Insulinomas are the most common functional PanNETs, accounting for 20.9% of cases [9]. Typically, insulinomas are benign and well-differentiated NETs; however, approximately 5.8% of insulinomas are malignant [13,14]. While insulinomas are usually sporadic, around 4–5% of patients with insulinomas have multiple endocrine neoplasia type 1 (MEN1) [15]. The gold standard for diagnosing insulinomas is measuring insulin levels after a 72 h fasting test, which demonstrates close to 100% sensitivity and specificity [16]. Once organic hyperinsulinism is confirmed in symptomatic patients (as outlined in Table 1), imaging is necessary to locate the tumor for surgical management. Various imaging modalities can be employed, including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS) with fine needle aspiration (FNA), arteriography, intra-arterial stimulation with venous sampling (ASVS), and somatostatin receptor scintigraphy [17]. 68Ga-DOTATATE positron emission tomography (PET/CT) and Fluorine-18-L-dihydroxyphenylalanine (18-F-DOPA) PET, which take advantage of PanNET’s propensity for decarboxylate amine precursors, have been found to be more sensitive than CT or MRI in identifying insulinomas or beta cell hyperplasia and are used when conventional imaging modalities yield inconclusive results [15,18]. Regarding the additional benefits of using EUS, a meta-analysis conducted by James et al. revealed that the implementation of EUS was associated with a higher detection rate of PanNETs even after the utilization of CT and MRI imaging. This contributed to an overall increase in PNET detection of more than 25% [19]. In a retrospective study conducted by Pais et al., the sensitivity of EUS-FNA in diagnosing PanNETs was found to be 87%. Notably, this sensitivity remained consistent in both functional and nonfunctional PanNETs. These findings further demonstrate that EUS can be a valuable tool to aid in the diagnosis of PanNETs [20].

The second most common functional PanNETs are gastrinomas (8.2%) [9]. Gastrinomas secrete gastrin and cause Zollinger–Ellison syndrome (ZES) [21]. This syndrome is characterized by hypersecretion of gastric acid leading to peptic ulcer disease and gastroesophageal reflux disease. It is estimated that 25% of gastrinomas occur in patients with MEN1 [22]. A more than one-thousand-fold increase in gastrin levels can be diagnostic [23]. If gastrin levels are only moderately elevated, a secretin test is required, during which gastrin levels are measured after intravenous administration of a secretin bolus [24]. However, gastrin levels can be elevated in patients with atrophic gastritis or in patients receiving proton pump inhibitor therapy [25]. As a result, the diagnostic criteria for ZES are not commonly fulfilled, and greater emphasis is placed on imaging modalities to detect the presence of an intra-abdominal tumor [26].

In a prospective study involving 80 patients with gastrinomas, somatostatin receptor scintigraphy (Octreotide scan) alone yielded a gastrinoma detection rate of 58%, while conventional imaging modalities such as ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and angiography had a detection rate ranging from 9% to 31% [27]. This scintigraphy test utilizes an indium-111 radiolabel that binds to somatostatin receptors, providing an overall sensitivity of 75–100% for detecting PanNETs [28,29]. To enhance its sensitivity, this technique can be combined with single-positron emission computed tomography (SPECT) [30]. More recently, somatostatin receptor PET imaging using three FDA-approved radiotracers, namely gallium-68-dodecanetetraacetic acid, tyrosine-3-octreotate (68-Ga-DOTATATE), 68-Ga-DOTATOC, and 64-Cu-DOTATAT, has emerged as superior to the traditional octreotide scan. These radiotracers have demonstrated high sensitivity, shorter imaging duration, and lower radiation doses. In PanNETs with lower somatostatin receptor expression, imaging with (18)F-FDG PET is preferred [31].

While EUS demonstrates excellent sensitivity and specificity for detecting gastrinomas in the pancreas, its sensitivity may decrease when gastrinomas are localized in the duodenum. However, the high sensitivity of EUS in detecting small PanNETs (less than 2 cm) has led some experts to propose an annual EUS screening for asymptomatic patients with MEN1 [32].

