodies (IFAs) is also advised to investigate the presence of AIG [15]. PCAs are the most sensitive serological marker for AIG, though false positives may occur, particularly with Helicobacter pylori infection or other autoimmune diseases. IFAs, while less sensitive (< 30% in many studies), are highly specific and typically appear later in the disease course [15]. Autoantibody positivity may precede clinical onset, especially in individuals with other autoimmune disorders. Regardless of etiology, patients with CAG should be tested for H. pylori and treated if positive, with subsequent non‐serological testing to confirm eradication [14, 15].

Patients with CAG have an elevated risk of iron and vitamin B12 deficiency due to impaired gastric acid secretion and intrinsic factor production. Iron deficiency is frequent, often preceding B12 deficiency, and occurs in up to half of cases [15]. Evaluation for both deficiencies is recommended in all CAG patients, and CAG should be considered in individuals with unexplained deficiency. AIG is frequently associated with other autoimmune disorders, most notably autoimmune thyroid disease, warranting targeted screening, with additional evaluation for conditions such as type 1 diabetes and Addison's disease when clinically indicated [15].

4. Step 3: Initial Risk Assessment

Although type I gNETs are generally considered indolent lesions with an excellent prognosis, a subset of patients may still experience disease progression, local invasion, or distant metastasis. Identifying factors associated with a worse clinical course is crucial to refining risk stratification and optimizing management strategies.

Several clinical and pathological features have been proposed as predictors of poor outcomes. Tumor size has consistently emerged as one of the most relevant risk factors. Lesions larger than 10 mm have been associated with a higher risk of angioinvasion, lymph node metastases, and adverse prognosis [6, 7]. In previous studies, tumor size exceeding 10 mm was independently predictive of poor outcome (p = 0.024) [6]; tumors larger than 20 mm were particularly associated with higher metastatic potential [7].

Tumor grade, defined by the Ki‐67 proliferative index, also plays a prognostic role; although its impact appears less pronounced compared to other gastrointestinal NENs. While higher Ki‐67 indices are generally associated with worse prognosis, in metastatic type I gNETs, a Ki‐67 index > 6% has been observed [7]. Nonetheless, in most non‐metastatic cases, the Ki‐67 remains low, limiting its individual prognostic value [6].

The number of lesions influences outcomes as well. Multiple small lesions, typical of type I gNETs, are associated with a favorable prognosis; whereas solitary larger tumors may reflect a more aggressive biological behavior [5, 21]. Male gender has been associated with worse prognosis in some series [22], although data remain partially conflicting. Age also appears relevant; patients older than 59 years have been reported to carry a higher risk [22]. Serum biomarkers such as hypergastrinemia have also been identified as a potential risk factor for tumor development and potential progression [7, 22, 23].

Despite these proposed risk factors, it is important to emphasize that the overall metastatic potential of type I gNETs remains negligible. Surveillance studies have shown that most tumors ≤ 10 mm in diameter remain stable for many years without intervention [21]. When metastatic disease does occur, it is typically associated with larger tumors (> 10–20 mm), higher Ki‐67 index, and, in some cases, significantly elevated gastrin levels [7, 24].

Tumor size greater than 10 mm, solitary lesion presentation, presence of angioinvasion, higher Ki‐67 index, male gender, advancing age, intestinal metaplasia, and hypergastrinemia represent the main factors associated with a worse prognosis in patients with type I gNETs. Risk stratification based on these parameters is essential to personalize surveillance and therapeutic strategies, balancing the need for intervention against the typically indolent nature of the disease. In the context of type I gNETs, the finding of R1 margins after endoscopic resection—indicating microscopic residual tumor at the resection edge—must be interpreted cautiously [25, 26]. Recent studies have shown that in small, well‐differentiated type I gNETs, an R1 resection does not necessarily translate into an increased risk of tumor recurrence or worse clinical outcome [27].

A tailored approach is therefore recommended. In patients with small (< 10 mm), G1 type I gNETs and an incidental R1 resection, close endoscopic follow‐up is generally favored over immediate re‐treatment. However, for larger lesions (> 10 mm) or tumors displaying aggressive features (such as grade 2 tumors or evidence of vascular invasion), additional endoscopic resection or surgical intervention should be considered.

