Gastrointestinal neuroendocrine tumors in 2020

Table 1 World Health Organization classification of gastrointestinal neuroendocrine tumors

Well-differentiated neuroendocrine neoplasms (NENs)
	Ki-67 index (%)		Mitotic index/10 HPF
NET grade 1 (G1)	< 3		< 2
NET grade 2 (G2)	3-20		2-20
NET grade 3 (G3)	> 20		> 20
Poorly differentiated neuroendocrine neoplasms (NENs)
	Ki-67 index (%)	Mitotic index/10 HPF
NEC grade 3	>20	>20
-Small cell type
-Large cell type
Mixed neuroendocrine neoplasms (MiNEN)
Source: Adapted from WHO Classification of Tumors of Endocrine Organs, Fourth edition (2017)[14]

HPF: High-power field; NET: Neuroendocrine tumor; NEC: Neuroendocrine carcinoma.

Table 2 Summary of different types of gastric neuroendocrine tumors

	Type I	Type II	Type III	Type IV
Distribution	70% to 80% of all GNETs	5% to 6% of all GNETs	15% to 20% of all GNETs	Most rare
Cell of origin; And location	ECL; Gastric body and fundus	ECL; Gastric body and fundus	ECL in most cases; Anywhere in stomach	Non-ECL; Anywhere in stomach
Gastrin status	Hypergastrinemia	Hypergastrinemia	Normogastrinemia	Hypergastrinemia -1/3rd of cases
Gastric mucosa	Atrophic	Hypertrophic	Normal	Atrophic most of the time but can be hypertrophic
Endoscopically	Multiple subcentimeter polypoid lesions	Multiple small (1 to 2 cm) polypoid lesions	Large (> 2 cm), solitary polypoid lesion	Large (> 4 cm) polypoid lesion
Treatment	Polypectomy, EMR, ESD, wedge resection of stomach, gastric antrectomy	Surgical resection of gastrinoma and aggressive gastrectomy	Partial or total gastrectomy and regional lymphadenectomy, chemotherapy	Partial or total gastrectomy with regional lymphadenectomy followed by adjuvant chemotherapy

ECL: Enterochromaffin-like cells; EMR: Endoscopic mucosal resection; ESD: Endoscopic submucosal dissection; GNETs: Gastric neuroendocrine tumors.

Table 3 Summary of different types of duodenal neuroendocrine tumors

	Gastrinomas	Somatostatinoma	Gangliocytic paraganglioma	Non-functioning d-NETs	Duodenal NECs
Location	Proximal duodenum. > 80% gastrinoma triangle	Ampullary or peri-ampullary region	Peri-ampullary region	Proximal duodenum	Peri-ampullary region
Presenting symptoms	Chronic diarrhea, recurrent and refractory peptic ulcer disease, gastroesophageal reflux disease	Nausea, abdominal pain, weight loss, obstructive jaundice or very rarely somatostatinoma syndrome	Asymptomatic, gastrointestinal bleeding, anemia, abdominal pain	Asymptomatic or nausea, vomiting	Asymptomatic, nausea, vomiting, gastrointestinal bleeding
Diagnosis	BAO/MAO > 0.6, positive Secretin suppression test, EUS, somatostatin receptor scintigraphy (SRS), CT, MRI, selective angiography, Indium 111-labeled diethylenetriamine penta-acetic acid (DTPA) octreotide and (68)Ga-DOTATE PET/CT scan	CT, MRI, endoscopy, EUS-FNA	Endoscopy, EUS-FNA, CT	Endoscopy, EUS-FNA	Endoscopy, EUS-FNA
Treatment	Surgical resection or enucleation of the tumor without pancreaticoduodenectomy for nonmetastatic duodenal gastrinoma. In patients with duodenal gastrinoma with hepatic metastasis treatment options include hormonal therapy with octreotide, chemotherapy (streptozocin, doxorubicin, 5- fluorouracil), radiotherapy with yttrium 90-DOTA-lanreotide, hepatic embolization alone or with chemoembolization, cytoreductive surgery and liver transplantation	Endoscopic resection should be adequate if the NET is less than 1 cm. Transduodenal excision should be done for 1-2 cm tumor. But Whipple’s surgery with local lymph node resection should be considered for more than 2 cm tumor	Endoscopic resection or radical excision including pancreaticoduodenectomy depending on the size, depth of invasion and lymph node metastasis	Transduodenal resection is indicated for d-NETs invading the muscularis propria. Radial surgery is advocated for d-NETs > 2 cm in diameter, d-NETs with lymph nodes involvement and all peri-ampullary d-NETs	radical surgery or chemotherapy

BAO: Basal acid output; MAO: Maximal acid output; (68)Ga-DOTATE PET/CT scan: Gallium -68 DOTATE positron emission tomography/computerized tomography scan; d-NETs: Duodenal neuroendocrine tumors; CT: Computerized tomography; MRI: Magnetic resonance imaging; EUS: Endoscopic ultrasonography; FNA: Fine needle aspiration.

Table 4 Appendiceal neuroendocrine tumor: Size and surgery

Appendiceal NET size	Surgery
< 1 cm	Simple appendectomy
1 cm to 2 cm	Appendectomy and periodic post-operative follow up is recommended for 5 yr. Right hemicolectomy should be considered in the presence of involvement of base of the appendix, cecal infiltration, invasion into the mesoappendix or serosa, involvement of tumor margin, positive lymph nodes, lymphovascular invasion, presence of goblet cells or poorly differentiated cells, Ki67 index > 2% or MiNEN
> 2 cm	Right hemicolectomy within 3 mo from the time of appendectomy but staging work up is required. This includes multiphasic computerized tomography or magnetic resonance imaging of abdomen and pelvis. SRS-based scan (Octreoscan) or (68)Ga-DOTATE PET/CT, serum CgA, 24 h 5-HIAA and colonoscopy to evaluate for synchronous colorectal cancer

NET: Neuroendocrine tumors; (68)Ga-DOTATE PET/CT scan: Gallium -68 DOTATE positron emission tomography/computerized tomography scan; CgA: Chromogranin A; 5-HIAA: 5 hydroxylindoleacetic acid; MiNEN: Mixed neuroendocrine neoplasm.