Gastroenteropancreatic neuroendocrine neoplasms: A clinical snapshot

Table 1 The enteroendocrine cells, secretory products, and their physiological functions[3,4]

EECs	Amine/peptide hormones	Physiological functions of the hormones
ECs	Serotonin	Regulation of appetite and gut motility
ECLs	Histamine	Regulation of gastric acidity
L-cells	GLP-1, GLP-2, peptide YY, glicentin and oxyntomodulin	Regulation of appetite, gut motility, and insulin kinetics
K-cells	GIP	Insulin kinetics
D-cells	Somatostatin	Regulation of gastric acidity, and insulin secretion
A-cells	Ghrelin and nesfatin-1	Regulation of appetite and growth hormone
G-cells	Gastrin	Regulation of gastric acidity
P-cells	Leptin	Regulation of appetite
S-cells	Secretin	Regulation of gastric acidity
I-cells	CCK	Modulation of appetite, gall bladder motility, and bile release
M-cells	Motilin	Regulation of gut motility
N-cells	Neurotensin	Regulation of gut motility

CCK: Cholecystokinin; EECs: Enteroendocrine cells; ECs: Enterochromaffin cells; ECLs: Enterochromaffin-like cells; GLP: Glucagon-like peptide; GIP: Glucose-dependent insulinotropic polypeptide.

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-NENs	Incidence million/year	Biomarker	Location of the NENs	Malignancy (proportion)	MEN1 association	Symptoms, signs, and laboratory testing features	Surgery: Indication and procedure
Insulinoma	30%-40%	1-32	Insulin	Pancreas: > 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 ZES	16%-30%	0.5-21.5	Gastrin	Duodenum: 70%. Pancreas: 25%. Others: 5%	60%-90%	20%-25%	Complicated or difficult to treat PUD, GORD, profuse diarrhoea. ↑Gastrin levels, ↓Gastric pH. Secretin stimulation test	Yes, except < 2 cm MEN1/ZES. Standard pancreatectomy
VIPoma or WDHA Verner-Morrison syndrome. Pancreatic cholera	< 10%	0.05-0.2	VIP	Pancreas: 90% Neural, adrenal, preganglionic: 10%	40%-70%	6%	Profuse watery diarrhoea, hypokalaemia, metabolic acidosis, achlorhydria, and dehydration; ↑VIP levels	Yes. Standard pancreatectomy
Glucagonoma	< 10%	0.01-0.1	Glucagon	Pancreas: 100%	50%-80%	1%-20%	Rash (necrolytic migratory erythema), weight loss, new onset diabetes mellitus and thromboembolic events. ↑Glucagon levels	Yes. Standard pancreatectomy
Somatostatinoma	< 5%	Rare	Somatostatin	Pancreas 55% Duodenum-jejunum: 44%	> 70%	45%	New onset diabetes, gallstones, weight loss, diarrhoea, steatorrhoea, ↑Somatostatin	Yes. Standard pancreatectomy
GRHoma	Rare	Unknown	GHRH	Pancreas: 30%, Lung 54%, Jejunum: 7%, and Others: 13%	> 60%	16%	Acromegaly with/without peptic ulcer, wheeze, flushing, renal stone, ↑GHRH levels	Yes. Standard pancreatectomy
ACTHoma	Rare	Rare	ACTH	Pancreas	> 95%	Rare	Ectopic Cushing’s syndrome. 4%-16% of all ectopic Cushing	Yes. Standard pancreatectomy
PTHrP-oma	Rare	Rare	PTHrP	Pancreas	84%	Rare	Rare cause of hypercalcemia. Pain abdomen: Liver metastasis	Yes. Standard pancreatectomy
Carcinoid syndrome arising from pNEN	Rare	Rare	Serotonin Tachykinin?	Pancreas: < 1% of all carcinoid syndrome	60%-88%	Rare	Flushing, diarrhoea, broncho-spasm, carcinoid heart disease↑ urinary 5-HIAA levels	Yes. Standard pancreatectomy

NENs: Neuroendocrine neoplasms; pNENs: Pancreatic NENs; f-pNENs: Functional-pNENs; MEN1: Multiple endocrine neoplasia 1; 5-HIAA: 5-hydroxy indole acetic acid; ZES: Zollinger Ellison syndrome; PVD: Peripheral vascular disease; GORD: Gastro-oesophageal reflux disease; WDHA: Watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria; VIP: Vasoactive intestinal peptide; GHRH: Growth hormone releasing hormone; PTHrP: Parathyroid hormone-related peptide; GRHomas: GHRH secreting pNENs; ACTH: Gastrin, somatostatin, adrenocorticotropin.