5. Step 4: Indications for Additional Imaging and Referral Strategies

The criteria for requesting additional diagnostic imaging beyond standard endoscopic evaluation are not clearly defined. However, it is well established that in cases of type I gNETs without risk factors—specifically tumors smaller than 1 cm in diameter and classified as G1—no routine imaging assessment, either radiologic or nuclear medicine‐based, is necessary [10]. These patients can be safely directed toward endoscopic surveillance according to established guidelines [10]. In cases considered high‐risk based on tumor size and grading, a radiologic and nuclear medicine staging strategy similar to that recommended for other types of digestive NENs should be implemented [28, 29].

The role of endoscopic ultrasound (EUS) in this setting remains highly debated. Current guidelines recommend the use of EUS in cases where the tumor measures greater than 1 cm, or whenever there is a need for a detailed assessment of the gastric wall to define the depth of invasion and to appropriately plan the endoscopic resection technique [9]. Furthermore, EUS may be indicated in high‐risk cases to rule out lymph node involvement. Nevertheless, supporting evidence for the routine use of EUS in this specific context is extremely limited. A recent systematic review [30] highlighted that while EUS can provide additional information on wall invasion and nodal status, its clinical impact on management decisions in patients with small, well‐differentiated type I gNETs is minimal, with a low rate of change in treatment strategy following EUS assessment.

Neuroendocrine neoplasms represent a model of rare tumors in which multidisciplinary management is strongly recommended [31, 32]. It has been clearly demonstrated that referring a patient with a diagnosis of NEN to a specialized center significantly impacts patient management, leading to improved clinical outcomes [33, 34]. In particular, histological review performed at the referral center, followed by discussion of the case within a dedicated multidisciplinary team, results in a change in patient management strategies in a substantial proportion of cases, up to 40% [35, 36, 37, 38]. This approach increases adherence to clinical guidelines, enhances access to clinical trials, and generally contributes to better clinical outcomes.

Specifically for type I gNETs, as for any other NEN diagnosis, it is strongly recommended that, once the initial diagnostic evaluation has been completed, the patient be referred to a specialized center. This ensures the best possible care and the safest and most effective management.

6. Step 5: Follow‐Up Recommendations

Once the initial diagnostic and therapeutic management of type I gNETs has been completed, a structured and evidence‐based follow‐up strategy is essential to ensure early detection of recurrences or the development of new lesions.

According to current international guidelines [10], patients with completely resected type I gNETs smaller than 1 cm, graded G1, and without high‐risk features (such as vascular invasion or solitary large lesions) can be safely managed with periodic endoscopic surveillance alone, without the need for additional imaging. Endoscopic surveillance is generally recommended to start 12 months after the initial diagnosis or treatment, with subsequent intervals adjusted based on lesion characteristics and patient‐specific risk factors. For low‐risk patients, performing surveillance endoscopy every 1–2 years is considered appropriate [9].

In cases where the initial lesion exceeds 1 cm, displays atypical features, or where resection was incomplete (R1) with high‐risk histological findings (e.g., G2 tumor, vascular invasion), a closer follow‐up schedule is advised, with gastroscopies recommended every 6–12 months [8, 10]. Radiologic imaging (CT or MRI) and/or functional imaging (68Ga‐DOTATOC PET/CT) are not routinely recommended during follow‐up unless there are specific clinical indications, such as suspected disease progression or the appearance of symptoms [5, 8, 10].

It is important to note that EUS is not included in the standard follow‐up strategy for type I gastric NETs, given the lack of evidence supporting its routine use for surveillance [10]. However, despite the absence of robust scientific evidence, EUS remains a valuable tool in the management of type I gNETs, particularly for planning the optimal resection technique, assessing the depth of gastric wall involvement, and, in rare high‐risk cases, ruling out possible lymph node involvement [30, 38].

Regarding biomarkers, no serum tumor markers have been validated for the follow‐up of type I gNETs. Serial measurements of serum gastrin or chromogranin A levels are not recommended, as they have shown poor correlation with disease recurrence or progression [10, 39]. As with other NENs, the validation and qualification of novel biomarkers, along with the integration of molecular, histopathological, and endoscopic data, will be essential for improving patient management [40].

