Pancreatic neuroendocrine tumors: A review of serum biomarkers, staging, and management

Table 1 Pancreatic neuroendocrine tumors-associated hormonal syndromes and biomarkers

Tumor/syndrome	Location	Incidence (million per year)	Biomarker	Main symptoms
Insulinoma	Pancreas	1-32	Insulin	Hypoglycaemia
Gastrinoma	Pancreas, duodenum	0.5-21.5	Gastrin	Zollinger-Ellison syndrome: Gastroesophageal reflux and complicated peptic ulcer disease
VIPoma	Pancreas	0.05-0.2	Vasoactive intestinal peptide	Verner-Morrison syndrome: Watery diarrhea, hypokalemia, and achlorhydria
Glucagonoma	Pancreas	0.01-0.1	Glucagon	Necrotic migratory erythema, weight loss, hypoalbuminemia, and diabetes mellitus or impaired glucose tolerance
SSoma	Pancreas, duodenum, jejunum	Rare	Somatostatin	Hyperglycemia, cholelithiasis, and maldigestion of food
ACTHoma	Pancreas	Rare	ACTH	Cushing syndrome
GRHoma	Pancreas, lung, jejunum	Rare	GRH	Acromegaly
Carcinoid syndrome caused by pNET	Pancreas	Rare	Serotonin, 5-hydroxyindoleacitic acid	Skin flushing, diarrhoea, bronchospasm, and cardiac valve fibrosis
Hypercalcemia caused by pNET	Pancreas	Rare	Parathyroid hormone-related peptide	Hypercalcaemia and abdominal pain

pNETs: Pancreatic neuroendocrine tumors; ACTH: Adrenocorticotropic hormone; GRH: Growth hormone; SSoma: Somatostatin-producing NETs.

Table 2 Definitions of American Joint Committee on Cancer and European Neuroendocrine Tumor Society staging for pancreatic neuroendocrine tumors

	AJCC 7th staging classification		AJCC 8th and ENETS staging classification
T1	Limited to the pancreas, ≤ 2 cm in greatest dimension	T1	Tumor limited to the pancreas, ≤ 2 cm
T2	Limited to the pancreas, > 2 cm in greatest dimension	T2	Tumor limited to the pancreas, 2-4 cm
T3	Beyond the pancreas but without involvement of the superior mesenteric artery	T3	Tumor limited to the pancreas, > 4 cm, or invading the duodenum or common bile duct
T4	Involvement of the celiac axis or superior mesenteric artery (unresectable tumor)	T4	Tumor invades adjacent structures
N0	No regional lymph node metastasis	N0	No regional lymph node metastasis
N1	Regional lymph node metastasis	N1	Regional lymph node metastasis
M0	No distant metastasis	M0	No distant metastasis
M1	Distant metastasis	M1	Distant metastasis
		M1a	Metastasis confined to liver
		M1b	Metastasis in at least one extrahepatic site
		M1c	Both hepatic and extrahepatic metastases

AJCC: American Joint Committee on Cancer; ENETS: European Neuroendocrine Tumor Society.

Table 3 Definitions of American Joint Committee on Cancer, European Neuroendocrine Tumor Society, and modified European Neuroendocrine Tumor Society staging for pancreatic neuroendocrine tumors

	AJCC 7th staging classification			AJCC 8th and ENETS staging classification			mENETS
Stage	T	N	M	T	N	M	T	N	M
IA	T1	N0	M0	T1	N0	M0	T1	N0	M0
IB	T2	N0	M0	T2	N0	M0	T2	N0	M0
IIA	T3	N0	M0	T3	N0	M0	T3	N0	M0
IIB	T1-3	N1	M0	T4	N0	M0	T1-3	N1	M0
III	T4	Any N	M0	Any T	N1	M0	T4	Any N	M0
IV	Any T	Any N	M1	Any T	Any N	M1	Any T	Any N	M1

AJCC: American Joint Committee on Cancer; ENETS: European Neuroendocrine Tumor Society; mENETS: Modified European Neuroendocrine Tumor Society.

Table 4 Several editions of World Health Organization (pathological classification)

Edition	Grading standards
2000/2004	G1: Well-differentiated NET; ≤ 2 cm in size, Ki-67 ≤ 2%	G2: Well-differentiated NEC; > 2 cm in size, Ki-67 3%-20% or angioinvasive	G3: Poorly differentiated NEC; Ki-67 > 20%
2010	NET-G1: Well-differentiated, mitotic count < 2/2 mm2, Ki-67 ≤ 2%	NET-G2: Well-differentiated, mitotic count 2-20/2 mm2, Ki-67 3%-20%	NEC-G3: Poorly differentiated, mitotic count > 20/2 mm2, Ki-67 > 20%
2017/2019	NET-G1: Well-differentiated, mitotic count < 2/2 mm2, Ki-67 ≤ 2%	NET-G2: Well-differentiated, mitotic count 2-20/2 mm2, Ki-67 3%-20%	NET-G3: Well-differentiated, mitotic count > 20/2 mm2, Ki-67 > 20%	NEC-G3: Poorly differentiated, mitotic count > 20/2 mm2, Ki-67 > 20%

NET: Neuroendocrine tumor; NEC: Neuroendocrine carcinoma.