Pancreatic neuroendocrine neoplasms (pNENs) and carcinoid tumors develop from the islets of Langerhans in the pancreas and enterochromaffin cells in the gastrointestinal tract, respectively.1 Functional gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) exhibit diverse clinical features depending on their site of origin and the type of hormones they secrete; examples include insulinoma, gastrinoma, VIPoma, glucagonoma, somatostatinoma, and carcinoid tumor.2 Non-functional GEP-NENs do not secrete hormones and have no associated systemic symptoms.3 The incidence of GEP-NENs has expanded over the past few decades, likely due to increased emphasis on screening and widespread use of cross-sectional imaging with computed tomography (CT) and magnetic resonance imaging (MRI).4 Also, recent technological advancements in endoscopy have facilitated the early diagnosis of neuroendocrine neoplasms. In this review, we will summarize the clinical presentations and diagnostic criteria of each functional GEP-NEN. We will also discuss the advanced applications of endoscopy and cross-sectional imaging in the clinical management of pNENs.
Insulinomas are functional pNENs that affect 1-3 patients per million per year. The clinical hallmark of insulinomas is Whipple’s triad: 1) symptoms are caused by hypoglycemia, 2) low plasma glucose levels of < 3mmol/L at the onset of the symptoms, and 3) symptomatic relief upon serum glucose normalization.5
Cryer et al. adequately categorized hypoglycemic symptoms into neuroglycopenic and autonomic symptoms. Neuroglycopenic symptoms are caused by decreased glucose supplies to the brain which can manifest as confusion, fatigue, loss of consciousness, and behavioral changes.
Autonomic symptoms are caused by increased sympathetic nervous system activity due to hypoglycemia including palpitations, tremors, anxiety, paresthesias, and increased appetite.6
The most dependable test to diagnose insulinomas is the measurement of serum glucose, proinsulin, and C-peptide levels after an overnight fast and every 4 hours for up to 72 hours. The test can be terminated if the patient develops hypoglycemic symptoms with a serum glucose level < 2.5 mmol/L. A serum proinsulin level greater than 5 pmol/L and a C-peptide level greater than 0.2 nmol/L with a serum glucose level less than 2.5 mmol/L revealed 100% sensitivity and specificity for diagnosing insulinomas.7
Gastrinomas are functional neuroendocrine neoplasms that produce a large amount of gastrin and result in markedly increased gastric acid secretion, with attendant consequences.8 The significant rise in gastric acid can cause ZollingerEllison syndrome (ZES), which manifests as severe peptic ulcer disease (often with multifocal ulcers in the esophagus, stomach, and duodenum), profound diarrhea, and other symptoms. Rossi et al. summarized the clinical symptoms of ZES including abdominal pain (75%), diarrhea (73%), heartburn (44%), and weight loss (17%).9 Gastrinomas can be diagnosed by measuring the gastric pH and fasting serum gastrin (FSG) levels. If gastric pH is < 2.0 and FSG is >10fold of the upper limit of normal (>1000 pg/mL), a gastrinoma can be diagnosed.10,11 If FSG is < 10-fold of the upper limit of normal (< 1000 pg/ ml), a provocative secretin stimulation test can help distinguish gastrinomas from other diseases that increase the FSG, such as atrophic gastritis or G-cell hyperplasia. The secretin stimulation that increases the previously measured FSG by >120 pg/mL has the highest sensitivity (94%) and specificity (100%) for diagnosing gastrinomas.12 It is important to withdraw any pharmacological intervention that may prevent gastric acid secretion, such as a proton pump inhibitor or histamine H2 receptor antagonist, prior to the FSG testing to avoid a false positive diagnosis from artificially elevated serum gastrin levels.13
VIPomas are functional neuroendocrine neoplasms that secrete a large amount of vasoactive intestinal peptides (VIPs). VIPs upregulate the secretory function of gastrointestinal cells, which manifests as diarrhea, achlorhydria, and depletion of electrolytes (including potassiums, phosphates, bicarbonates, and magnesiums).14 In severe cases of water depletion or electrolyte imbalances, patients can develop life-threatening conditions such as hypovolemic shock or cardiac arrhythmias.15 To diagnose a VIPoma, patients must present with secretory diarrhea and plasma VIPs > 500 pg/mL.14,16 A 2019 systemic review revealed that patients with VIPomas had median plasma VIPs of 636 pg/mL.14
