John Buscombe, and Christophe Van de Wiele.
© 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc.
CT computed tomography EUS endoscopic ultrasound
MANEC mixed adenoneuroendocrine cancer MRI magnetic resonance imaging NEN neuroendocrine neoplasm NET neuroendocrine tumor
SRS somatostatin receptor scintigraphy Sstr somatostatin receptor
VIP vasoactive intestinal peptide WHO World Health Organization
Overexpression of somatostatin receptors on the cells of neuroendocrine tumors (NETs) gives the possibility of the specific diagnostic and therapeutic options.
Somatostatin receptors are present in 80–100% of functioning and nonfunctioning neuroendocrine neoplasms (NENs) [1–3]. Though the distribution of somatostatin receptors in NETs is generally homogenous, there are differences in the incidence and
the PlAce of somAtostAtin recePtor scintigrAPhy in
clinicAl setting: introduction
Department of Endocrinology with Nuclear Medicine Unit, Medical College, Jagiellonian University, Krakow, Poland
THE PlACE Of SOMATOSTATIN RECEPTOR SCINTIgRAPHy IN ClINICAl SETTINg 87
density of these receptors depending on the type of the tumor and the degree of tumor’s differentiation [1–3]. According to Reubi et al., pancreatic NENs such as gastrinomas express sstr2 in about 100%, sstr5 in 35%, sstr3 in 20%, and sstr1 in 10%; insulinomas express especially sstr2 but only in 70%, sstr1 in 60%, sstr3 in 35%, sstr5 in 15%, and sstr4 in about 3%; and jejunoileal NENs express sstr2 in about 95%, sstr1 in 50%, sstr5 in 48%, sstr3 in 15%, and sstr4 in 3% . Moreover, somatostatin receptor subtypes differ in their affinity for the radioligand, which also influences tumor detectability.
The current WHO 2010 classification system divides NENs by their mitotic index or Ki67 into NET g1 (with Ki67 ≤2%), NET g2 (Ki67 3–20%), and neuroendocrine cancer (NEC) with Ki67 over 20% [4, 5]. There are also mixed adenoneuroendocrine cancers (MANEC) distinguished [4, 5]. The sensitivity of standard somatostatin receptor scintigraphy (SRS) depending on the type of NET and the degree of its differentiation is presented in Table 4.4.1.
Sensitivity of SRS differs also between primary lesion and metastases. In some cases of NENs, liver metastases may appear isointense due to a similar degree of tracer accumulation by the normal hepatic tissue. Therefore, correlation with anatomic imaging and SPECT imaging may be helpful [3, 6]. Hybrid imaging results in more accurate characterization of foci showing elevated radiopharmaceutical uptake and a more precise anatomical localization. CT can be also used to generate attenuation maps to correct the SPECT imaging. The usefulness of this technology is especially visible in the abdominal lesions with sensitivity of 95% and specificity of 92% [3, 7].
tAble 4.4.1 sensitivity of standard srs depending on the type of neuroendocrine tumor and the degree of its differentiation
high sensitivity > 75%
(a) NET g1 (according to WHO 2010) (excluding insulinoma) – functioning endocrine tumors, that is, gastrinoma
– Nonfunctioning endocrine pancreatic tumors and jejunoileal NENs (b) NET g2 (according to WHO 2010)
– functioning tumors of pancreatic and extrapancreatic origin (gastrinoma, VIPoma, glucagonoma, jejunoileal NETs)
– Nonfunctioning pancreatic tumors 2. Other endocrine tumors
– Malignant pheochromocytoma – Small cell lung cancer intermediate sensitivity 40–75%
(a) NET g1 (according to WHO 2010) – Insulinoma
(b) NEC g3 (according to WHO 2010)
(c) MANEC (mixed adenoneuroendocrine cancer) 2. Other endocrine tumors
– Medullary thyroid cancer
– Differentiated thyroid cancer including Hurthle cell cancer – Pheochromocytoma
The advantage of SRS is that it can examine all body regions, whereas conventional imaging can only examine suspected areas. In normal scintigraphic imaging, the thy-roid, spleen, liver, kidney, pituitary, and adrenal glands are visualized due to the sstr expression in those glands. The urinary bladder and bowel are usually visualized to var-iable degrees. Uptake in the kidneys is mainly the consequence of the reabsorption of the radiolabeled peptide in the renal tubular cells after glomerular filtration. While inter-preting results of SRS, it has to be taken into consideration that somatostatin receptors exist also on white body cells. This may lead to false‐positive results in cases of inflammation or infection and existing healing processes after surgical treatment.
false‐positive uptake in SRS may be visible in radiation pneumonia, bacterial pneu-monia, respiratory infections, accessory spleen, surgical scar tissue, nodular goiter, focal collection of stool, gallbladder, ventral hernia, cerebrovascular accident, concomitant granulomatous disease, urine contamination, and concomitant second primary tumor.
