Ectopic Insulinoma in the Pyloric Antrum Portion of the Stomach: A Case Report and Review of the Associated Diagnostic Challenges.

Introduction
Insulinoma is a rare neuroendocrine tumor with an annual incidence of approximately 4 cases per million individuals (1). The annual incidence is approximately four cases per million, with 1-2% of insulinomas occurring outside the pancreas, which are referred to as ectopic insulinomas (2,3). Although insulinomas primarily produce insulin, reports indicate that they can also produce multiple hormones (4), reflecting the heterogeneous nature of these tumors. In a comprehensive literature review conducted by Zhang et al. in 2021, only 13 cases of ectopic insulinomas have been identified over the past four decades (5). Among these cases, only one was reported to originate from the gastric antrum, highlighting the exceptional rarity of this presentation. A thorough PubMed search also confirmed that no additional reports of ectopic gastric insulinoma were identified, thus emphasizing the unique nature of our current report.
These tumors, classified as pancreatic neuroendocrine tumors, originate from insulin-producing β-cells within the pancreatic islets. While most insulinomas are confined to the pancreas, rare cases of extrapancreatic tumors, known as ectopic insulinomas, have also been reported. We herein report a rare case of an ectopic insulinoma arising from the gastric antrum.

Case Report
A 64-year-old woman presented with dizziness while fasting. She experienced palpitations during fasting in 2019, which were relieved by food intake. Initially mild, her symptoms had worsened by March 2022, prompting her to seek medical care. Hypoglycemia (blood glucose level, 40 mg/dL) was confirmed, and she was referred to our Diabetes Center for evaluation.
Her medical history included a uterine myomectomy at 41 years of age and right breast cancer surgery at 49 years of age with no recurrence. She had no history of gastric surgery including gastric bypass. Her father had rectal cancer and her mother had type 2 diabetes. She did not take regular medications or supplements, and had no significant lifestyle factors.
Upon examination, she was alert and oriented with stable vital signs: temperature 37.0°C, blood pressure, 158/91 mmHg; pulse rate, 76 bpm (regular); respiratory rate, 12 breaths per minute, and SpO2 98% on room air. She measured 159 cm in height, weighed 52.8 kg, and had a BMI of 20.7 kg/m2. No pallor, jaundice, lymphadenopathy, leg edema, or abdominal abnormalities were observed.
Initial blood tests showed no abnormalities in hematological, biochemical, coagulation, or tumor marker levels. Her fasting blood glucose level was low (74 mg/dL), with relatively elevated insulin levels (42.3 μIU/mL). Glycoalbumin, HbA1c, pituitary hormone, adrenal cortical hormone, thyroid function, and anti-insulin antibody levels were all normal (Table 1). A 75 g oral glucose tolerance test (OGTT) showed no obvious reactive hypoglycemia (Fig. 1). We performed a fasting test that was interrupted after 45 h owing to a decrease in the plasma glucose levels to 36 mg/dL. At 43 h in the fasting test, the glucose level was 42 mg/dL, the insulin level was 14.3 μIU/mL and the C-reactive protein (CRP) level was 0.7 ng/mL, indicating endogenous hyperinsulinemia, which was not suppressed by low glucose (Fig. 2). Continuous glucose monitoring (CGM) revealed that hypoglycemia, defined as a glucose level of less than 70 mg/dL during the day, accounted for 23%.
Contrast-enhanced computed tomography (CT) showed no mass in the pancreas but revealed a 20-mm hypervascular tumor in the pyloric antrum (Fig. 3). A retrospective review of a 2012 CT scan identified a 12-mm lesion at the same site; however, direct comparison was difficult because of differences in the contrast phases. Esophagogastroduodenoscopy identified a 20-mm subepithelial lesion with a smooth surface in the anterior gastric antrum (Fig. 4a). No central depressions, ulcerations, or dilated vessels were observed on the mucosal surface. Boring biopsy samples were insufficient for a definitive diagnosis. Endoscopic ultrasonography (EUS) showed a homogeneously hypoechoic, well-demarcated tumor originating from the submucosal layer (third layer) with no irregular margins. Color Doppler imaging revealed hypervascularity (Fig. 4b). In addition, a thorough EUS evaluation of the pancreas confirmed the absence of any pancreatic lesions.
To confirm the malignancy and diagnosis, a biopsy was performed using the unroofing technique (3), as adequate tissue acquisition was considered challenging with EUS-fine needle aspiration owing to the small tumor size. A histopathological examination revealed a neuroendocrine tumor (NET, G1) with amyloid deposition. Immunohistochemical staining was positive for chromogranin A, synaptophysin, somatostatin receptor 2, and insulin, thus confirming insulinoma (Fig. 5).
Octreotide scintigraphy revealed a radiotracer uptake localized to the gastric lesion (Fig. 6), which supported the diagnosis of ectopic gastric insulinoma. Imaging ruled out multiple endocrine neoplasia type 1.
The patient underwent laparoscopic distal gastrectomy with D1 lymphadenectomy (Fig. 7). A pathological examination confirmed an NET (G1), measuring 15 mm in diameter, confined to the submucosal layer, without either vascular or lymphatic invasion. The Ki-67 index was 0.45% (Fig. 8). A histopathological evaluation also excluded non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS) with no evidence of either nesidioblastosis or islet cell hyperplasia.
Postoperatively, her hypoglycemic symptoms resolved completely. Although the hypoglycemic state was 23% on the day before surgery based on the CGM, it improved to 2% after surgery. Additionally, the 75 g OGTT after surgery showed a significant decrease in insulin secretion after glucose loading (Table 2). Follow-up tests showed no recurrence of hypoglycemia or hyperinsulinemia. Contrast-enhanced CT scans showed no recurrence, and the patient has remained disease-free for two years.