Glucagonomas are functional neuroendocrine neoplasms that secrete excess amounts of glucagon and present with so-called “glucagon syndrome.” The glucagonoma triad includes necrolytic migratory erythema (82%), diabetic mellitus (68%), and weight loss (60%).17 Other less common, yet still prevailing clinical symptoms of glucagonomas include diarrhea, depression, stomatitis, anemia, and deep vein thrombosis.16,17 Clinical documentation of necrolytic migratory erythema with a fasting plasma glucagon value > 500 pg/mL can confirm the diagnosis.18 It is important to note that there are other conditions that can cause hyperglucagonemia including cirrhosis, chronic renal failure, chronic hepatic failure, and pancreatitis.19
Somatostatinomas are somatostatin-secreting neuroendocrine neoplasms that most frequently arise in the pancreas (70%) and duodenum (19%).21 The clinical symptoms of somatostatinomas include diabetes mellitus, cholelithiasis, steatorrhea, and anemia.20 Many of these clinical symptoms arise from the suppressive effects of somatostatins on other neuroendocrine hormones; for example, patients can develop diabetes mellitus from decreased insulin secretion or achlorhydria from decreased gastric acid secretion.16,21
Somatostatinomas are usually diagnosed after immunohistochemical staining for somatostatin.22 The diagnosis can also be verified by measuring a fasting serum somatostatin level > 3 times of the normal somatostatin values.23
Neuroendocrine neoplasms can present with carcinoid syndrome, which is a paraneoplastic syndrome caused by increased secretion of polypeptides, vasoactive amines, and prostaglandins.24 It is most associated with neuroendocrine neoplasms that develop in the midgut and disseminate to the liver because the bioactive substances can circumvent metabolism before entering the systemic circulation.25 Interestingly, a recent Surveillance, Epidemiology, and End Result (SEER) database revealed that 19%37% of small bowel neuroendocrine neoplasms presented with carcinoid syndrome without hepatic metastasis, showing that the disease may be more protean in nature than previously thought.26,27
Flushing is observed in over 90% of patients with carcinoid syndrome and is caused by increased plasma vasoactive substances such as serotonin, kallikreins, catecholamines, and prostaglandins.24,28 Secretory diarrhea is observed in 80% of carcinoid syndrome and is caused by increased plasma serotonins that upregulate gastrointestinal motility.29 Other less common but still prevailing symptoms of carcinoid syndrome include abdominal pain (35%), right-sided valvular heart disease (19-60%), wheezing (15%), and pellagra (5%).24 In patients with suspected carcinoid syndrome, measuring urinary 5-Hydroxyindoleacetic acid (5HIAA) for 24 hours (the normal value for urinary 5-HIAA ranges 3-15 mg/day) is the recommended initial test, with a sensitivity and specificity of 73% and 100%, respectively.30 Measuring urinary serotonin and 5-HIAA simultaneously provides higher sensitivity and equal specificity for diagnosing carcinoid syndrome with 84% and 100%, respectively.31
Multiple endocrine neoplasia type 1 (MEN-1) syndrome
MEN-1 syndrome is a disorder caused by inactivating mutation of the MEN1 gene, which completely disables the function of menin, a tumor suppressor protein. Malfunctioning menin increases the risk of developing tumors in the neuroendocrine system, most classically in the pancreas, pituitary glands, and parathyroid glands. Literature reviews revealed that more than 30-80% of MEN-1 syndrome patients developed pNENs.32 Among patients with MEN-1 syndrome, gastrinomas were the most prevalent pNENs (ranging from 20-61%), followed by insulinomas (ranging from 7-31%), and glucagonomas (ranging from 1-5%).33 All patients with MEN-1 syndrome should undergo active surveillance throughout their lives to reduce the risk of malignant transformation of pNENs. It is a common practice to annually measure biochemical markers such as chromogranin A, glucagon, and pancreatic polypeptides for early screening of pNENs in patients with MEN1 syndrome.34 However, a recent retrospective analysis revealed that the diagnostic value of the serum biochemical markers for early diagnosis of MEN-1-associated pNENs, compared to sporadic pNENs, was unreliable; therefore, imaging studies are recommended screening tools for MEN1-associated pNENs.35 Among many imaging modalities used to screen for early diagnosis of pNENs in MEN-1 syndrome patients, Endoscopic Ultrasound (EUS) outperformed CT, MRI, and somatostatin receptor scintigraphy (SRS). One cross-sectional study on 41 patients with MEN-1 syndrome demonstrated that EUS detected 101 pancreatic lesions in 34/41 patients, while CT, MRI, and SRS jointly detected 32 pancreatic lesions in 18/41 patients.36
Role of endoscopy in managing pNENs
