Discussion
Insulinomas are commonly encountered as solitary benign tumors, typically measuring less than 2 cm in diameter, and they constitute 87% of all pancreatic tumors.[4] On the other hand, the malignant ones account for the remaining 13%. These malignant variants tend to be larger, with an average size of 6.2 cm. The most frequent locations for insulinomas are the tail, body, and head of the pancreas. Notably, they often coincide with a significant elevation in insulin levels. The five-year survival rates differ markedly between benign and malignant tumors, standing at 95.4% and 66.8%, respectively. [5] Approximately 4% to 7% of insulinomas are associated with multiple endocrine neoplasia type-1 (MEN-1), a condition characterized by an earlier age of onset and multifocality. [6] Despite extensive research, the etiology and pathogenesis of insulinomas remain elusive. Clinically, the patients with an insulinoma manifest primarily as episodic hypoglycemia, primarily due to excessive insulin secretion from the tumor tissue. The diagnostic criteria for insulinoma include the Whipple’s triad sign: (1) spontaneous periodic episodes of hypoglycemic symptoms, coma, and associated psychoneurological symptoms, often occurring during fasting or after physical exertion; (2) blood glucose levels below 50.4 mg/dL during these episodes; and (3) prompt resolution of the symptoms following oral or intravenous glucose administration. In cases with atypical clinical manifestations, a 72-hour starvation test is essential for a definitive diagnosis. [7, 8] The symptoms and the test results of the patient in our reported case meet the qualitative diagnostic criteria for insulinoma.
Benign insulinomas commonly respond well to surgical resection, and we now have a variety of alternative therapeutic options. These include endoscopic ultrasound-guided radiofrequency ablation, percutaneous alcohol ablation, and transarterial embolization of the insulinoma.[9, 10] The preoperative localization of insulinomas directly impacts the clearance rate, reoperation rate, and prognosis of the lesion. Accurate localization diagnosis remains a significant challenge in insulinoma diagnosis and treatment. Advancements in imaging technology have ushered in an era of simple and non-invasive preoperative localization and diagnosis of insulinomas. Invasive techniques, such as digital subtraction angiography, percutaneous hepatic portal vein blood sampling, and selective arterial calcium-stimulated venous blood collection, have fallen out of favor. Routine imaging modalities, including ultrasound of the upper abdomen, Magnetic Resonance Imaging (MRI), Contrast-Enhanced Computed Tomography (CECT) of the abdomen, and pancreatic CT perfusion imaging, are widely employed for localization and diagnosis. In a single-center study, 286 patients with functional pancreatic neuroendocrine tumors (pNETs) were included, of whom 266 had insulinomas. The study demonstrated that CT, DSA, ultrasonography, and MRI achieved favorable localization and diagnostic rates of 76.2%, 83.8%, 87.1%, and 92.9%, respectively.[11] Computed tomography (CT) and magnetic resonance imaging (MRI) serve as primary imaging modalities for localization and diagnosis of insulinomas. However, their sensitivity remains inadequate, particularly for small-volume lesions. Improving the detection rate and addressing deficiencies in lesion characterization are ongoing challenges. Emerging imaging techniques, including 68Gallium-DOTA-Tyr3-Octreotate Positron Emission Tomography-Computed Tomography (68Ga-DOTATATE-PET-CT) and 68Gallium-NOTA-exendin-4 Positron Emission Tomography-Computed Tomography (68Ga-NOTAexendin-4PET-CT), and other radionuclide receptor imaging tests, exploit receptor-binding based imaging for precise localization. In a prospective study, 68Ga-DOTATATE-PET-CT demonstrated superior sensitivity for lesion detection and tumor-staging guiding, compared to whole-body diffusion-weighted MRI (WB DWI) and 99mTc-HYNIC-Octreotide SPECT/CT. Diagnostic performance metrics for pancreatic neuroendocrine tumors were as follows: sensitivity 100%, specificity 80%, accuracy 84%, positive predictive value 57%, and negative predictive value 100%.[12] Despite their clinical significance, wider adoption of these novel imaging tests remains limited due to availability constraints in many hospitals. In this case, abdominal enhancement CT failed to detect the lesion, and radionuclide receptor imaging was not performed. Hence, alternative localization methods are necessary for further clarification.
Given that surgical removal of the tumor remains the sole effective treatment, to prevent undue harm to the patient resulting from misdiagnosis, a preoperative “gold standard” diagnosis is imperative, which necessitates the pathologic examination. Endoscopic ultrasound (EUS) offers the advantages of high resolution, proximity, and minimal interference from intestinal gas. During both preoperative and intraoperative phases, it allows comprehensive observation of the lesion from all angles, eliminating blind spots and facilitating precise tumor localization. In comparison to alternative imaging modalities, endoscopic ultrasound offers notable benefits, particularly in enhancing the detection rate of small lesions. Additionally, it can be used in conjunction with fine-needle aspiration biopsy to perform histologic and cytologic examinations on the lesion. Furthermore, it enables qualitative diagnosis of the lesion, informing treatment decisions. In situations where conventional imaging results are inconclusive, it serves as a crucial complementary tool.[13]
However, EUS as an invasive procedure has several drawbacks. The diagnostic effectiveness of insulinomas via EUS is constrained by the location and size of the tumors. Specifically, EUS is less effective in detecting insulinomas situated in the tail or the leptomeningeal region of the pancreas, both of which tend to be small. The reliability of EUS depends on the subjective interpretation of the sonographer, introducing limitations. Detecting isoechoic insulinomas poses challenges for EUS, and it cannot identify extra-pancreatic lesions like lymph node or liver metastases. In this case, the patient underwent the EUS examination, and a small lesion in the pancreatic neck, a location prone to oversight, was identified. The fine-needle aspiration biopsy was subsequently conducted to ascertain the lesion’s nature, confirming it as a neuroendocrine tumor. The precise diagnosis of the lesion’s location and nature enabled the patient to proceed with the next stage of surgical treatment.
After pancreaticoduodenectomy, the patient did not encounter hypoglycemic episodes. Hyperglycemia was attributed to secondary diabetes mellitus. Exogenous insulin treatment resulted in adequate glycemic control. Postoperatively, the patient underwent follow-up, with no evidence of recurrence or metastasis.
The EUS-guided fine-needle aspiration biopsy (EUS-FNAB) serves as a critical adjunctive technique when conventional imaging fails to precisely localize and diagnose occult insulinomas. Furthermore, novel molecular imaging technologies, including 68Ga-DOTATATE-PET-CT and 68Ga-NOTAexendin-4PET-CT, also offer precise and reliable localization of the tumors. These advancements enhance clinicians’ diagnostic and therapeutic capabilities for occult insulinomas, minimizing misdiagnoses and enabling early intervention.