The negative results may be connected with the lack of sstr on tumor cell membrane, sstr type, and sstr functional status. The receptor‐negative lesions may be poorly differenti-ated and characterized by aggressive growth and poor prognosis.
Indications to SRS includes detection and localization of different types of NENs and their metastases, staging in patients with NEN, selection of patients with metastatic tumors and/or inoperable primary lesion for treatment with “cold” and radiolabeled somatostatin analogues, prediction of the effect of PRRT, and follow‐up of patients to evaluate potential recurrence [1, 8–10].
Sensitivity of different imaging modalities varies for locating specific NETs .
SRS specificity for detection of primary gastrointestinal NETs is 86–95% and is higher than for location of pancreatic gastrin‐/VIP‐/somatostatin‐secreting NETs (75%) and insulinomas (50–60%) . for pancreatic NETs, the imaging modality with higher specificity is endoscopic ultrasound (EUS) (82–93%) . Specificities of dual‐phase multidetector computed tomography (CT) and magnetic resonance imaging (MRI) in the case of pancreatic NENs are 57–94% and 74–94%, respectively . In the case of gastrointestinal NENs, specificities of CT enteroclysis and MRI enteroclysis are 85 and 86%, respectively . for detection of neuroendocrine liver metastases, specificities of CT and MRI are 44–82% and 82–95%, respectively .
It is worth mentioning here that the assessment of somatostatin receptor expres-sion is possible also with the use of positron emisexpres-sion tomography/computed tomog-raphy (PET/CT) with different somatostatin analogues (DOTA‐NOC, DOTA‐TOC, DOTA‐TATE) labeled with 68ga [10, 11], and this imaging method is being increas-ingly introduced into clinical practice.
 Reubi, J.C. Neuroendocrinology 2004, 80, 51–56.
 Appetecchia, M.; Baldelli, R. Journal of Experimental and Clinical Cancer Research 2010, 29, 19.
 Pepe, g.; Moncayo, R.; Bombardieri, E.; et al. European Journal of Nuclear Medicine and Molecular Imaging 2012, 39, 41–51.
 Bosman, f.; Carneiro, f.; Hruban R. H.; et al. WHO Classification of Tumours of the Digestive System; IARC Press, lyon: 2010.
 Salazar, R.; Wiedenmann, B.; Rindi, g.; et al. Neuroendocrinology 2012, 95, 71–73.
 Kwekkeboom, D. J.; Kam, B. l.; van Essen M.; et al. Endocrine‐Related Cancer 2010, 17, 53–73.
 Bombardieri, E.; Coliva, A.; Maccauro, M.; et al. Quarterly Journal of Nuclear Medicine and Molecular Imaging 2010, 54, 3–15.
 Kwekkeboom, D. J.; Krenning, E. P.; Scheidhauer, K.; et al. Neuroendocrinology 2009, 90, 184–189.
 Őberg, K.; Reubi, J. C.; Kwekkeboom, D. J.; et al. gastroenterology 2010; 139, 742–753.
 Ramage, J. K.; Ahmed, A.; Ardill, J.; et al. gut 2010, 61, 6–32.
 Ambrosini, V.; Campana, D.; Tomasetti, P. et al. European Journal of Nuclear Medicine and Molecular Imaging 2012, 39, 52–60.
Somatostatin Analogues: From Research to Clinical Practice, First Edition. Edited by Alicja Hubalewska-Dydejczyk, Alberto Signore, Marion de Jong, Rudi A. Dierckx, John Buscombe, and Christophe Van de Wiele.
© 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc.
18F‐DOPA 6‐[fluoride‐18]fluoro‐levodopa 5‐HIAA 5‐hydroxyindoleacetic acid 5‐HTP 5‐hydroxytryptophan ACTH adrenocorticotropic hormone CEUS contrast‐enhanced ultrasonography CgA chromogranin A
CT computed tomography
d‐NENs duodenal neuroendocrine neoplasms EUS endoscopic ultrasonography
FDG PET fluorodeoxyglucose positron emission tomography FNAC/B fine‐needle aspiration cytology/biopsy
GCC goblet cell carcinoma