The anatomic location of the pancreas, being adjacent to the stomach and the duodenum, permits the use of EUS. EUS allows a detailed examination of the pNENs, providing information on the location and size of the lesion that will direct treatment and management plans for the patients.37 EUS also allows for direct tissue sampling of any pancreatic lesions identified (Figures 1 and 2). Two systemic reviews and meta-analyses in 2013 and 2018 revealed that EUS could detect pNENs with an overall sensitivity of 81-87% and specificity of 90-98%.38,39 Because of its high diagnostic accuracy, EUS is recommended after negative non-invasive imaging studies for those with high clinical suspicion of pNENs.40 One retrospective study on 32 patients revealed that a combined CT scan and EUS revealed a sensitivity of 100% in diagnosing insulinoma, demonstrating that CT and EUS should be considered as joint modalities.41
EUS is an especially powerful diagnostic tool when the size of pNENs is < 20 mm. CT, which is generally the first imaging modality obtained in patients with suspected pNENs, failed to detect pancreatic lesions in > 68% of cases when the size of the tumor was less than 10 mm, and > 15% of cases when the size of the tumor was less than 20 mm.42 In contrast, EUS maintained a high sensitivity of 82% and specificity of 92% in detecting small-size (2-5 mm) pNENs that were previously undetected by the CT.43
Other features of EUS are fine needle aspiration (FNA) and fine needle biopsy (FNB), which permit non-invasive extraction of pancreatic tissues and facilitate grading of pNENs through the evaluation of the Ki-67 index.44 FNA obtains samples for cytologic evaluation, and FNB obtains true tissue cores for histologic evaluation. A recent systemic review and meta-analysis on 864 patients revealed that the Ki-67 index of EUS-FNA extracted tissue and surgically biopsied tissues matched 80.3%, proving that grading from EUS-FNA extracted pancreatic tissues is dependable.45 Interestingly, one retrospective study showed that EUS-FNB biopsies, when compared with EUS-FNA samples, had a higher Ki-67 index correlation with surgically biopsied core pancreatic tissues. In the same study, a significantly higher Ki-67 index feasibility was witnessed with EUS-FNB over EUS-FNA when the size of the pNENs was less than 20mm (96.1% vs. 88.2%).46 This study suggests that EUS-FNB should be the standard of care for sampling and grading pNENs. Contrast-enhanced EUS is a novel technique useful in localizing focal pNENs by observing vascular flow in real-time. pNENs exhibit high vascularity when compared with normal pancreatic tissues on contrast-enhanced EUS.47 One study revealed that the overall sensitivity and specificity of contrast-enhanced EUS in detecting pNENs were 78.9% and 98.7%, respectively, which has similar diagnostic accuracy to CT scans.48 Moreover, contrast-enhanced EUS can generate time-intensity curves (TIC), which help differentiate pNENs from other pancreatic lesions at the endoscopic level and in real-time. In one clinical trial, an investigator successfully differentiated pNENs from other pancreatic lesions, such as chronic pancreatitis or adenocarcinoma, for 20/22 cases (91%) using the TIC analysis.49
Cross-sectional imaging studies in diagnosing pNENs
CT scans are used to establish the primary location and metastatic extension in most patients with pNENs. However, the detection rate of CT scans in diagnosing pNENs is suboptimal, with a sensitivity and specificity of 73% and 96%, respectively.50 In recent years, somatostatin receptor positron emission tomography/computed tomography with gallium-68 radiolabeled peptides (68Ga-SSR-PET/ CT) has emerged as a new method in diagnosing GEP-NENs. Neuroendocrine tumors distinctively express somatostatin receptors, and gallium-68 radiolabeled peptides target these receptors to enhance the detection rate of PET/CT.51 One study revealed that the sensitivity and specificity of 68GaSSR-PET/CT in localizing neuroendocrine tumors were 93% and 96%, respectively, outperforming CT scans.52,53 A recent meta-analysis by Bauckneht et al. revealed a reduced sensitivity (79.6%) of 68GASSR-PET/CT in diagnosing neuroendocrine tumors when the study focused on the pNENs, likely due to fewer somatostatin receptors in pNENs compared to carcinoid tumors in the gastrointestinal tract.54 Assessing the extent of metastasis is essential for a comprehensive diagnosis as it can drastically influence the management of the pNENs.51 In one systemic review and meta-analysis, 68Ga-SSRPET/CT and whole-body MRI revealed high overall diagnostic accuracy in detecting metastatic disease, with 92% and 91% respectively. The sensitivity between the two imaging modalities varied depending on which organ harbored metastatic disease. 68Ga-SSR-PET/CT was more sensitive for metastatic lesions in lymph nodes (100% vs. 73%), but whole-body MRI was more sensitive for metastatic lesions in the liver (99% vs. 92%) and bone (96% vs. 82%).55 This study suggests that 68Ga-SSR-PET/CT and whole-body MRI should be considered as joint modalities to minimize falsenegative tests in diagnosing neuroendocrine tumors and metastatic diseases.
