Imaging of gastroenteropancreatic neuroendocrine tumors

Table 1 Guide to World Health Organization classification of neuroendocrine tumors

Behaviour	Metastasis	Muscularis propria invasion	Differentiation	Size (cm)	Angioinvasion	Ki-67 (%)	Hormonal index
WHO criteria (gastrointestinal)
Benign	-	-	Well-differentiated	≤ 1	-	< 2	-
Benign/Low-grade malignant	-	-	Well-differentiated	1-2	-/+	< 2	-
Low-grade malignant	+	+	Well-differentiated	> 2	+	2-20	+
High-grade malignant	+	+	Poorly-differentiated	Any	+	> 20	-
WHO criteria (pancreas)
Benign	-	-	Well-differentiated	≤ 1	-	< 2	-/+
Benign/Low-grade malignant	-	-	Well-differentiated	> 2	-/+	< 2	-/+
Low-grade malignant	+	+	Well-differentiated	> 4	+	2-20	+
High-grade malignant	+	+	Poorly-differentiated	Any	+	> 20	-

Exceptions: Malignant duodenal gastrinomas are usually < 1 cm and confined to submucosa. Benign neuroendocrine tumors of the appendix usually invade the muscularis propria. WHO: World Health Organization.

Table 2a Tumor node metastasis staging (gastric, duodenum, ampulla, jejunum, ileum, pancreas)

TNM staging	Gastric	Duodenum/ampulla/proximal jejunum	Pancreas	Lower jejunum/Ileum
Tx	Primary tumor cannot be assessed	Primary tumor cannot be assessed	Primary tumor cannot be assessed	Primary tumor cannot be assessed
T0	No evidence of primary tumor	No evidence of primary tumor	No evidence of primary tumor	No evidence of primary tumor
Tis	In situ tumor/dysplasia (> 0.5 mm)	-	-	-
T1	Tumor invades lamina propria or submucosa and </= 1 cm	Tumor invades lamina propria or submucosa and </= 1 cm	Tumor limited to pancreas and size < 2 cm	Tumor invades mucosa or submucosa and size </= 1 cm
T2	Tumor invades muscularis propria or subserosa or > 1 cm	Tumor invades muscularis propria or > 1 cm	Tumor limited to pancreas and size 2-4 cm	Tumor invades muscularis propria or size > 1 cm
T3	Tumor penetrates serosa	Tumor invades pancreas or retroperitoneum	Tumor limited to pancreas and size > 4 cm or invading duodenum or bile duct	Tumor invades subserosa
T4	Tumors invade adjacent structures (for any T, add M for multiple tumors)	Tumor invades peritoneum or other structures (for any T, add m for multiple tumors)	Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall or large vessels (celiac or superior mesenteric artery)	Tumor invades peritoneum/other organs (for any T, add m for multiple tumors)
Nx	Regional lymph nodes cannot be assessed	Regional lymph nodes cannot be assessed	Regional lymph nodes cannot be assessed	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis	No regional lymph node metastasis	No regional lymph node metastasis	No regional lymph node metastasis
N1	Regional lymph node metastasis	Regional lymph node metastasis	Regional lymph node metastasis	Regional lymph node metastasis
Mx	Distant metastasis cannot be assessed	Distant metastasis cannot be assessed	Distant metastasis cannot be assessed	Distant metastasis cannot be assessed
M0	No distant metastasis	No distant metastasis	No distant metastasis	No distant metastasis
M1	Distant metastasis	Distant metastasis	Distant metastasis	Distant metastasis

Table 2b Tumor node metastasis Staging (appendix, colon, rectum)

