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Preoperative assessment of microvessel density in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs)

Published:August 08, 2022DOI:https://doi.org/10.1016/j.surg.2022.06.017

      Abstract

      Background

      Hypervascularization is a typical feature of pancreatic neuroendocrine tumors, and it frequently allows their recognition at imaging studies. However, the density of microvessels in pancreatic neuroendocrine tumors changes according to their biological behavior, and a low microvessel density is associated with higher disease aggressiveness. The primary aim was to investigate the relationship between microvessel density and aggressiveness of nonfunctioning pancreatic neuroendocrine tumors. The secondary aim was to evaluate the ability of contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound in predicting tumor microvessel density.

      Methods

      The patients who underwent surgery for nonfunctioning pancreatic neuroendocrine tumors (n = 66) with an available preoperative contrast-enhanced computed tomography (n = 39) and/or contrast-enhanced endoscopic ultrasound (n = 37) performed at San Raffaele Hospital (2016–2020) were included. The tumor vascularization was assessed by CD-34 staining, contrast-enhanced computed tomography, and contrast-enhanced endoscopic ultrasound. Median microvessel density (165 microvessels/mm2) was chosen as the cutoff to define low microvessel density and high microvessel density.

      Results

      The patients with a low microvessel density showed a significantly higher frequency of nodal metastases (P = .026), G2–G3 tumors (P = .022), and death domain-associated protein/α-thalassemia/mental retardation syndrome X-linked loss (P = .011) compared to patients with high microvessel density. The contrast-enhanced computed tomography tumor density in the arterial phase was significantly higher in patients with high microvessel density compared to those with low microvessel density (P = .016). The patients with a low microvessel density showed a significantly higher frequency of contrast-enhanced endoscopic ultrasound arterial hypoenhancement (P = .042) and late washout (P = .034). Contrast-enhanced computed tomography arterial hypoenhancement (P = .007) and contrast-enhanced endoscopic ultrasound late washout (P = .048) independently predicted a low microvessel density in the patients who underwent contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound, respectively.

      Conclusion

      A low microvessel density represents a marker of aggressiveness in the patients with nonfunctioning pancreatic neuroendocrine tumors. Contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound are reliable and easily available tools for preoperative assessment of microvessel density.
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      References

