FRONTIERS IN ENDOSCOPY, SERIES #84

Pancreatic Neuroendocrine Tumors : Diagnosis and Management with an Emphasis on Endoscopy

November 2022 • Volume XLVI, Issue 11
Sung Kim,Douglas G. Adler

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INTRODUCTION

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.

Insulinoma

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

Gastrinoma

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

VIPoma

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

Glucagonoma

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

Somatostatinoma

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

Carcinoid syndrome

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.

CONCLUSION

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.

References

  1. Vortmeyer AO, Huang S, Lubensky I, Zhuang Z. Non-islet origin of pancreatic islet cell tumors. J Clin Endocrinol Metab. 2004 Apr;89(4):1934-8. doi: 10.1210/jc.2003031575. PMID: 15070966.
  2. Cives M, Strosberg JR. Gastroenteropancreatic Neuroendocrine Tumors. CA Cancer J Clin. 2018 Nov;68(6):471-487. doi: 10.3322/caac.21493. Epub 2018 Oct 8. PMID: 30295930.
  3. Exarchou K, Howes N, Pritchard DM. Systematic review: management of localised low-grade upper gastrointestinal neuroendocrine tumours. Aliment Pharmacol Ther. 2020 Jun;51(12):1247-1267. doi: 10.1111/apt.15765. Epub 2020 May 11. PMID: 32390152.
  4. Hallet J, Law CH, Cukier M, Saskin R, Liu N, Singh S. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer. 2015 Feb 15;121(4):58997. doi: 10.1002/cncr.29099. Epub 2014 Oct 13. PMID: 25312765.
  5. Dobrindt EM, Mogl M, Goretzki PE, Pratschke J, Dukaczewska AK. Insulinoma in pregnancy (a case presentation and systematic review of the literature). Rare Tumors. 2021 Feb 7;13:2036361320986647. doi: 10.1177/2036361320986647. PMID: 33613925; PMCID: PMC7874339.
  6. Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service FJ; Endocrine Society. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009 Mar;94(3):709-28. doi: 10.1210/jc.2008-1410. Epub 2008 Dec 16. PMID: 19088155.
  7. Vezzosi D, Bennet A, Fauvel J, Caron P. Insulin, C-peptide and proinsulin for the biochemical diagnosis of hypoglycaemia related to endogenous hyperinsulinism. Eur J Endocrinol. 2007 Jul;157(1):75-83. doi: 10.1530/EJE-070109. Erratum in: Eur J Endocrinol. 2007 Nov;157(5):693. PMID: 17609405.
  8. Wilcox CM, Seay T, Arcury JT, Mohnen J, Hirschowitz BI. Zollinger-Ellison syndrome: presentation, response to therapy, and outcome. Dig Liver Dis. 2011 Jun;43(6):43943. doi: 10.1016/j.dld.2010.11.007. Epub 2010 Dec 30. PMID: 21193359.
  9. Rossi RE, Elvevi A, Citterio D, Coppa J, Invernizzi P, Mazzaferro V, Massironi S. Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies. World J Gastroenterol. 2021 Sep 21;27(35):5890-5907. doi: 10.3748/wjg.v27.i35.5890. PMID: 34629807; PMCID: PMC8475006.
  10. Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT. Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Medicine (Baltimore). 2006 Nov;85(6):295330. doi: 10.1097/01.md.0000236956.74128.76. PMID: 17108778.
  11. Roy PK, Venzon DJ, Feigenbaum KM, Koviack PD, Bashir S, Ojeaburu JV, Gibril F, Jensen RT. Gastric secretion in Zollinger-Ellison syndrome. Correlation with clinical expression, tumor extent and role in diagnosis–a prospective NIH study of 235 patients and a review of 984 cases in the literature. Medicine (Baltimore). 2001 May;80(3):189222. doi: 10.1097/00005792-200105000-00005. PMID: 11388095.
