Copyright ©The Author(s) 2021.
World J Gastrointest Surg. Mar 27, 2021; 13(3): 231-255
Published online Mar 27, 2021. doi: 10.4240/wjgs.v13.i3.231
Table 1 The enteroendocrine cells, secretory products, and their physiological functions[3,4]
EECsAmine/peptide hormonesPhysiological functions of the hormones
ECsSerotonin Regulation of appetite and gut motility
ECLsHistamine Regulation of gastric acidity
L-cellsGLP-1, GLP-2, peptide YY, glicentin and oxyntomodulinRegulation of appetite, gut motility, and insulin kinetics
K-cells GIPInsulin kinetics
D-cellsSomatostatin Regulation of gastric acidity, and insulin secretion
A-cellsGhrelin and nesfatin-1Regulation of appetite and growth hormone
G-cellsGastrin Regulation of gastric acidity
P-cellsLeptin Regulation of appetite
S-cells Secretin Regulation of gastric acidity
I-cellsCCKModulation of appetite, gall bladder motility, and bile release
M-cells Motilin Regulation of gut motility
N-cellsNeurotensin Regulation of gut motility
Table 2 Clinical features, incidence, cancer risk, multiple endocrine neoplasia 1 association, and treatment of various functional pancreatic neuroendocrine neoplasms[29-32]
Name of f-pNENs Proportion of f-NENsIncidence million/year Biomarker Location of the NENsMalignancy (proportion)MEN1 associationSymptoms, signs, and laboratory testing featuresSurgery: Indication and procedure
Insulinoma 30%-40%1-32 InsulinPancreas: > 99%< 10%4%-5%Hypoglycemia symptoms Whipple’s triad, weight gain. ↑Insulin, ↑proinsulin levels. ↑C-peptide on 72 h fast test Always. Parenchymal sparing pancreatectomy
Gastrinoma ZES16%-30%0.5-21.5 GastrinDuodenum: 70%. Pancreas: 25%. Others: 5%60%-90%20%-25%Complicated or difficult to treat PUD, GORD, profuse diarrhoea. ↑Gastrin levels, ↓Gastric pH. Secretin stimulation testYes, except < 2 cm MEN1/ZES. Standard pancreatectomy
VIPoma or WDHA Verner-Morrison syndrome. Pancreatic cholera< 10%0.05-0.2VIPPancreas: 90% Neural, adrenal, preganglionic: 10% 40%-70%6%Profuse watery diarrhoea, hypokalaemia, metabolic acidosis, achlorhydria, and dehydration; ↑VIP levelsYes. Standard pancreatectomy
Glucagonoma< 10%0.01-0.1GlucagonPancreas: 100%50%-80%1%-20%Rash (necrolytic migratory erythema), weight loss, new onset diabetes mellitus and thromboembolic events. ↑Glucagon levelsYes. Standard pancreatectomy
Somatostatinoma< 5%Rare Somatostatin Pancreas 55% Duodenum-jejunum: 44%> 70%45%New onset diabetes, gallstones, weight loss, diarrhoea, steatorrhoea, ↑SomatostatinYes. Standard pancreatectomy
GRHomaRare Unknown GHRHPancreas: 30%, Lung 54%, Jejunum: 7%, and Others: 13%> 60%16%Acromegaly with/without peptic ulcer, wheeze, flushing, renal stone, ↑GHRH levelsYes. Standard pancreatectomy
ACTHomaRare Rare ACTHPancreas> 95%Rare Ectopic Cushing’s syndrome. 4%-16% of all ectopic CushingYes. Standard pancreatectomy
PTHrP-omaRare RarePTHrPPancreas84%RareRare cause of hypercalcemia. Pain abdomen: Liver metastasisYes. Standard pancreatectomy
Carcinoid syndrome arising from pNEN Rare RareSerotonin Tachykinin?Pancreas: < 1% of all carcinoid syndrome60%-88%RareFlushing, diarrhoea, broncho-spasm, carcinoid heart disease↑ urinary 5-HIAA levelsYes. Standard pancreatectomy
Table 3 World Health Organization grading of neuroendocrine neoplasms[79]
GradeTerminologyDifferentiationMitotic rateKi-67 index
LowNET, G1Well< 2< 3
IntermediateNET, G2Well2-203-20
HighNET, G3Well> 20> 20
HighNEC, small cell typePoor> 20> 20
HighNEC, large cell typePoor> 20> 20
VariableMiNENWell or PoorVariableVariable
Table 4 Tumor-node-metastasis staging of pancreatic neuroendocrine neoplasms based on the American Joint Committee on Cancer and the European Neuroendocrine Tumor Society (modified European Neuroendocrine Tumor Society staging)[80] and tumor-node-metastasis staging of the small intestinal neuroendocrine neoplasms based on American Joint Committee on Cancer[81]
