Current updates and future directions in diagnosis and management of gastroenteropancreatic neuroendocrine neoplasms

Table 1 World Health Organization 2019 Classification

Terminology, grade	Differentiation	Mitotic count (HPF2)	Ki-67 index (%)
NET, G1	Well-differentiated	< 2/10	< 3
NET, G2	Well-differentiated	2-20/10	3-20
NET, G3	Well-differentiated	> 20/10	> 20
NEC, G3 (small or large cell type)	Poorly differentiated	> 20/10	> 20

NET: Neuroendocrine tumor; NEC: Neuroendocrine carcinoma; HPF: High powered field.

Table 2 Gastric neuroendocrine tumors[88,90,91]

	Type 1	Type 2	Type 3	Type 4
Proportion of gastric neuroendocrine tumors	70%-80%	5%	15%-25%	Very rare
Associated conditions	Atrophic gastritis	Zollinger-Ellison and MEN-1	Sporadic	Sporadic
Location	Gastric fundus and body	Gastric fundus and body	Antrum	Anywhere
Endoscopic findings	Multiple, small polyps	Multiple, small polyps	Solitary, larger	Solitary, larger
Gastrin level	Increased	Increased	Normal	Normal
pH	Increased	Decreased	Normal	Normal
Prognosis	Excellent	Good	Poor	Very poor
Metastasis	10%-20%	10%-30%	30%-80%	80%-100%
Evaluation	Gastric pH, gastrin, EUS 1-2 cm lesions	Gastric pH, gastrin, EUS 1-2 cm lesions, abdominal imaging	Gastric pH, gastrin, EUS, abdominal imaging	Gastric pH, gastrin, EUS, abdominal imaging
Treatment	Endoscopic resection for larger lesions and surveillance for lesions < 2 cm	Similar to type 1	Surgery, endoscopic resection for superficial, well-differentiated lesions < 1 cm	Surgery for local disease, systemic chemotherapy for metastatic
Surveillance	EGD every year	EGD every 6-12 mo, abdominal imaging every year	EGD every 6-12 mo, abdominal imaging every 3 mo

EUS: Endoscopic ultrasound; EGD: Esophagogastroduodenoscopy; MEN1: Multiple endocrine neoplasia type 1.

Table 3 Small intestinal neuroendocrine tumors[96,97,101,102,104,108,109]

	Duodenal	Ampullary	Jejuno-ileal
Epidemiology	2%-3% GEP-NETs	0.3%-1% GEP-NETs	1.2 cases/100000 incidence quadrupled over past 30 yr
Evaluation	> 2 cm: CT and EUS	CT, EUS	Chromogranin A, urine 5-HIAA, CT/MRI, gallium-DOTATATE PET CT, colonoscopy into terminal ileum
5-yr survival	No metastases: 80%-95%; Regional metastases: 65%-75%; Zollinger-Ellison or MEN-1: > 90%	59%	Local disease: 80%-100%; Regional disease: 70%-80%; Distant metastases: 35%-80%
Treatment	< 1 cm: Endoscopic resection; 1-2 cm: Endoscopic or surgical resection; > 2 cm: EMR or ESD, surgical resection for regional disease	< 2 cm superficial without metastases: Pancreaticoduodenectomy or consider endoscopic ampullectomy; > 2 cm: Pancreaticoduodenectomy	Surgery; Carcinoid syndrome: Long-acting SSA (octreotide LAR 20-30 mg IM)
Surveillance	EGD at least every 2 yr	EGD at 1-2 yr interval	NANETS: Curative surgery-CT every 3-6 mo then 6-12 mo for 7 yr; Advanced disease- CT every 6 mo; ENETS: Curative surgery: Chromogranin A, urine 5-HIAA, CT every 6-12 mo; Slow-growing treated without curative intent: every 3-6 mo

EUS: Endoscopic ultrasound; EGD: Esophagogastroduodenoscopy; GEP-NETs: Gastroenteropancreatic neuroendocrine tumors; PET: Positron emission tomography; CT: Computed tomography; MRI: Magnetic resonance imaging; SSAs: Somatostatin analogues; LAR: Long-acting release; HIAA: Hydroxyindoleacetic acid.