For the diagnosis of glucagonomas, glucagon levels above 500 pg/mL are commonly observed [33]. However, it is important to note that elevated glucagon levels can also be seen in other conditions such as cirrhosis and diabetes. Therefore, the interpretation of elevated glucagon levels should be combined with the presence of typical glucagonoma syndrome symptoms, including weight loss, necrotic migratory erythema, and hypoalbuminemia [34].

In a study investigating a cohort of 1000 patients with various causes of diarrhea, elevated vasoactive intestinal peptide (VIP) levels were found to be 100% specific in diagnosing VIPomas [35]. This finding is particularly relevant as VIPomas typically present with symptoms such as watery diarrhea, hypokalemia, and achlorhydria. The study demonstrated the high specificity of VIP levels in aiding the diagnosis of VIPomas. It is worth noting that other peptides, including gastrin and insulinoma, can also be elevated in patients with VIPomas [36].

Somatostatinomas can produce a “stomatostatinoma syndrome”, which is characterized by anemia, diabetes, diarrhea, and gallbladder disease [6]. Fasting plasma somatostatin level greater than 14 mol/L and CT of the abdomen are often diagnostic, as these tumors, like glucagonomas, are often large upon presentation [37].

Nonfunctional PanNETs typically do not cause symptoms until they reach a significant tumor burden or when complications arise from mass effect or metastatic disease. Despite their indolent nature, over 11% of nonfunctional PanNETs are diagnosed as distant metastases. The diagnosis of nonfunctional PanNETs involves a combination of biochemical, radiographic, and histologic evaluations [6,37,38,39].

Neuroendocrine biomarkers play a role in diagnosing and surveilling and are applicable to both functional and nonfunctional PanNETs [40]. One of the most ubiquitously measured biomarkers is a glycoprotein produced by neuroendocrine cells known as chromogranin A (CgA). It has been shown that CgA can affect several elements in the tumor microenvironment, including endothelial cells and fibroblasts. These findings have also suggested that its abnormal secretion could play a role in tumor progression [41]. In the diagnosis of functional and nonfunctional PanNETs, CgA has been found to have a sensitivity of 66% and specificity of 95% [42]. CgA can also be false-positively elevated in several clinical conditions including inflammatory bowel disease, renal failure, liver failure, or pancreatitis. In addition, proton pump inhibitor (PPI) therapy as well steroids have also been shown to increase CgA levels [43,44], and this effect by PPIs can last up to 2 weeks [45]. While these circumstances may limit CgA’s use as a diagnostic biomarker, evidence is favorable for its use as a prognostic factor for progression-free survival (PFS) and overall survival (OS) [42,44].

Neuron-specific enolase (NSE), a glycolytic enzyme expressed in neuroendocrine cells, is another biomarker that has demonstrated prognostic value in progression-free survival and overall survival. The expression of NSE occurs as a late event in the neural cell differentiation process [46]. Its utility as a biomarker is based on its expression in neural maturation and tumor proliferation. While NSE has a diagnostic sensitivity of 31% in comparison to CgA in PanNETs, elevated baseline NSE values similarly showed prognostication on progression-free survival and overall survival [47,48]. Furthermore, early decreases in CgA and NSE levels after treatment can serve as a prognostic marker in patients with advanced PanNETs. The combined use of CgA and NSE has been shown to be more accurate in predicting and prognosticating disease [49].

One of the more novel biomarkers involves measuring circulating neuroendocrine tumor transcripts (NETest). This test uses PCR to measure 51 different transcripts related to neuroendocrine tumors or associated with neoplastic behavior and was found to have a sensitivity of 80% and specificity of 94% for PanNETs in a study that investigated 206 patients with neuroendocrine tumors [50]. The genes tested include KRAS, RAF1, and APLP2, among others. NETest is also associated with disease progression and can potentially be a better predictor of disease than CgA [50,51].