  12. Berna MJ, Hoffmann KM, Long SH, Serrano J, Gibril F, Jensen RT. Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features. Medicine (Baltimore). 2006 Nov;85(6):331-364. doi: 10.1097/MD.0b013e31802b518c. PMID: 17108779.
  13. Metz DC, Starr JA. A retrospective study of the usefulness of acid secretory testing. Aliment Pharmacol Ther. 2000 Jan;14(1):103-11. doi: 10.1046/j.1365-2036.2000.00676.x. PMID: 10632653.
  14. Schizas D, Mastoraki A, Bagias G, Patras R, Moris D, Lazaridis II, Arkadopoulos N, Felekouras E. Clinicopathological data and treatment modalities for pancreatic vipomas: a systematic review. J BUON. 2019 Mar-Apr;24(2):415-423. PMID: 31127985.
  15. Una Cidon E. Vasoactive intestinal peptide secreting tumour: An overview. World J Gastrointest Oncol. 2022 Apr 15;14(4):808-819. doi: 10.4251/wjgo.v14.i4.808. PMID: 35582098; PMCID: PMC9048535.
  16. Guilmette JM, Nosé V. Neoplasms of the Neuroendocrine Pancreas: An Update in the Classification, Definition, and Molecular Genetic Advances. Adv Anat Pathol. 2019
  17. Sandru F, Carsote M, Albu SE, Valea A, Petca A, Dumitrascu MC. Glucagonoma: From skin lesions to the neuroendocrine component (Review). Exp Ther Med. 2020 Oct;20(4):33893393. doi: 10.3892/etm.2020.8966. Epub 2020 Jul 3. PMID: 32905095; PMCID: PMC7465236.
  18. John AM, Schwartz RA. Glucagonoma syndrome: a review and update on treatment. J Eur Acad Dermatol Venereol. 2016 Dec;30(12):2016-2022. doi: 10.1111/jdv.13752. Epub 2016 Jul 16. PMID: 27422767.
  19. Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 2012 Dec;26(6):737-53. doi: 10.1016/j.bpg.2012.12.003. PMID: 23582916; PMCID: PMC3627221.
  20. Parbhu SK, Adler DG. Pancreatic neuroendocrine tumors: contemporary diagnosis and management. Hosp Pract (1995). 2016 Aug;44(3):109-19. doi: 10.1080/21548331.2016.1210474. Epub 2016 Jul 18. PMID: 27404266.
  21. Sandru F, Carsote M, Valea A, Albu SE, Petca RC, Dumitrascu MC. Somatostatinoma: Beyond neurofibromatosis type 1 (Review). Exp Ther Med. 2020 Oct;20(4):33833388. doi: 10.3892/etm.2020.8965. Epub 2020 Jul 3. PMID: 32905002; PMCID: PMC7465002.
  22. Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 2012 Dec;26(6):737-53. doi: 10.1016/j.bpg.2012.12.003. PMID: 23582916; PMCID: PMC3627221.
  23. Nesi G, Marcucci T, Rubio CA, Brandi ML, Tonelli F. Somatostatinoma: clinico-pathological features of three cases and literature reviewed. J Gastroenterol Hepatol. 2008 Apr;23(4):521-6. doi: 10.1111/j.1440-1746.2007.05053.x. Epub 2007 Jul 20. PMID: 17645474.
  24. Rubin de Celis Ferrari AC, Glasberg J, Riechelmann RP. Carcinoid syndrome: update on the pathophysiology and treatment. Clinics (Sao Paulo). 2018 Aug 20;73(suppl 1):e490s. doi: 10.6061/clinics/2018/e490s. PMID: 30133565; PMCID: PMC6096975.
  25. Tran CG, Sherman SK, Chandrasekharan C, Howe JR. Surgical Management of Neuroendocrine Tumor Liver Metastases. Surg Oncol Clin N Am. 2021 Jan;30(1):39-55. doi: 10.1016/j.soc.2020.08.001. Epub 2020 Oct 20. PMID: 33220808; PMCID: PMC7739028.
  26. Ahmed M. Gastrointestinal neuroendocrine tumors in 2020. World J Gastrointest Oncol. 2020 Aug 15;12(8):791-807. doi: 10.4251/wjgo.v12.i8.791. PMID: 32879660; PMCID: PMC7443843.
