Neuroendocrine tumors of the gastro-entero-pancreatic system

Table 1 WHO classification[12]

Site	Well differentiated endocrine tumor		Well-differentiated endocrine carcinoma	Poorly-differentiated endocrine carcinoma
	BB	UB
Pancreas	< 2 cm	≥ 2 cm	Local invasion	Small cells
	< 2 mitoses1	> 2 mitoses	2-10 mitoses	> 10 mitoses
	< 2% Ki-67	> 2% Ki-67	> 5% Ki-67	> 15% Ki-67
	No vascular invasion	Vascular invasion	Vascular invasion ± metastases	Vascular/perineural invasion
Stomach	Mucosa/Submucosa	Mucosa/Submucosa	Invasion of muscularis propria ± metastases	Small cells
	≤ 1 cm	> 1 cm
	No vascular invasion	Vascular invasion
Duodenum/	Mucosa/Submucosa	Mucosa/Submucosa	Invasion of muscularis propria ± metastases	Small cells
Jejunum	≤ 1 cm	> 1 cm
	No vascular invasion	Vascular invasion
Ileum/	Mucosa/Submucosa	Mucosa/Submucosa	Invasion of muscularis propria ± metastases	Small cells
Colon/	≤ 1 cm (ileum)	> 1 cm (ileum)
Rectum	≤ 2 cm (colon)	> 2 cm (colon)
	No vascular invasion	Vascular invasion
Appendix	≤ 2 cm	> 2 cm	Extensive invasion of mesoappendix ± metastases	Small cells
	No vascular invasion	Vascular invasion

¹Mitoses expressed as number/10 high power field. BB: Benign behavior; UB: Uncertain behavior.

Table 2 TNM staging for pancreatic NETs[13], foregut and midgut gastrointestinal carcinoids[14]

	Pancreatic NETs			Foregut and midgut gastrointestinal carcinoids
T-primary tumor
Tx	Primary tumor cannot be assessed			Primary tumor cannot be assessed
T0	No evidence of primary tumor			No evidence of primary tumor
T1	Tumor limited to the pancreas and size < 2 cm			Tumor invades mucosa or submucosa and size ≤ 1 cm
T2	Tumor limited to the pancreas and size 2-4 cm			Tumor invades muscularis propria and size > 1 cm
T3	Tumor limited to the pancreas and size > 4 cm or invading duodenum or bile duct			Tumor invades subserosa
T4	Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis or superior mesenteric artery)			Tumor invades adjacent structures
	For any T, add (m) for multiple tumors			For any T, add (m) for multiple tumors
N-regional lymph nodes
Nx	Regional lymph nodes cannot be assessed			Regional lymph nodes cannot be assessed
N0	No regional lymph node metastases			No regional lymph node metastases
N1	Regional lymph node metastases			Regional lymph node metastases
M- distant metastases
Mx	Distant metastases cannot be assessed			Distant metastases cannot be assessed
M0	No distant metastases			No distant metastases
M1	Distant metastases			Distant metastases
Disease stage
I	T1	N0	M0	T1	N0	M0
IIa	T2	N0	M0	T2	N0	M0
IIb	T3	N0	M0	T3	N0	M0
IIIa	T4	N0	M0	T4	N0	M0
IIIb	Any T	N1	M0	Any T	N1	M0
IV	Any T	Any N	M1	Any T	Any N	M1

Criteria for carcinoids of the appendix and colon rectum differ only for the tumor size.

Table 3 Carcinoid syndrome

Clinical features	Incidence (%)	Characteristics	Mediators
Flushing	90	Foregut tumors: prolonged fit, red-purple, localized to face and trunk. Midgut tumors: quick fit, pink-red.	Serotonin, histamine, P substance, prostaglandins
Diarrhea	70	Secretory	Serotonin, histamine, VIP, prostaglandins, gastrin
Abdominal pain	40	Long lasting	Obstruction, hepatomegaly, intestinal ischemia, fibrosis
Profuse sweating	15		Serotonin, histamine
Telangiectasias	25	Face	Unknown cause
Heart disease	30 (right)	Valvulopathies (tricuspid valve, pulmonary valve). Right heart failure. Dyspnea	P substance, serotonin
	10 (left)
Pellagra	5	Dermatitis	Deficit of niacin

Table 4 Clinical features of the main endocrine pancreatic tumors

Tumor (syndrome)	Clinical features and diagnostic tests	MEN-1 (%)	Metastases (%)	SnSRS (%)
Insulinoma	Spontaneous or fasting hypoglycemia (Whipple's triad)	8-10	10	50
	Positive fasting test (hypoglycemia with hyperinsulinism)
Gastrinoma (Zollinger-Ellison syndrome)	Peptic ulcers, diarrhea, GERD, BAO > 15 mEq/h	30	60	80
	Positive secretin test (serum gastrinemia > 200 ng/L within 10 min from secretin venous infusion, 2 U/kg per min)
VIP-oma (Verner Morrison syndrome)	Severe watery diarrhea (> 1L/die), hypokalemia, hypochlorhydria	Rare	70	80
Glucagonoma	Necrolytic migratory erythema, diabetes, weight loss, anemia, hypoaminoacidemia, venous thrombosis	Rare	60	80
Somatostatinoma	Diarrhea, steatorrhea, weight loss, diabetes, cholelithiasis	Not associated	84	80
CRH/ACTH-oma	Cushing's syndrome	-	90	-
GHRH-oma	Acromegaly	-	-	-

SnSRS: Sensitivity of ¹¹¹In-Pentetreotide scintigraphy (Octreoscan^®).

Table 5 Results of studies of molecularly targeted agents in patients with neuroendocrine tumours[54,55]

Agent	Response rate (%)	PFS rate (%)/Duration
VEGF monoclonal antibody
Bevacizumab[56]	18	95 at 18 wk
mTOR inhibitor
RAD001 (everolimus)	13	71 at 24 wk
Temsirolimus[57]	5.6	50 at 6 mo
VEGF TKI
Sunitinib	10	Median, 42 wk
Vatalanib	In progress	(time to progression)
Sorafenib	In progress
Pazopanib	In progress
PDGFR/Kit/Abl inhibitor
Imatinib[58]	4	Median, 5.9 mo
EGFR inhibitor
Gefitinib	4	61 (carcinoids) and 31 (pancreatic tumor) at 6 mo
Other
Bortezomib[59]	0	Median, 3 mo
		(Time to treatment failure)

PFS: Progression free survival.