	Appendix	Colon/rectum
Tx	Primary Tumor cannot be assessed	Primary Tumor cannot be assessed
T0	No evidence of primary tumor	No evidence of primary tumor
T1	Tumor invades lamina propria or submucosa and </= 1 cm	Tumor invades mucosa or submucosa, T1a < 1 cm, T1b 1-2 cm
T2	Tumor invades submucosa, muscularis propria and/or minimally (up to 3 mm) invading subserosa/mesoappendix and </= 2 cm	Tumor invades muscularis propria or > 2 cm
T3	Tumor > 2 cm and/or invasion (more than 3 mm) of the serosa/ mesoappendix	Tumor invades subserosa/pericolic/perirectal fat
T4	Tumors invade peritoneum/other organs	Tumor directly invades other organs and/or perforates visceral peritoneum
Nx	Regional lymph nodes cannot be assessed	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis	No regional lymph node metastasis
N1	Regional lymph node metastasis	Regional lymph node metastasis
Mx	Distant metastasis cannot be assessed	Distant metastasis cannot be assessed
M0	No distant metastasis	No distant metastasis
M1	Distant metastasis	Distant metastasis

Table 2c ESMO tumor node metastasis clinical classification of neuroendocrine tumors

Disease stage	T	N	M
Gastric, duodenum, ampulla, jejunum, ileum, pancreas
Stage I	T1	N0	M0
Stage IIa	T2	N0	M0
Stage IIb	T3	N0	M0
Stage IIIa	T4	N0	M0
Stage IIIb	Any T	N1	M0
Stage IV	Any T	Any N	M1
Appendix
Stage I	T1	N0	M0
Stage IIa	T2	N0	M0
Stage IIb	T3	N0	M0
Stage IIIa	T4	N0	M0
Stage IIIb	Any T	N1	M0
Stage IV	Any T	Any N	M1
Colon/rectum
Stage Ia	T1a	N0	M0
Stage Ib	T1b	N0	M0
Stage IIa	T2	N0	M0
Stage IIb	T3	N0	M0
Stage IIIa	T4	N0	M0
Stage IIIb	Any T	N1	M0
Stage IV	Any T	Any N	M1

Table 3 Summary comparison of the various imaging modalities

	Advantages	Disadvantages	Utility
Ultrasound	Widely available modality, dynamic visualization of lesions, no ionizing radiation	Limited to solid organ systems, inter-operator variability	Possible use as a screening tool for assessing the liver and pancreatic head
CT	Widely available modality, wide field of view, allowing evaluation of nodal disease and metastasis, good sensitivity	Ionizing radiation, non specific modality, low negative predictive value for small volume nodes	First line imaging modality
MRI	Superior to CT for assessment in solid organs, no ionizing radiation, gadolinium contrast agent safety profile better than CT agents in terms of allergic reaction and nephrotoxicity, ability to further characterize lesions using different sequencing	Not as widely available as compared with CT or ultrasound, more specialized diagnostic imaging expertise in interpretation, lower specificity in characterizing neuroendocrine lesions as compared with functional imaging modalities	Local staging of disease, including vascular involvement, use in pediatric age group in which ionizing radiation is of greater concern
SRS	Good sensitivity and specificity, able to accurately characterize lesions; single modality staging; allows for dosimetric evaluation of suitability for peptide receptor radionuclide therapy; proven impact on clinical management	Ionizing radiation; not as widely available as CT or ultrasound, requiring nuclear imaging capabilities; more specialized diagnostic imaging expertise in interpretation	Gold standard in the evaluation of neuroendocrine tumors
Flurodeoxyglucose PET	Possible use in disease prognostication and management stratification, possible use in post treatment assessment to evaluate for tumor dedifferentiation	Generally poor sensitivity for neuroendocrine tumors, ionizing radiation	Not routinely performed for neuroendocrine tumor assessment, possible utility in prognostication and post therapy assessment
Dihydroxyphenylalanine PET	Good sensitivities in the evaluation of neuroendocrine tumors, shows promise especially in assessments of insulinomas	Requires more specialized nuclear facilities (e.g. gaseous F18) for synthesis of the radioisotope, PET based SRS has generally similar or better accuracies in the detection and staging of neuroendocrine tumors, ionizing radiation	Possible clinical utility in the evaluation of insulinomas

CT: Computed tomography; MRI: Magnetic resonance imaging; PET: Positron emission tomography; SRS: Somatostatin receptor scintigraphy.