Treatment of pNENs
The management of pNENs is multidisciplinary, which involves octreotide (somatostatin analogs), sunitinib (tyrosine kinase inhibitor), everolimus (an mTor inhibitor), peptide receptor radionuclide therapy, and chemotherapy depending on grading and extent of metastatic disease at the time of diagnosis.56 Surgical resection remains the only curative treatment for pNENs, although the relapse rate is high.57 Patients with pNENs who underwent surgical resection experienced a superior survival rate compared to those who did not (114 months vs. 35 months).58 Therefore, functional pNENs with tumor size > 20 mm are generally recommended for surgical resection. Non-functional pNENs with tumor size < 20 mm are generally recommended for surveillance due to their slow-growing natures but can be removed if the patient does not want to undergo primary surveillance. A systemic review and meta-analysis of 344 patients with small, nonfunctional pNENs reported that 22% of patients experienced an increase in tumor size during surveillance, but only 12% of patients ultimately needed surgical resection.59 pNENs can develop hepatic metastasis for up to 64.3-77% of cases.60,61 Among patients with pNENs and hepatic metastases, surgical resection of liver lesions can significantly increase survival rates and alleviate hormonal symptoms, although this practice is not performed at all centers. Studies demonstrated that the odds ratio for 5-year survival for pNENs patients who underwent resection of liver metastases, compared to those who did not, was 6.134.62 Also, up to 95% of patients experienced symptomatic relief after the surgery.63
In recent years, EUS-guided radiofrequency and ethanol ablation have emerged as novel techniques for the treatment of patients with pNENs.64 In one systematic review, the clinical success rates for EUS-radiofrequency and EUS-ethanol ablation were 85.2% and 82.2%, respectively. This study defined clinical success as symptomatic relief in patients with functional pNENs and tumor size reduction in patients with non-functional pNENs.65 The adverse event rates of EUS-radiofrequency and EUS-ethanol ablation were 32.2% and 21.2%, respectively; the common adverse events included abdominal pain (7.6%), acute pancreatitis (5.7%), and pancreatic fluid collections (3.2%).66 The morbidity of EUS-guided ablative treatment, compared to the morbidity of surgery, was considered mild.
Furthermore, there was no associated mortality rate with EUSguided ablative therapy.67,68 For patients who are contraindicated for surgery (due to co-morbidities or other reasons), EUS-guided ablation may be an appropriate and safe alternative management for pNENs.
Functional neuroendocrine neoplasms commonly arise in the pancreas or GI tract and manifest with unique clinical features depending on which hormones are oversecreted. The symptoms can present as mild to life-threatening depending on the severity; therefore, physicians need to be aware of the clinical characteristics of each type of functional neuroendocrine neoplasm and understand the diagnostic criteria. Once the diagnosis of functional neuroendocrine neoplasms is confirmed, the goal is to alleviate hormonal symptoms and delay neoplasm growth through multidisciplinary management, including somatostatin analogs, peptide receptor radionuclide therapy, and chemotherapy. Surgical resection is potentially a curable treatment option that prolongs overall survival. Patients who are suboptimal candidates for surgical resection may be recommended for EUS-guided ablative therapies as an alternative option.
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