  27. Halperin DM, Shen C, Dasari A, Xu Y, Chu Y, Zhou S, Shih YT, Yao JC. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. Lancet Oncol. 2017 Apr;18(4):525-534. doi: 10.1016/S14702045(17)30110-9. Epub 2017 Feb 24. PMID: 28238592; PMCID: PMC6066284.
  28. Gade AK, Olariu E, Douthit NT. Carcinoid Syndrome: A Review. Cureus. 2020 Mar 5;12(3):e7186. doi: 10.7759/ cureus.7186. PMID: 32257725; PMCID: PMC7124884.
  29. Clement D, Ramage J, Srirajaskanthan R. Update on Pathophysiology, Treatment, and Complications of Carcinoid Syndrome. J Oncol. 2020 Jan 21;2020:8341426. doi: 10.1155/2020/8341426. PMID: 32322270; PMCID: PMC7160731.
  30. Maroun J, Kocha W, Kvols L, Bjarnason G, Chen E, Germond C, Hanna S, Poitras P, Rayson D, Reid R, Rivera J, Roy A, Shah A, Sideris L, Siu L, Wong R. Guidelines for the diagnosis and management of carcinoid tumours. Part 1: the gastrointestinal tract. A statement from a Canadian National Carcinoid Expert Group. Curr Oncol. 2006 Apr;13(2):67-76. PMID: 17576444; PMCID: PMC1891174.
  31. Feldman JM, O’Dorisio TM. Role of neuropeptides and serotonin in the diagnosis of carcinoid tumors. Am J Med. 1986 Dec 22;81(6B):41-8. doi: 10.1016/0002-9343(86)90583-8. PMID: 2432780.
  32. Marini F, Giusti F, Tonelli F, Brandi ML. Pancreatic Neuroendocrine Neoplasms in Multiple Endocrine Neoplasia Type 1. Int J Mol Sci. 2021 Apr 14;22(8):4041. doi: 10.3390/ ijms22084041. PMID: 33919851; PMCID: PMC8070788.
  33. Jensen RT, Norton JA. Treatment of Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1: Some
    Clarity But Continued Controversy. Pancreas. 2017 May/ Jun;46(5):589-594. doi: 10.1097/MPA.0000000000000825. PMID: 28426491; PMCID: PMC5407310.
  34. Akerström G, Hessman O, Hellman P, Skogseid B. Pancreatic tumours as part of the MEN-1 syndrome. Best Pract Res Clin Gastroenterol. 2005 Oct;19(5):819-30. doi: 10.1016/j. bpg.2005.05.006. PMID: 16253903.
  35. Qiu W, Christakis I, Silva A, Bassett RL Jr, Cao L, Meng QH, Gardner Grubbs E, Zhao H, Yao JC, Lee JE, Perrier ND. Utility of chromogranin A, pancreatic polypeptide, glucagon and gastrin in the diagnosis and follow-up of pancreatic neuroendocrine tumours in multiple endocrine neoplasia type 1 patients. Clin Endocrinol (Oxf). 2016 Sep;85(3):400-7. doi: 10.1111/cen.13119. Epub 2016 Jun 30. PMID: 27256431; PMCID: PMC4988913.
  36. van Asselt SJ, Brouwers AH, van Dullemen HM, van der Jagt EJ, Bongaerts AH, Kema IP, Koopmans KP, Valk GD, Timmers HJ, de Herder WW, Feelders RA, Fockens P, Sluiter WJ, de Vries EG, Links TP. EUS is superior for detection of pancreatic lesions compared with standard imaging in patients with multiple endocrine neoplasia type 1. Gastrointest Endosc. 2015 Jan;81(1):159-167.e2. doi:
    10.1016/j.gie.2014.09.037. PMID: 25527055.
  37. Rustagi T, Farrell JJ. Endoscopic diagnosis and treatment of pancreatic neuroendocrine tumors. J Clin Gastroenterol. 2014 Nov-Dec;48(10):837-44. doi: 10.1097/ MCG.0000000000000152. PMID: 24828360.
  38. Wang H, Ba Y, Xing Q, Du JL. Diagnostic value of endoscopic ultrasound for insulinoma localization: A systematic review and meta-analysis. PLoS One. 2018 Oct 23;13(10):e0206099. doi: 10.1371/journal.pone.0206099. PMID: 30352083; PMCID: PMC6198953.