Due to the risk of nutritional deficiencies, patients with CAG require ongoing monitoring beyond vitamin B12 and iron status. Lifelong vitamin B12 parenteral supplementation is often necessary; folic acid should also be assessed to aid interpretation of vitamin B12 or homocysteine results. Iron deficiency, which may precede megaloblastic anemia by years, arises from reduced gastric acid secretion and should be evaluated with serum iron, transferrin, and ferritin. Additional deficiencies, such as calcium and vitamin D, may also occur and warrant consideration [14].

As far as the risk of recurrence is concerned, recent studies have reported relatively high recurrence rates even in low‐grade tumors. In a cohort of 170 patients with type I gNETs, 41.2% experienced a first recurrence after a median follow‐up of 31 months, with cumulative recurrence‐free survival rates at 1, 2, and 3 years of 71.8%, 56.8%, and 50.3%, respectively [41]. In a recent retrospective cohort including 113 patients with type I gNETs, after a median follow‐up of 66 months, approximately 40% of patients developed local or metachronous recurrence, despite no disease‐specific mortality being recorded in this subgroup [39]. Notably, despite relatively high recurrence rates, disease‐specific mortality remains extremely low, further supporting the indolent behavior of most type I gNETs. Thus, the primary goal of follow‐up is not only the early identification of recurrence or new lesions but also the long‐term monitoring of the gastric mucosa and the management of underlying conditions contributing to tumorigenesis. In addition to surveillance for tumor recurrence, long‐term monitoring of the gastric mucosa is crucial in patients with underlying CAG. According to the MAPS III guidelines [9], patients with extensive atrophy or intestinal metaplasia involving both the antrum and corpus (corresponding to OLGA/OLGIM stages III–IV) should undergo endoscopic surveillance every 3 years. Surveillance should ideally be performed with high‐definition endoscopy, combined with virtual chromoendoscopy techniques such as NBI or BLI.

7. Conclusions

In summary, the incidental diagnosis of type I gNETs represents a growing clinical scenario in routine endoscopic practice. While most lesions display an indolent course, appropriate recognition, risk stratification, and structured follow‐up are essential to ensure optimal patient outcomes. A stepwise approach—grounded in endoscopic expertise, histopathological accuracy, and multidisciplinary evaluation—remains the cornerstone of safe and effective management (Table 1). Adhering to guideline‐based protocols not only improves diagnostic precision but also ensures long‐term surveillance tailored to individual patient risk.

TABLE 1.

Step‐by‐step approach to type I gastric NETs.

Step	Key message
Step 1 Recognizing a Gastric NET During Endoscopy	Suspect type I gastric NETs when multiple small, sessile lesions are seen in the fundus/body on a background of atrophic mucosa; use high‐definition endoscopy with virtual chromoendoscopy (e.g., NBI) and perform targeted biopsies.
Step 2 Biopsy and Histopathological Confirmation	Confirm chronic atrophic gastritis through systematic biopsies (antrum and corpus), and ensure pathology reports include Ki‐67 index, mitotic count, and CAG status to define tumor type.
Step 3 Initial Risk Assessment	Assess prognosis based on lesion size (> 10 mm), solitary presentation, higher Ki‐67, angioinvasion, age, sex, and biomarkers (CgA, gastrin). Most small G1 lesions have an excellent prognosis.
Step 4 Additional Imaging and Referral	Imaging (CT, PET/CT, EUS) is reserved for high‐risk lesions; always refer patients to a NET‐expert center for histological review and multidisciplinary discussion.
Step 5 Follow‐Up Recommendations	Low‐risk lesions require endoscopic surveillance every 1–2 years; in CAG with OLGA/OLGIM III–IV or autoimmune gastritis, follow‐up every 3 years is recommended. Biomarker monitoring (CgA/gastrin) is not useful for follow‐up.

Conflicts of Interest

The authors declare no conflicts of interest.

Baldini L., Dell'Unto E., Rinzivillo M., Esposito G., and Panzuto F., “Step‐by‐Step Approach to the Incidental Diagnosis of Type I Gastric Neuroendocrine Tumors: Practical Insights,” JGH Open 9, no. 9 (2025): e70260, 10.1002/jgh3.70260.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.