Table 3 World Health Organization grading of neuroendocrine neoplasms[79]

Grade	Terminology	Differentiation	Mitotic rate	Ki-67 index
Low	NET, G1	Well	< 2	< 3
Intermediate	NET, G2	Well	2-20	3-20
High	NET, G3	Well	> 20	> 20
High	NEC, small cell type	Poor	> 20	> 20
High	NEC, large cell type	Poor	> 20	> 20
Variable	MiNEN	Well or Poor	Variable	Variable

NEC: Neuroendocrine carcinoma; NET: Neuroendocrine tumours; G1: Grade 1; G2: Grade 2; G3: Grade 3.

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 tumours					TNM staging of small intestinal neuroendocrine tumours
T0						No documented evidence of a primary tumour
T1	Tumour limited to pancreas, ≤ 2 cm					Tumour invading lamina propria/submucosa, and size ≤ 1 cm
T2	Tumour limited to pancreas, 2-4 cm					Tumour invading muscularis propria or size ≥ 1 cm
T3	Tumour limited to pancreas, > 4 cm, or invading duodenum/bile duct					Tumour invading sub-serosa (without penetrating the serosa)
T4	Tumour invades adjacent structures					Tumour invading peritoneum/other organs/adjacent structures
N0	Absence of regional lymph node metastasis					Absence of regional lymph node metastasis
N1	Presence of regional lymph node metastasis					Presence of regional lymph node metastasis in < 12 nodes
N2	Absence of distant metastasis					Presence of large mesenteric masses (> 2 cm) or ≥ 12 nodes
M0	Presence of distant metastasis					Absence of distant metastasis
M1	Metastasis confined to hepatic tissue					Presence of distant metastasis
M1a	Metastasis in at least one extrahepatic tissue					Metastasis confined to hepatic tissue
M1b	Both hepatic and extrahepatic metastatic involvement					Metastasis in at least one extrahepatic tissue
M1c	Tumour limited to pancreas, ≤ 2 cm					Both hepatic and extrahepatic metastatic involvement
Stage IA	Stage IB	Stage IIA	Stage IIB	Stage III	Stage IV	Stage I	STAGE IIA	Stage IIB	Stage IIIA	Stage IIIB	Stage IV
T1N0M0	T2N0M0	T3N0M0	T1-3N1M0	T4NanyM0	TanyNanyM1	T1N0M0	T2N0M0	T3N0M0	T4N0M0	TanyN0M0	TanyNanyM1

TNM: Tumor-node-metastasis.

Table 5 Endoscopic and surgical management of gastroenteropancreatic-neuroendocrine neoplasms based on the location, grade, and size of the tumor[112,113]

Site of NENs	Type of NENs	Laboratory tests required	Abnormal results expected	Surveillance	Endoscopy (EMR/ESD)	Operation
Gastric NEN	Type 1 and type 2	CgA and gastrin	Raised CgA and gastrin	< 1 cm	1-2 cm: EMR or ESD	> 2 cm; local wedge resection
	Type 3 and type 4	CgA and gastrin	Raised CgA, normal gastrin	-	< 1 cm G1/2 type 3	> 1 cm; treat as adenocarcinoma
Duodenal NENs	1st part duodenum	CgA, gastrin, PP, 5-HIAA	Raised 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
	Ampullary	CgA, somatostatin	Consider MEN1/NF1/VHL/TSC	-	< 2 cm G1: Papillectomy	> 2 cm or < 2 cm with G2/3: Surgery
Jejunoileal NENs	-	CgA, 5-HIAA, NKA	Raised CgA, 5-HIAA and NKA	-	-	Preoperative SSAs, look for CaHD, peroperative palpation-multifocal
Appendiceal NENs	-	CgA, 5-HIAA, NKA, PP	Not raised unless metastatic	-	-	< 2 cm: Appendectomy; > 2 cm: Right hemicolectomy
Colonic NENs	-	CgA, 5-HIAA, NKA, PP	Raised 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-hCG	Raised 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 conditions	CgA, insulin, gastrin, VIP, glucagon, somatostatin, glucose, calcium, PTH, PP, prolactin, MEN1 genetics	Raised 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 cm	Sporadic 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

NENs: Neuroendocrine neoplasms; pNENs: Pancreatic NENs; F-pNENs: Functional pNENs; NF-pNENs: Non-functional pNENs; CgA: Chromogranin A; 5-HIAA: 5-hydroxy indole acetic acid; NKA: Neurokinin A; PTH: Parathyroid hormone; PP: Pancreatic polypeptide; VIP: Vasoactive intestinal peptide; hCG: Human chorionic gonadotrophin; MEN1: Multiple endocrine neoplasia 1; NF1: Type 1 neurofibromatosis; VHL: Von Hippel-Lindau; TSC: Tuberous sclerosis; ZES: Zollinger Ellison syndrome; NEC: Neuroendocrine carcinoma; SSAs: Somatostatin analogues; CaHD: Carcinoid heart disease; EMR: Endoscopic mucosal resection; ESD: Endoscopic submucosal dissection; G1: Grade 1; G2: Grade 2; G3: Grade 3.