  39. Puli SR, Kalva N, Bechtold ML, Pamulaparthy SR, Cashman MD, Estes NC, Pearl RH, Volmar FH, Dillon S, Shekleton MF, Forcione D. Diagnostic accuracy of endoscopic ultrasound in pancreatic neuroendocrine tumors: a systematic review and meta analysis. World J Gastroenterol. 2013 Jun 21;19(23):3678-84. doi: 10.3748/wjg.v19.i23.3678. PMID: 23801872; PMCID: PMC3691045.
  40. Chiti G, Grazzini G, Cozzi D, Danti G, Matteuzzi B, Granata V, Pradella S, Recchia L, Brunese L, Miele V. Imaging of Pancreatic Neuroendocrine Neoplasms. Int J Environ Res Public Health. 2021 Aug 24;18(17):8895. doi: 10.3390/ ijerph18178895. PMID: 34501485; PMCID: PMC8430610.
  41. Gouya H, Vignaux O, Augui J, Dousset B, Palazzo L,
    Louvel A, Chaussade S, Legmann P. CT, endoscopic sonography, and a combined protocol for preoperative evaluation of pancreatic insulinomas. AJR Am J Roentgenol. 2003 Oct;181(4):987-92. doi: 10.2214/ajr.181.4.1810987. PMID: 14500214.
  42. Manta R, Nardi E, Pagano N, Ricci C, Sica M, Castellani D, Bertani H, Piccoli M, Mullineris B, Tringali A, Marini F, Germani U, Villanacci V, Casadei R, Mutignani M, Conigliaro R, Bassotti G, Zullo A. Pre-operative Diagnosis of Pancreatic Neuroendocrine Tumors with Endoscopic Ultrasonography and Computed Tomography in a Large Series. J Gastrointestin Liver Dis. 2016 Sep;25(3):317-21.
    doi: 10.15403/jgld.2014.1121.253.ned. PMID: 27689195.
  43. Rösch T, Lightdale CJ, Botet JF, Boyce GA, Sivak MV Jr, Yasuda K, Heyder N, Palazzo L, Dancygier H, Schusdziarra V, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. 1992 Jun 25;326(26):1721-6. doi: 10.1056/NEJM199206253262601. PMID: 1317506.
  44. Li J, Lin JP, Shi LH, Wang WJ, Li AQ, Si JM, Chen SJ. How reliable is the Ki-67 cytological index in grading pancreatic neuroendocrine tumors? A meta-analysis. J Dig Dis. 2016 Feb;17(2):95-103. doi: 10.1111/1751-2980.12310. PMID: 26713749.
  45. Tacelli M, Bina N, Crinò SF, Facciorusso A, Celsa C, Sbrozzi Vanni A, Fantin A, Antonini F, Falconi M, Monica F, Capurso G, Arcidiacono PG, Barresi L; Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO).
    RELIABILITY OF PREOPERATIVE PANCREATIC NEUROENDOCRINE TUMORS GRADING ON ENDOSCOPIC ULTRASOUND SPECIMENS: A SYSTEMATIC REVIEW WITH META-ANALYSIS OF AGGREGATE AND INDIVIDUAL DATA. Gastrointest
    Endosc. 2022 Jul 18:S0016-5107(22)01831-4. doi: 10.1016/j.
    gie.2022.07.014. Epub ahead of print. PMID: 35863518.
  46. Crinò SF, Ammendola S, Meneghetti A, Bernardoni L, Conti Bellocchi MC, Gabbrielli A, Landoni L, Paiella S, Pin F, Parisi A, Mastrosimini MG, Amodio A, Frulloni L, Facciorusso A, Larghi A, Manfrin E. Comparison between EUS-guided fine-needle aspiration cytology and EUSguided fine-needle biopsy histology for the evaluation of pancreatic neuroendocrine tumors. Pancreatology. 2021 Mar;21(2):443-450. doi: 10.1016/j.pan.2020.12.015. Epub 2020 Dec 24. PMID: 33390343.
  47. Ishikawa T, Itoh A, Kawashima H, Ohno E, Matsubara H, Itoh Y, Nakamura Y, Nakamura M, Miyahara R, Hayashi K, Ishigami M, Katano Y, Ohmiya N, Goto H, Hirooka Y. Usefulness of EUS combined with contrast-enhancement in the differential diagnosis of malignant versus benign and preoperative localization of pancreatic endocrine tumors.
    Gastrointest Endosc. 2010 May;71(6):951-9. doi: 10.1016/j. gie.2009.12.023. PMID: 20438884.
