Abstract
Objectives
To establish and validate a model to predict somatostatin receptor 2 (SSTR2), vascular endothelial growth factor receptor 2 (VEGFR2) and O6-methylguanine-DNA methyltransferase (MGMT) expression in pancreatic neuroendocrine neoplasms (pNENs) based on CT images.
Methods
The data from 85 patients with 88 pathologically confirmed pNENs, who underwent contrast-enhanced CT examination before radical resection, were retrospectively collected. Immunohistochemical detection was performed for SSTR2 (n = 86), VEGFR2 (n = 53) and MGMT (n = 84) expressions. The CT features were evaluated by radiologists. The patients were randomly divided into training and test dataset for each immunohistochemical group. Nomograms were developed based on CT features associated with these immunohistochemical expressions in the training sets, then validated and evaluated.
Results
Sex, tumour boundary and location were statistically different between SSTR2 positive and negative groups; sex, tumour maximum diameter, boundary, enhanced ratio in venous phase, and CT ratio in arterial and venous phases were statistically different between the VEGFR2 positive and negative groups; tumour maximum diameter, boundary, shape, CT ratio in unenhanced, arterial, and venous phases, and enhanced ratio in arterial phase were statistically different between the MGMT positive and negative groups (P < 0.05). The nomograms showed good discrimination ability, with AUCs of 0.88 and 0.94 for the training and test sets in the SSTR2 group, 0.96 and 0.84 in the VEGFR2 group, 0.81 and 0.82 in the MGMT group, respectively. Each nomogram exhibited good calibration and clinical usefulness.
Conclusion
CT-based nomograms effectively predict SSTR2, VEGFR2 and MGMT expression in pNENs and may assist clinicians in pretreatment decisions.
Similar content being viewed by others
Data availability
The datasets generated and analysed during the current study are not publicly available due to participant privacy and ethical restrictions, but are available from the corresponding author on reasonable request.
Abbreviations
- MGMT:
-
O6-methylguanine-methyltransferase
- NENs:
-
Neuroendocrine neoplasms
- PNENs:
-
Pancreatic neuroendocrine neoplasms
- PRRT:
-
Peptide receptor radionuclide therapy
- rCBF:
-
Relative cerebral blood flow
- SSA:
-
Somatostatin analogues
- SSTR2:
-
Somatostatin receptor 2
- VEGF:
-
Vascular endothelial growth factor
- VEGFR2:
-
Vascular endothelial growth factor receptor 2
References
Asa SL. Pancreatic endocrine tumors. Mod Pathol. 2011;24(2):S66–77. https://doi.org/10.1038/modpathol.2010.127.
Ishida H, Lam AK-Y. Pancreatic neuroendocrine neoplasms: the latest surgical and medical treatment strategies based on the current World Health Organization classification. Crit Rev Oncol Hematol. 2020;145:102835. https://doi.org/10.1016/j.critrevonc.2019.102835.
Colao A, de Nigris F, Modica R, Napoli C. Clinical epigenetics of neuroendocrine tumors: the road ahead. Front Endocrinol (Lausanne). 2020;11:604341. https://doi.org/10.3389/fendo.2020.604341.
Oberg KE, Reubi J-C, Kwekkeboom DJ, Krenning EP. Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology. 2010. https://doi.org/10.1053/j.gastro.2010.07.002.
Walter T, van Brakel B, Vercherat C, Hervieu V, Forestier J, Chayvialle JA, Molin Y, Lombard-Bohas C, Joly MO, Scoazec JY. O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: prognostic relevance and association with response to alkylating agents. Br J Cancer. 2015;112:523–31. https://doi.org/10.1038/bjc.2014.660.
