Pancreatic neuroendocrine tumors: A case-based evidence review

Table 1 Classification of pancreatic neuroendocrine tumors, modified from World Health Organisation Classification of Neuroendocrine Neoplasms[20]

Terminology	WHO grade	Differentiation	Mitotic rate	Ki-67 index
NET	G1	Well-differentiated NET	< 2/2 mm²	< 3%
	G2		2-20/2 mm²	3%-20%
	G3		> 20%/2 mm²	> 20%
Small cell NEC	High grade	Poorly differentiated NEC	> 20/2 mm²	> 70%
Large cell NEC	High grade

NET: Neuroendocrine tumors; NEC: Neuroendocrine carcinoma.

Table 2 Biomarkers for the diagnosis of pNEN[23]

Circulating biomarkers
Non-specific biomarkers	Specific to functional pNEN	Specific to nonfunctional pNEN
Chromogranin A	Insulin	Pancreatic polypeptide
Pancreastatin	Glucagon	Human chorionic gonadotropin
Chromogranin B	Gastrin	Neurotensin
Neuron-specific enolase	Somatostatin	Ghrelin
Alpha fetoprotein	Vasoactive intestinal peptide	Calcitonin
	Growth hormone or GHRH
	Adrenocorticotropic hormone
Immunohistochemical biomarkers
Differentiation markers	Site of origin markers	Prognostic markers
Chromogranin A	NESP55	ATRX/DAXX
Synaptophysin	PGR	SSTR2a
INSM1	PDX1	PD-L1
	ARX
	ISL1
Molecular biomarkers
Circulating tumor cells (CTCs)
Circulating cell-free DNA (cfDNA)
Circulating microRNAs (miRNAs)
Circulating transcripts (NETest score)
G protein-coupled receptor-associated sorting protein 1 (GPRASP1)
Delta-like protein 3 (DLL3)
Tumor-associated macrophages (TAMs)
Glucose transporter 1 (GLUT1)

INSM1: Insulinoma-associated protein 1; NESP55: Neuroendocrine secretory protein 55; PGR: Progesterone receptor; PDX1: Pancreatic and duodenal homeobox 1; ISL-2: Insulin gene enhancer binding protein 2; ATRX/DAXX: Alpha-thalassemia/mental retardation X-linked and death domain-associated protein; SSTR2a: Somatostatin receptors 2a; PD-L1: Programmed cell death ligand 1.

Table 3 Tumor, node, metastasis and American Joint Committee on Cancer classifications for staging of pancreatic neuroendocrine tumors[27]

AJCC	TNM	Description
I	T1 N0 M0	Tumor < 2 cm, local to pancreas. No nodal disease/metastasis
II	T2 N0 M0	2 cm < Tumor < 4 cm, local to pancreas. No nodal disease/metastasis
	T3 N0 M0	Tumor > 4 cm, extended to duodenum/common bile duct. No nodal disease or metastasis
III	T1-3/4 N1 M0	Tumor extended to adjacent organs (stomach, spleen, colon/adrenals) or spread haematogenously (T4). It may present with lymph node spread (N1) but no distant metastasis
IV	Tx Nx M1	Any size (Tx), any nodal spread (Nx), but distant metastasis (M1)