TNM staging of pancreatic neuroendocrine tumoursTNM staging of small intestinal neuroendocrine tumours
T0No documented evidence of a primary tumour
T1Tumour limited to pancreas, ≤ 2 cmTumour invading lamina propria/submucosa, and size ≤ 1 cm
T2Tumour limited to pancreas, 2-4 cmTumour invading muscularis propria or size ≥ 1 cm
T3Tumour limited to pancreas, > 4 cm, or invading duodenum/bile ductTumour invading sub-serosa (without penetrating the serosa)
T4Tumour invades adjacent structuresTumour invading peritoneum/other organs/adjacent structures
N0Absence of regional lymph node metastasisAbsence of regional lymph node metastasis
N1Presence of regional lymph node metastasisPresence of regional lymph node metastasis in < 12 nodes
N2Absence of distant metastasisPresence of large mesenteric masses (> 2 cm) or ≥ 12 nodes
M0Presence of distant metastasisAbsence of distant metastasis
M1Metastasis confined to hepatic tissuePresence of distant metastasis
M1aMetastasis in at least one extrahepatic tissueMetastasis confined to hepatic tissue
M1bBoth hepatic and extrahepatic metastatic involvementMetastasis in at least one extrahepatic tissue
M1cTumour limited to pancreas, ≤ 2 cmBoth hepatic and extrahepatic metastatic involvement
Stage IAStage IBStage IIAStage IIBStage IIIStage IVStage ISTAGE IIAStage IIBStage IIIAStage IIIBStage IV
Table 5 Endoscopic and surgical management of gastroenteropancreatic-neuroendocrine neoplasms based on the location, grade, and size of the tumor[112,113]
Site of NENsType of NENs Laboratory tests required Abnormal results expected SurveillanceEndoscopy (EMR/ESD)Operation
Gastric NENType 1 and type 2CgA and gastrinRaised CgA and gastrin< 1 cm1-2 cm: EMR or ESD> 2 cm; local wedge resection
Type 3 and type 4CgA and gastrinRaised CgA, normal gastrin-< 1 cm G1/2 type 3 > 1 cm; treat as adenocarcinoma
Duodenal NENs1st part duodenumCgA, gastrin, PP, 5-HIAARaised CgA, consider MEN1-< 1 cm G1 (EMR, not ESD; ESD increase perforation)< 1 cm any other grade; > 1 cm any grade; gastrinoma and NEC any size
AmpullaryCgA, somatostatinConsider MEN1/NF1/VHL/TSC-< 2 cm G1: Papillectomy> 2 cm or < 2 cm with G2/3: Surgery
Jejunoileal NENs-CgA, 5-HIAA, NKARaised CgA, 5-HIAA and NKA--Preoperative SSAs, look for CaHD, peroperative palpation-multifocal
Appendiceal NENs-CgA, 5-HIAA, NKA, PPNot raised unless metastatic--< 2 cm: Appendectomy; > 2 cm: Right hemicolectomy
Colonic NENs-CgA, 5-HIAA, NKA, PPRaised CgA, 5-HIAA and NKA-< 1 cm for G1, lack of submucosa infiltration< 1 cm for G2/G3, muscle infiltrate or angioinvasion; > 1 cm any grade: Treat as adenocarcinoma with segmental colectomy and wide regional lymphadenectomy
Rectal NENs-CgA, PP, enteroglucagon, β-hCGRaised CgA, PP, β-hCG and enteroglucagon-< 1 cm G1/2 (EMR/ESD)1-2 cm G1/2, no nodal metastasis: Transanal resection; > 2 cm G1/2 with nodal spread, any size G3: Treat as adenocarcinoma
Pancreatic NENs Functional pNEN, Non-functional pNEN, pNEN with MEN1 and inherited conditionsCgA, insulin, gastrin, VIP, glucagon, somatostatin, glucose, calcium, PTH, PP, prolactin, MEN1 geneticsRaised CgA: Metastatic NENs Raised hormones: F-pNENs Raised calcium, prolactin, PTH: Consider MEN1 Sporadic or MEN1 related NF-pNENs asymptomatic and < 2 cm; MEN1 related ZES < 2 cmSporadic or MEN1 related asymptomatic NF-pNEN and < 2 cm; insulinoma (pNENs with very low cancer risk)NF-pNENs symptomatic or ≥ 2 cm; functional pNEN of any size except insulinoma. Open or robot assisted surgery. Robot assisted surgery: For precise reconstruction