Table 4 Risk of metastases by tumor size in appendiceal neuroendocrine tumors[169]

Tumor size	Nodal metastases	Distant metastases
≤ 1 cm	0%	0%
1-2 cm	7.5%	4%
≥ 2 cm	33%	12%

Table 5 Colorectal neuroendocrine tumors[103,112,114,121,124,126,170-173]

	Appendiceal	Colonic	Rectal
Epidemiology	1.45% of appendectomies	< 10% NETs	29% GEP-NETs
Presentation	Incidental or acute appendicitis; Carcinoid syndrome rare	Incidental (yellowish polypoid or donut-shaped); 46% advanced at diagnosis	Incidental (small, yellowish polypoid)
Evaluation	(1) Colonoscopy; (2) CT/MRI if > 2 cm, incomplete resection1, suspected metastases; (3) Gallium DOTATATE PET CT: Incomplete resection1, suspected metastases, carcinoid syndrome; and (4) Chromogranin A and urine 5-HIAA: liver metastases or carcinoid syndrome	CT, EUS, Gallium DOTATATE PET CT	Colonoscopy; EUS; > 2 cm, invasion beyond submucosa, lymph node disease: Gallium DOTATATE PET CT
5-yr survival	< 2 cm without regional or distant disease: 100%; 2-3 cm with regional nodes or ≥ 3 cm: 78%; Distant metastases: 32%	Stage I: 90%; Stage II: 77%; Stage III: 53%; Stage IV: 14%	Localized: 98%-100%; Regional metastases: 54%-74%; Distant metastases: 15%-37%
Treatment	Right hemicolectomy with lymph node dissection: (1) > 2 cm; and (2) 1-2 cm with high-risk features2; Appendectomy: (1) < 1 cm, well-differentiated; and (2) 1-2 cm without high-risk features2	Local disease: segmental colectomy and lymphadenectomy; Metastatic disease: chemotherapy	< 1 cm without invasion beyond submucosa: Endoscopic resection; 1-2 cm: Endoscopic resection or transanal resection; > 2 cm without metastatic disease: Radical surgical resection
Surveillance	(1) ≤ 2 cm without high-risk features2 and confined to appendix: No follow-up; and (2) Larger or node positive, and right hemicolectomy: CT/MRI 3-12 mo post-surgery; consider baseline gallium DOTATATE PET CTAfter first year, annual CT/MRI		< 1 cm: None; 1-2 cm: EUS or MRI at 6 and 12 mo; > 2 cm: CT/MRI at 3 and 12 mo, then every 12-24 mo

¹Incomplete resection: Positive margin and/or lymph nodes.

²High-risk features: Large tumor size, G2, lymphovascular invasion, mesoappendiceal invasion.

NET: Neuroendocrine tumor; EUS: Endoscopic ultrasound; EGD: Esophagogastroduodenoscopy; GEP-NENs: Gastroenteropancreatic neuroendocrine neoplasms; PET: Positron emission tomography; CT: Computed tomography; MRI: Magnetic resonance imaging; HIAA: Hydroxyindoleacetic acid.

Table 6 Diagnosing pancreatic neuroendocrine tumors[136,174]

	Diagnostic evaluation
All pancreatic NET	Multiphasic CT/MRI
	If results impact management, gallium DOTATATE PET CTEUS with biopsy
Insulinoma	72 h fast test: Hypoglycemia with elevated insulin
	Oral glucose tolerance test: May be necessary in minority with only postprandial hypoglycemia
Gastrinoma	Fasting gastrin 10 times upper limit of normal + gastric pH < 2
	If gastrin less elevated + gastric pH < 2, measure BAO with secretin test
	BAO > 15 mEq/h or serum gastrin increase > 120 pg/mL
Glucagonoma	Fasting serum glucagon > 500 pg/mL
Somatostatinoma	Fasting plasma somatostatin > 30 pg/mL
VIPoma	Large volume diarrhea + serum VIP > 75 pg/mL

NET: Neuroendocrine tumor; CT: Computed tomography; MRI: Magnetic resonance imaging; PET: Positron emission tomography; EUS: Endoscopic ultrasound; BAO: Basal acid output.