Wang Y, Wang W, Jin K, Fang C, Lin Y, Xue L, Feng S, Zhou Z, Shao C, Chen M, Yu X, Chen J. Somatostatin receptor expression indicates improved prognosis in gastroenteropancreatic neuroendocrine neoplasm, and octreotide long-acting release is effective and safe in Chinese patients with advanced gastroenteropancreatic neuroendocrine tumors. Oncol Lett. 2017;13:1165–74. https://doi.org/10.3892/ol.2017.5591.
Taelman VF, Radojewski P, Marincek N, Ben-Shlomo A, Grotzky A, Olariu CI, Perren A, Stettler C, Krause T, Meier LP, Cescato R, Walter MA. Upregulation of key molecules for targeted imaging and therapy. J Nucl Med. 2016;57:1805–10.
Luo Y, Chen X, Chen J, Song C, Shen J, Xiao H, Chen M, Li Z-P, Huang B, Feng S-T. Preoperative prediction of pancreatic neuroendocrine neoplasms grading based on enhanced computed tomography imaging: validation of deep learning with a convolutional neural network. Neuroendocrinology. 2020;110:338–50. https://doi.org/10.1159/000503291.
Song C, Wang M, Luo Y, Chen J, Peng Z, Wang Y, Zhang H, Li Z-P, Shen J, Huang B, Feng S-T. Predicting the recurrence risk of pancreatic neuroendocrine neoplasms after radical resection using deep learning radiomics with preoperative computed tomography images. Ann Transl Med. 2021;9:833. https://doi.org/10.21037/atm-21-25.
Thaiss WM, Kaufmann S, Kloth C, Nikolaou K, Bösmüller H, Horger M. VEGFR-2 expression in HCC, dysplastic and regenerative liver nodules, and correlation with pre-biopsy dynamic contrast enhanced CT. Eur J Radiol. 2016;85:2036–41. https://doi.org/10.1016/j.ejrad.2016.09.012.
Suh CH, Kim HS, Jung SC, Choi CG, Kim SJ. clinically relevant imaging features for promoter methylation in multiple glioblastoma studies: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2018;39:1439–45. https://doi.org/10.3174/ajnr.A5711.
Han Y, Yan L-F, Wang X-B, Sun Y-Z, Zhang X, Liu Z-C, Nan H-Y, Hu Y-C, Yang Y, Zhang J, Yu Y, Sun Q, Tian Q, Hu B, Xiao G, Wang W, Cui G-B. Structural and advanced imaging in predicting MGMT promoter methylation of primary glioblastoma: a region of interest based analysis. BMC Cancer. 2018;18:215. https://doi.org/10.1186/s12885-018-4114-2.
Volante M, Brizzi MP, Faggiano A, La Rosa S, Rapa I, Ferrero A, Mansueto G, Righi L, Garancini S, Capella C, De Rosa G, Dogliotti L, Colao A, Papotti M. Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy. Mod Pathol. 2007;20:1172–82.
Martins SF, Garcia EA, Luz MAM, Pardal F, Rodrigues M, Filho AL. Clinicopathological correlation and prognostic significance of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression in colorectal cancer. Cancer Genom Proteom. 2013;10:55–67.
Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007;13:2986–91.
Gallotti A, Johnston RP, Bonaffini PA, Ingkakul T, Deshpande V, Fernández-del Castillo C, Sahani DV. Incidental neuroendocrine tumors of the pancreas: MDCT findings and features of malignancy. AJR Am J Roentgenol. 2013;200:355–62. https://doi.org/10.2214/AJR.11.8037.
Kawamoto S, Johnson PT, Shi C, Singhi AD, Hruban RH, Wolfgang CL, Edil BH, Fishman EK. Pancreatic neuroendocrine tumor with cystlike changes: evaluation with MDCT. AJR Am J Roentgenol. 2013;200:W283–90. https://doi.org/10.2214/AJR.12.8941.
Canellas R, Burk KS, Parakh A, Sahani DV. Prediction of pancreatic neuroendocrine tumor grade based on CT features and texture analysis. AJR Am J Roentgenol. 2018;210:341–6. https://doi.org/10.2214/AJR.17.18417.
