Management of early gastrointestinal neuroendocrine neoplasms

Table 1 Comparison of the WHO classification 2010 for gastroenteropancreatic neuroendocrine neoplasms with previous WHO classifications

WHO 1980	WHO 2000	WHO 2010
I Carcinoid	WDETa	NET G1 (carcinoid) G2a
	WDECa
	PDEC	NEC G3 Large cell or small cell type
	MEEC	MANEC
II Pseudotumour lesions	TLL	Hyperplastic and preneoplastic lesions

G: Grade (for definition, see text and table 2);

^aIn case that the Ki67 proliferation rate exceeds 20%, this NET may be graded G3. WHO: World Health Organization; WDET: Well-differentiated endocrine tumor; WDEC: Well-differentiated endocrine carcinoma; MEEC: Mixed exocrineendocrine carcinoma; TLL: Tumour-like lesions; NET: Neuroendocrine tumor; NEC: Neuroendocrine carcinoma; MANEC: Mixed adenoneuroendocrine carcinoma.

Table 2 Grading of gastrointestinal neuroendocrine neoplasms according to proliferative activity^a

Grade	Ki-67 index (%)b
G1	≤ 2
G2	3-20
G3	> 20

^aModified according to reference[4,5,19];

^bMIB1 antibody, % of 100 tumor cells in areas of highest nuclear labeling.

Table 3 Clinicopathological characteristics of gastric neuroendocrine neoplasms[4,23-26]

Gastric NETs/carcinoids				Gastric NECs (poorlydifferentiated NENs)
	Type 1	Type 2	Type 3	Type 4
Relative frequency	70%-80%	5%-6%	14%-25%	6%-8%
Features	Mostly small (< 1-2 cm) and multiple	Mostly small (< 1-2 cm) and multiple	Solitary often > 2 cm	Solitary mostly exulcerated, > 2 cm
Associated conditions	CAG	MEN1/ZES	No	No
Histology	Well differentiated G1	Well differentiated G1	Well/moderate differentiated* G2a	Poorly differentiated G3
Serum gastrin	(Very) high	(Very) high	Normal	(Mostly) normal
Gastric pH	Anacidic	Hyperacidic	Normal	(Mostly) normal
Metastases	< 10%	10%-30%	50%-100%	80%-100%
Tumor-related deaths	no	< 10%	25%-30%	≥ 50%

NET: Neuroendocrine tumor; NEC: Neuroendocrine carcinoma; CAG: Chronic atrophic gastritis, due to pernicious anemia or Helicobacter pylori infection; MEN1: Multiple endocrine neoplasia type1; ZES: Zollinger-Ellison syndrome; MEN1/ZES: ZES associated with MEN1; G1-3 histological differentiation: see Table 2; ENETS and NANETS nomenclature are identical for G1 and G3 grading: G1: Well differentiated; G3: Poorly differentiated. For G2 grading ENETS and NANETS nomenclature differ: *ENETS-nomenclature: G2: Well-differentiated;

^aNANETS-nomenclature: G2: Moderate differentiated (modified from Scherübl et al[13])

Table 4 Impact of endoscopic screening on the size of detected rectal NENs/carcinoids[14]

Size of the primary	Without screening (%)	Endoscopic screening (%)
< 10 mm	65-80	93.3-100
11-20 mm	10-22	0-6.7
> 20 mm	10-15	0

Table 5 Therapy of gastric NENs

	No risk factors (for metastatic disease)		risk factorsa
Size	≤ 1 cm	1-2 cm
Type 1	Surveillanceb optionally EMR	EMR followed by surveillance	Surgeryc
Type 2	Surveillanceb	EMR followed by surveillance	Surgeryc
Type 3	EMR	Surgeryc	Surgeryc
Type 4	-	-	Surgeryd

^arisk factors for metastatic disease are angioinvasion or G2-G3 histological grading or infiltration of the muscularis propria or tumor size > 2cm;

^bsomatostatin analogs are being tested in ongoing clinical trials, they should not be used except in clinical trials;

^cfollowed by endoscopic surveillance of the gastric remnant. Adjuvant (medical) therapy is not established in NET/carcinoid disease;

^dsurgery in localized type 4 gastric/d NEC disease (or systemic cytoreductive chemotherapy in advanced type 4 gastric NEC disease). Type 4 gastric NECs are never benign, they are neuroendocrine carcinomas. EMR: Endoscopic mucosal resection; NENs: Neuroendocrine neoplasms.

Table 6 Therapy of duodenal NENs

Type	≤1 cma	1-2 cma	Any size but risk factorsb
Sporadic NET (no gastrinoma, no MEN1 )	EMR	Surgery (in case of surgical risk: EMR followed by surveillance)	Surgery
Sporadic gastrinoma	Surgeryc	Surgeryc	Surgeryc
Gastrinoma and MEN1	PPI therapy and surveillance (or surgery)	Surgery (particularly if the gastrinoma is growing) or PPI therapy combined with surveillance	Surgery (or PPI therapy combined with surveillance in G1 gastrinomas and/or surgical risk)
NEC (G3)	-	-	Surgery or cytoreductive chemotherapy

^awithout risk factors (for metastatic disease) such as G2-G3, angioinvasion, infiltration of the muscularis propria or tumor size > 2 cm;

^bin the presence of risk factors for metastatic disease, surgery is generally indicated, regardless of tumor size;

^cSurgery is the therapy of choice for sporadic gastrinoma (without distant metastases). In (very) elderly patients conservative management may, however, be preferred to surgery. Adjuvant (medical) therapy is not established in NET/carcinoid disease. NET: Well differentiated neuroendocrine tumor; EMR: Endoscopic mucosal resection; PPI: Proton pump inhibitor; MEN1: Multiple endocrine neoplasia type 1.

Table 7 Therapy of rectal NENs

	No risk factors (for metastatic disease)		Risk factorsa
Grade/Size	≤ 1.0 cm	1.1 - 2 cm	Any size
G1	EMR or polypectomy or ESD	Surgeryb (EMR or ESD in case of surgical risk or for carcinoids of 11-14 mm in diameter)	Surgeryb
G2	EMR, ESD, surgeryb	Surgeryb	Surgeryb
G3	-	-	Surgeryb

^arisk factors for metastatic disease are angioinvasion or infiltration of the muscularis propria, or tumor size of > 2cm;

^bsurgery only in localized NET/NEC disease and systemic medical therapy in advanced tumor/cancer disease. Adjuvant medical therapy is not established for curatively resected, well-differentiated NETs/carcinoids of the rectum. G3 neuroendocrine neoplasms of the rectum are always neuroendocrine carcinomas. EMR: Endoscopic mucosal resection; ESD: endoscopic submucosal dissection; NENs: Neuroendocrine neoplasms.