Discussion
Insulinoma is a rare neuroendocrine tumor originating from pancreatic islet β-cells and is characterized by excessive insulin secretion, which causes hypoglycemia (1). Clinical symptoms include autonomic manifestations, such as sweating and palpitations, and in severe cases, central nervous system symptoms, such as seizures and coma (6). The diagnostic criteria for insulinoma include the demonstration of Whipple's triad: symptomatic hypoglycemia, plasma glucose level ＜55 mg/dL, and a resolution of symptoms after glucose intake. In this case, the patient's 48-hour fasting test revealed a glucose level of 43 mg/dL, an insulin level of 14.3 μIU/mL (cutoff ＞6 μIU/mL), and a CPR level of 0.7 ng/mL (cutoff ＞0.6 ng/mL), indicating endogenous hyperinsulinemia. These results, combined with the absence of anti-insulin antibodies and normal pituitary, adrenal, and thyroid functions, strongly confirmed the diagnosis of insulinoma (Table 1). Furthermore, differential diagnoses, such as post-gastric bypass hypoglycemia and NIPHS, were excluded. The patient had no history of gastric surgery, including gastric bypass. A histopathological evaluation revealed no evidence of either nesidioblastosis or islet cell hyperplasia, effectively ruling out NIPHS.
These tumors are thought to arise from ectopic pancreatic tissue, which is defined as the pancreatic tissue separated from the main pancreas (7,8). Autopsy studies indicate that ectopic pancreatic tissue is present in 0.4% to 1% of individuals, commonly in the stomach, duodenum, and Meckel's diverticulum (9-11). Heterotopic pancreas is most commonly found in the stomach (25-38%), particularly in the antrum and prepyloric region, followed by the duodenum (17-36%) and jejunum (15-21%) (12). Notably, gastric lesions are predominantly detected in the antrum (85-95%) (12). Given these distributions, the pyloric antrum, where ectopic insulinoma was located in our patient, is a well-documented site for heterotopic pancreatic tissue, suggesting the possibility of its origin in this case.
Non-functional insulin-secreting tumors that do not present with Whipple's triad have been reported, likely because of their small size. For instance, a 6-mm neuroendocrine tumor in the duodenal bulb exhibited insulin immunoreactivity and amyloid deposition without inducing hypoglycemia (13). In this case, retrospective CT imaging performed 10 years earlier showed a lesion at the same site, suggesting that the tumor may have initially been non-functional and later enlarged, thus becoming functional and causing hypoglycemia.
Although somatostatin receptor scintigraphy (SRS) did not detect any pancreatic lesions, the possibility of metastasis from a microlesion in the pancreatic head to the gastroduodenal region cannot be entirely ruled out. However, insulinomas have a lower somatostatin receptor expression than other neuroendocrine neoplasms, which may reduce SRS sensitivity (14). Differences in the detection sensitivity between pancreatic insulinomas and ectopic insulinomas have not been reported. However, most insulinomas are benign, with a reported malignancy rate of 5.8% to 8% (15). Malignancy is defined as local invasion or distant metastasis, typically to the liver or lymph nodes. Gastrointestinal tract metastasis is exceedingly rare (16), thus making malignancy unlikely. Furthermore, the slow growth of the ectopic tumor over the past 10 years and the low Ki-67 index of 0.45% further support the benign nature of this lesion.
Selective arterial secretagogue injection (SASI) testing is a valuable diagnostic tool for localization (17). However, because the gastric pyloric antrum is supplied by the gastroduodenal artery, which also supplies the pancreatic head and duodenal bulb, differentiating a pancreatic lesion from a gastric lesion can be challenging. Therefore, a SASI test was not performed.
The European Neuroendocrine Tumor Society (ENETS) 2023 guidelines provide comprehensive management strategies for functional pancreatic neuroendocrine tumors, emphasizing biochemical and imaging assessments alongside therapeutic management (18). In line with these guidelines, we used a stepwise diagnostic approach, including contrast-enhanced CT, magnetic resonance imaging, and EUS. Importantly, EUS allowed not only the identification of the gastric lesion but also a thorough evaluation of the pancreas, confirming the absence of pancreatic abnormalities. While the ENETS guidelines provide a structured approach to insulinoma localization, their direct applicability to ectopic insulinomas remains uncertain because of differences in anatomical location, biological behavior, and imaging characteristics.
The ENETS 2023 guidelines provide comprehensive management strategies for functional pancreatic neuroendocrine tumors, emphasizing biochemical and imaging assessments alongside therapeutic management (18). However, the recommendations for ectopic insulinomas are limited.
Prognostic factors for pancreatic neuroendocrine tumors include tumor size, Ki-67 index, and lymphovascular invasion (19). In this case, the tumor was classified as World Health Organization Grade 1, with a low Ki-67 index and no lymphovascular invasion, indicating a favorable prognosis. Laparoscopic distal gastrectomy with D1 lymphadenectomy is considered to be an appropriate treatment approach.
Although the long-term behavior of ectopic insulinomas is uncertain, recurrence has been reported 4-20 years after primary tumor resection (20). For example, a case of ectopic duodenal insulinoma recurred with metastatic lymph node involvement and hypoglycemia four years after enucleation (21). Thus, long-term follow-up is therefore crucial to monitor potential recurrence in this patient.

Conclusion
This report presents a rare case of an ectopic insulinoma arising from the gastric pyloric antrum. The diagnosis was established through comprehensive evaluations, including clinical presentation, imaging studies, and histopathological examination. Laparoscopic distal gastrectomy with D1 lymphadenectomy successfully resected the tumor and resolved the patient's hypoglycemic symptoms. To date, the patient has remained disease-free for two years.

The authors state that they have no Conflict of Interest (COI).