Harrell FE. Regression modeling strategies, vol. 330. New York: Springer; 2017. p. 14. https://doi.org/10.1007/978-1-4757-3462-1.
Kimura N, Pilichowska M, Date F, Kimura I, Schindler M. Immunohistochemical expression of somatostatin type 2A receptor in neuroendocrine tumors. Clin Cancer Res. 1999;5:3483–7.
Silva SR, Bowen KA, Rychahou PG, Jackson LN, Weiss HL, Lee EY, Townsend CM, Evers BM. VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis. Int J Cancer. 2011;128:1045–56. https://doi.org/10.1002/ijc.25441.
Dasgupta P. Somatostatin analogues: multiple roles in cellular proliferation, neoplasia, and angiogenesis. Pharmacol Ther. 2004;102:61–85.
Guo C, Chen X, Xiao W, Wang Q, Sun K, Wang Z. Pancreatic neuroendocrine neoplasms at magnetic resonance imaging: comparison between grade 3 and grade 1/2 tumors. Onco Targets Ther. 2017;10:1465–74. https://doi.org/10.2147/OTT.S127803.
Estrella JS, Ma LT, Milton DR, Yao JC, Wang H, Rashid A, Broaddus RR. Expression of estrogen-induced genes and estrogen receptor β in pancreatic neuroendocrine tumors: implications for targeted therapy. Pancreas. 2014. https://doi.org/10.1097/MPA.0000000000000203.
Muscogiuri G, Barrea L, Feola T, Gallo M, Messina E, Venneri MA, Faggiano A, Colao A. Pancreatic neuroendocrine neoplasms: does sex matter? Trends Endocrinol Metab. 2020;31:631–41. https://doi.org/10.1016/j.tem.2020.02.010.
Kumar U, Grigorakis SI, Watt HL, Sasi R, Snell L, Watson P, Chaudhari S. Somatostatin receptors in primary human breast cancer: quantitative analysis of mRNA for subtypes 1–5 and correlation with receptor protein expression and tumor pathology. Breast Cancer Res Treat. 2005;92:175–86.
Mei W, Ding Y, Wang S, Jia Y, Cao F, Li F. Head and body/tail pancreatic neuroendocrine tumors have different biological characteristics and clinical outcomes. J Cancer Res Clin Oncol. 2020;146:3049–61. https://doi.org/10.1007/s00432-020-03303-w.
Badarna M, Percik R, Aharon-Hananel G, Uri I, Tirosh A. Anatomic site as prognostic marker of pancreatic neuroendocrine tumors: a cohort study. Eur J Endocrinol. 2019;181:325–30. https://doi.org/10.1530/EJE-19-0332.
Kumar M, Liu Z-R, Thapa L, Chang Q, Wang D-Y, Qin R-Y. Antiangiogenic effect of somatostatin receptor subtype 2 on pancreatic cancer cell line: Inhibition of vascular endothelial growth factor and matrix metalloproteinase-2 expression in vitro. World J Gastroenterol. 2004;10:393–9.
Nakashima Y, Ohtsuka T, Nakamura S, Mori Y, Nakata K, Miyasaka Y, Ishigami K, Matsuda R, Oda Y, Nakamura M. Clinicopathological characteristics of non-functioning cystic pancreatic neuroendocrine tumors. Pancreatology. 2019;19:50–6. https://doi.org/10.1016/j.pan.2018.11.010.
Trenti A, Tedesco S, Boscaro C, Trevisi L, Bolego C, Cignarella AE. Angiogenesis, immunity and cell metabolism: solving the puzzle. Int J Mol Sci. 2018. https://doi.org/10.3390/ijms19030859.
Gargett CE, Zaitseva M, Bucak K, Chu S, Fuller PJ, Rogers PAW. 17Beta-estradiol up-regulates vascular endothelial growth factor receptor-2 expression in human myometrial microvascular endothelial cells: role of estrogen receptor-alpha and -beta. J Clin Endocrinol Metab. 2002;87:4341–9.