  48. Kitano M, Kudo M, Yamao K, Takagi T, Sakamoto H, Komaki T, Kamata K, Imai H, Chiba Y, Okada M, Murakami T, Takeyama Y. Characterization of small solid tumors in the pancreas: the value of contrast-enhanced harmonic endoscopic ultrasonography. Am J Gastroenterol. 2012 Feb;107(2):303-10. doi: 10.1038/ajg.2011.354. Epub 2011 Oct 18. PMID: 22008892.
  49. Buxbaum J, Ko C, Varghese N, Lee A, Sahakian A, King K, Serna J, Lee H, Tchelepi H, Van Dam J, Duddalwar V. Qualitative and Quantitative Contrast-enhanced Endoscopic Ultrasound Improves Evaluation of Focal Pancreatic Lesions. Clin Gastroenterol Hepatol. 2020 Apr;18(4):917925.e4. doi: 10.1016/j.cgh.2019.08.054. Epub 2019 Sep 6. PMID: 31499247.
  50. Sundin A, Vullierme MP, Kaltsas G, Plöckinger U; Mallorca Consensus Conference participants; European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: radiological examinations. Neuroendocrinology. 2009;90(2):167-83. doi: 10.1159/000184855. Epub 2009 Aug 28. PMID: 19077417.
  51. Ghobrial SN, Menda Y, Zamba GK, Mott SL, GaimariVarner K, Dick D, Dillon J, Howe JR, Graham M, Sunderland J, Bellizzi A, O’Dorisio TM, O’Dorisio MS. Prospective Analysis of the Impact of 68Ga-DOTATOC Positron Emission Tomography-Computerized Axial Tomography on Management of Pancreatic and Small Bowel Neuroendocrine
    Tumors. Pancreas. 2020 Sep;49(8):1033-1036. doi: 10.1097/ MPA.0000000000001625. PMID: 32769854; PMCID: PMC7447173.
  52. Geijer H, Breimer LH. Somatostatin receptor PET/CT in neuroendocrine tumours: update on systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2013 Oct;40(11):1770-80. doi: 10.1007/s00259-013-2482-z. Epub 2013 Jul 20. PMID: 23873003.
  53. Deppen SA, Blume J, Bobbey AJ, Shah C, Graham MM, Lee P, Delbeke D, Walker RC. 68Ga-DOTATATE Compared with 111In-DTPA-Octreotide and Conventional Imaging for Pulmonary and Gastroenteropancreatic
    Neuroendocrine Tumors: A Systematic Review and MetaAnalysis. J Nucl Med. 2016 Jun;57(6):872-8. doi: 10.2967/ jnumed.115.165803. Epub 2016 Jan 14. PMID: 26769864; PMCID: PMC5362941.
  54. Bauckneht M, Albano D, Annunziata S, Santo G, Guglielmo P, Frantellizzi V, Branca A, Ferrari C, Vento A, Mirabile A, Nappi AG, Evangelista L, Alongi P, Laudicella R. Somatostatin Receptor PET/CT Imaging for the Detection and Staging of Pancreatic NET: A Systematic Review and Meta-Analysis. Diagnostics (Basel). 2020 Aug 16;10(8):598. doi: 10.3390/diagnostics10080598. PMID: 32824388; PMCID: PMC7459584.
  55. Schraml C, Schwenzer NF, Sperling O, Aschoff P, Lichy MP, Müller M, Brendle C, Werner MK, Claussen CD, Pfannenberg C. Staging of neuroendocrine tumours: comparison of [68Ga]DOTATOC multiphase PET/CT and wholebody MRI. Cancer Imaging. 2013 Mar 5;13(1):63-72. doi: 10.1102/1470-7330.2013.0007. PMID: 23466785; PMCID: PMC3589947.
  56. Scott AT, Howe JR. Evaluation and Management of Neuroendocrine Tumors of the Pancreas. Surg Clin North Am. 2019 Aug;99(4):793-814. doi: 10.1016/j. suc.2019.04.014. Epub 2019 May 27. PMID: 31255207; PMCID: PMC6601637.
  57. Nigri G, Petrucciani N, Debs T, Mangogna LM, Crovetto A, Moschetta G, Persechino R, Aurello P, Ramacciato G. Treatment options for PNET liver metastases: a systematic review. World J Surg Oncol. 2018 Jul 14;16(1):142. doi: 10.1186/s12957-018-1446-y. PMID: 30007406; PMCID: PMC6046097.
  58. Hill JS, McPhee JT, McDade TP, Zhou Z, Sullivan ME, Whalen GF, Tseng JF. Pancreatic neuroendocrine tumors: the impact of surgical resection on survival. Cancer. 2009 Feb 15;115(4):741-51. doi: 10.1002/cncr.24065. PMID: 19130464.
  59. Sallinen V, Le Large TY, Galeev S, Kovalenko Z, Tieftrunk E, Araujo R, Ceyhan GO, Gaujoux S. Surveillance strategy for small asymptomatic non-functional pancreatic neuroendocrine tumors – a systematic review and meta-analysis.
    HPB (Oxford). 2017 Apr;19(4):310-320. doi: 10.1016/j.
    hpb.2016.12.010. Epub 2017 Feb 21. PMID: 28254159.
  60. Pavel M, Baudin E, Couvelard A, Krenning E, Öberg K, Steinmüller T, Anlauf M, Wiedenmann B, Salazar R; Barcelona Consensus Conference participants. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2012;95(2):157-76. doi: 10.1159/000335597. Epub 2012 Feb 15. PMID: 22262022.
  61. Panzuto F, Nasoni S, Falconi M, Corleto VD, Capurso G, Cassetta S, Di Fonzo M, Tornatore V, Milione M, Angeletti S, Cattaruzza MS, Ziparo V, Bordi C, Pederzoli P, Delle Fave G. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer. 2005 Dec;12(4):1083-92. doi: 10.1677/erc.1.01017. PMID: 16322345.
  62. Yuan CH, Wang J, Xiu DR, Tao M, Ma ZL, Jiang B, Li ZF, Li L, Wang L, Wang H, Zhang TL. Meta-analysis of Liver Resection Versus Nonsurgical Treatments for Pancreatic Neuroendocrine Tumors with Liver Metastases. Ann Surg Oncol. 2016 Jan;23(1):244-9. doi: 10.1245/s10434-0154654-5. Epub 2015 Jun 26. PMID: 26111625.
  63. Saxena A, Chua TC, Perera M, Chu F, Morris DL. Surgical resection of hepatic metastases from neuroendocrine neoplasms: a systematic review. Surg Oncol. 2012 Sep;21(3):e131-41. doi: 10.1016/j.suronc.2012.05.001. Epub 2012 May 30. PMID: 22658833.
  64. Dhaliwal A, Kolli S, Dhindsa BS, Choa J, Mashiana HS, Ramai D, Chandan S, Bhogal N, Sayles H, Bhat I, Singh S, Adler DG. Efficacy of EUS-RFA in pancreatic tumors: Is it ready for prime time? A systematic review and meta-analysis. Endosc Int Open. 2020 Oct;8(10):E1243-E1251. doi: 10.1055/a-1221-5012. Epub 2020 Sep 22. PMID: 33015325; PMCID: PMC7508651.
  65. Garg R, Mohammed A, Singh A, Harnegie MP, Rustagi T, Stevens T, Chahal P. EUS-guided radiofrequency and ethanol ablation for pancreatic neuroendocrine tumors: A systematic review and meta-analysis. Endosc Ultrasound. 2022 May-Jun;11(3):170-185. doi: 10.4103/EUS-D-21-00044. PMID: 35313416; PMCID: PMC9258014.
  66. Zhang L, Tan S, Huang S, Zhong C, Lü M, Peng Y, Tang X. The safety and efficacy of endoscopic ultrasound-guided ablation therapy for solid pancreatic tumors: a systematic review. Scand J Gastroenterol. 2020 Sep;55(9):1121-1131. doi: 10.1080/00365521.2020.1797870. Epub 2020 Jul 30. PMID: 32730715.
  67. Jilesen AP, van Eijck CH, in’t Hof KH, van Dieren S, Gouma DJ, van Dijkum EJ. Postoperative Complications, In-Hospital Mortality and 5-Year Survival After Surgical Resection for Patients with a Pancreatic Neuroendocrine Tumor: A Systematic Review. World J Surg. 2016 Mar;40(3):72948. doi: 10.1007/s00268-015-3328-6. PMID: 26661846; PMCID: PMC4746219.
  68. Spadaccini M, Di Leo M, Iannone A, von den Hoff D, Fugazza A, Galtieri PA, Pellegatta G, Maselli R, Anderloni A, Colombo M, Siersema PD, Carrara S, Repici A. Endoscopic ultrasound-guided ablation of solid pancreatic lesions: A systematic review of early outcomes with pooled analysis. World J Gastrointest Oncol. 2022 Feb 15;14(2):533-542. doi: 10.4251/wjgo.v14.i2.533. PMID: 35317325; PMCID: PMC8918998.

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