Banerjee SK, Sarkar DK, Weston AP, De A, Campbell DR. Over expression of vascular endothelial growth factor and its receptor during the development of estrogen-induced rat pituitary tumors may mediate estrogen-initiated tumor angiogenesis. Carcinogenesis. 1997;18:1155–61.
de Mestier L, Couvelard A, Blazevic A, Hentic O, de Herder WW, Rebours V, Paradis V, Ruszniewski P, Hofland LJ, Cros J. Critical appraisal of MGMT in digestive NET treated with alkylating agents. Endocr Relat Cancer. 2020;27:R391–405. https://doi.org/10.1530/ERC-20-0227.
Moon W-J, Choi JW, Roh HG, Lim SD, Koh Y-C. Imaging parameters of high grade gliomas in relation to the MGMT promoter methylation status: the CT, diffusion tensor imaging, and perfusion MR imaging. Neuroradiology. 2012;54:555–63. https://doi.org/10.1007/s00234-011-0947-y.
Cloyd JM, Kopecky KE, Norton JA, Kunz PL, Fisher GA, Visser BC, Dua MM, Park WG, Poultsides GA. Neuroendocrine tumors of the pancreas: degree of cystic component predicts prognosis. Surgery. 2016;160:708–13. https://doi.org/10.1016/j.surg.2016.04.005.
Mei S, Cammalleri M, Azara D, Casini G, Bagnoli P, Dal Monte M. Mechanisms underlying somatostatin receptor 2 down-regulation of vascular endothelial growth factor expression in response to hypoxia in mouse retinal explants. J Pathol. 2012;226:519–33. https://doi.org/10.1002/path.3006.
Chahal M, Xu Y, Lesniak D, Graham K, Famulski K, Christensen JG, Aghi M, Jacques A, Murray D, Sabri S, Abdulkarim B. MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib. Neuro Oncol. 2010;12:822–33. https://doi.org/10.1093/neuonc/noq017.
Czabanka M, Bruenner J, Parmaksiz G, Broggini T, Topalovic M, Bayerl SH, Auf G, Kremenetskaia I, Nieminen M, Jabouille A, Mueller S, Harms U, Harms C, Koch A, Heppner FL, Vajkoczy P. Combined temozolomide and sunitinib treatment leads to better tumour control but increased vascular resistance in O6-methylguanine methyltransferase-methylated gliomas. Eur J Cancer. 2013;49:2243–52. https://doi.org/10.1016/j.ejca.2013.02.019.
Yazdani S, Kasajima A, Tamaki K, Nakamura Y, Fujishima F, Ohtsuka H, Motoi F, Unno M, Watanabe M, Sato Y, Sasano H. Angiogenesis and vascular maturation in neuroendocrine tumors. Hum Pathol. 2014;45:866–74. https://doi.org/10.1016/j.humpath.2013.09.024.
Cooke VG, LeBleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S, Sugimoto H, Rocha RM, Damascena A, Brentani RR, Kalluri R. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell. 2012;21:66–81. https://doi.org/10.1016/j.ccr.2011.11.024.
Funding
This study has received funding by National Natural Science Foundation of China (No. 81571750, 81801761) and 2020 SKY Imaging Research Fund of the Chinese International Medical Foundation (No. Z-2014-07-2003-07).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors have no competing interests to declare that are relevant to the content of this article.
Ethical approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the ethical review board of the first affiliated hospital of Sun Yat-Sen University ([2021]013).
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhou, X., Song, C., Li, L. et al. CT-based nomogram development and validation to predict SSTR2, VEGFR2 and MGMT expression for pancreatic neuroendocrine neoplasms. Chin J Acad Radiol 6, 100–115 (2023). https://doi.org/10.1007/s42058-023-00124-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s42058-023-00124-x