        • Rindi G.
        • Bordi C.
        Highlights of the biology of endocrine tumours of the gut and pancreas.
        Endocr Relat Cancer. 2003; 10: 427-436
        • Panzuto F.
        • Boninsegna L.
        • Fazio N.
        • et al.
        Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression.
        J Clin Oncol. 2011; 29: 2372-2377
        • Scarpa A.
        • Chang D.K.
        • Nones K.
        • et al.
        Whole-genome landscape of pancreatic neuroendocrine tumours.
        Nature. 2017; 543: 65-71
        • Boyar Centinkaya R.
        • Vatn M.
        • Aabakken L.
        • Bergestuen D.S.
        • Thiis-Evensen E.
        Survival and prognostic factors in well-differentiated pancreatic neuroendocrine tumors.
        Scand J Gastroenterol. 2014; 49: 734-741
        • Partelli S.
        • Javed A.A.
        • Andreasi V.
        • et al.
        The number of positive nodes accurately predicts recurrence after pancreaticoduodenectomy for nonfunctioning neuroendocrine neoplasms.
        Eur J Surg Oncol. 2018; 44: 778-783
        • Pomianowska E.
        • Gladhaug I.P.
        • Grzyb K.
        • et al.
        Survival following resection of pancreatic endocrine tumors: importance of R-status and the WHO and TNM classification systems.
        Scand J Gastroenterol. 2010; 45: 971-979
        • Rindi G.
        • D’Adda T.
        • Froio E.
        • Fellegara G.
        • Bordi C.
        Prognostic factors in gastrointestinal endocrine tumors.
        Endocr Pathol. 2007; 18: 145-149
        • Panzuto F.
        • Nasoni S.
        • Falconi M.
        • et al.
        Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization.
        Endocr Relat Cancer. 2005; 12: 1083-1092
        • Madeira I.
        • Terris B.
        • Voss M.
        • et al.
        Prognostic factors in patients with endocrine tumours of the duodenopancreatic area.
        Gut. 1998; 43: 422-427
        • Basturk O.
        • Tang L.
        • Hruban R.H.
        • et al.
        Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases.
        Am J Surg Pathol. 2014; 38: 437-447
        • Singhi A.D.
        • Klimstra D.S.
        Well-differentiated pancreatic neuroendocrine tumours (PanNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs): concepts, issues and a practical diagnostic approach to high-grade (G3) cases.
        Histopathology. 2018; 72: 168-177
        • Kim D.W.
        • Kim H.J.
        • Kim K.W.
        • et al.
        Neuroendocrine neoplasms of the pancreas at dynamic enhanced CT: comparison between grade 3 neuroendocrine carcinoma and grade 1/2 neuroendocrine tumour.
        Eur Radiol. 2015; 25: 1375-1383
        • Öberg K.
        Biology, diagnosis, and treatment of neuroendocrine tumors of the gastrointestinal tract.
        Curr Opin Oncol. 1994; 6: 441-451
        • Couvelard A.
        • O’Toole D.
        • Turley H.
        • et al.
        Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression.
        Br J Cancer. 2005; 92: 94-101
        • Marion-Audibert A.
        • Barel C.
        • Gouysse G.
        • et al.
        Low microvessel density is an unfavorable histoprognostic factor in pancreatic endocrine tumors.
        Gastroenterology. 2003; 125: 1094-1104
        • Takahashi Y.
        • Akishima-Fukasawa Y.
        • Kobayashi N.
        • et al.
        Prognostic value of tumor architecture, tumor-associated vascular characteristics, and expression of angiogenic molecules in pancreatic endocrine tumors.
        Clin Cancer Res. 2007; 13: 187-196
        • Schmitt A.M.
        • Schmid S.
        • Rudolph T.
        • et al.
        VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors.
        Endocr Relat Cancer. 2009; 16: 1219-1227
        • Khanna L.
        • Prasad S.R.
        • Sunnapwar A.
        • et al.
        Pancreatic neuroendocrine neo-plasms: 2020 update on pathologic and imaging findings and classification.
        Radiographics. 2020; 40: 1240-1262
        • Cappelli C.
        • Boggi U.
        • Mazzeo S.
        • et al.
        Contrast enhancement pattern on multidetector CT predicts malignancy in pancreatic endocrine tumours.
        Eur Radiol. 2015; 25: 751-759
        • Kim C.
        • Byun J.H.
        • Hong S.M.
        • et al.
        A comparison of enhancement patterns on dynamic enhanced CT and survival between patients with pancreatic neuroendocrine tumors with and without intratumoral fibrosis.
        Abdom Radiol. 2017; 42: 2835-2842
        • d’Assignies G.
        • Couvelard A.
        • Bahrami S.
        • et al.
        Pancreatic endocrine tumors: tumor blood flow assessed with perfusion CT reflects angiogenesisand correlates with prognostic factors.
        Radiology. 2009; 250: 407-416
        • Takumi K.
        • Fukukura Y.
        • Higashi M.
        • et al.
        Pancreatic neuroendocrine tumors: Correlation between the contrast-enhanced computed tomography features and the pathological tumor grade.
        Eur J Radiol. 2015; 84: 1436-1443
        • Palazzo M.
        • Napoléon B.
        • Gincul R.
        • et al.
        Contrast harmonic EUS for the prediction of pancreaticneuroendocrine tumor aggressivenes.
        Gastrointest Endosc. 2018; 87: 1481-1488
        • Ishikawa R.
        • Kamata K.
        • Hara A.
        • et al.
        Utility of contrast-enhanced harmonic endoscopicultrasonography for predicting the prognosis of pancreaticneuroendocrine neoplasms.
        Dig Endosc. 2021; 33: 829-839
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gøtzsche P.C.
        • Vandenbroucke J.P.
        The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies.
        Int J Surg. 2014; 12: 1495-1499
        • Lloyd R.
        • Osamura R.
        • Klopper G.
        • Rosai J.
        WHO Classification of Tumours of Endocrine Organs.
        4th ed. IARC Press, Lyon, France2017
        • Rindi G.
        • Klöppel G.
        • Alhman H.
        • et al.
        TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system.
        Virchows Arch. 2006; 449: 395-401
        • Zlobec I.
        • Suter G.
        • Perren A.
        • Lugli A.
        A next-generation tissue microarray (ngTMA) protocol for biomarker studies.
        J Vis Exp. 2014; 51893
        • Scoazec J.Y.
        Angiogenesis in neuroendocrine tumors: therapeutic applications.
        Neuroendocrinology. 2013; 97: 45-56
        • Benedetti G.
        • Mori M.
        • Panzeri M.M.
        • et al.
        CT-derived radiomic features to discriminate histologic characteristics of pancreatic neuroendocrine tumors.
        Radiol Med. 2021; 126: 745-760
        • Fujino M.
        • Aishima S.
        • Shindo K.
        • et al.
        Expression of glucose transporter-1 is correlated with hypoxia-inducible factor 1α and malignant potential in pancreatic neuroendocrine tumors.
        Oncol Lett. 2016; 12: 3337-3343
        • Hoshino A.
        • Aimoto T.
        • Suzuki H.
        • et al.
        A case of nonfunctioning pancreatic endocrine tumor with atypical imaging findings due to prominent fibrosis of the tumor stroma.
        J Nippon Med Sch. 2014; 81: 346-352
        • Takaji R.
        • Matsumoto S.
        • Mori H.
        • et al.
        Carcinoid tumors of the pancreas: dynamic CT and MRI features with pathological correlation.
        Abdom Imaging. 2009; 34: 753-758
        • de Palma M.
        • Biziato D.
        • Petrova T.V.
        Microenvironmental regulation of tumour angiogenesis.
        Nat Rev Cancer. 2017; 17: 457-474
        • Loi S.
        • Mori M.
        • Benedetti G.
        • et al.
        Robustness of CT radiomic features against image discretization and interpolation in characterizing pancreatic neuroendocrine neoplasms.
        Phys Med. 2020; 76: 125-133
        • Mori M.
        • Benedetti G.
        • Partelli S.
        • et al.
        Ct radiomic features of pancreatic neuroendocrine neoplasms (panNEN) are robust against delineation uncertainty.
        Phys Med. 2019; 57: 41-46
        • Bezzi C.
        • Mapelli P.
        • Presotto L.
        • et al.
        Radiomics in pancreatic neuroendocrine tumors: methodological issues and clinical significance.
        Eur J Nucl Med Mol Imaging. 2021; 48: 4002-4015
        • Tacelli M.
        • Petrone M.
        • Capurso G.
        • et al.
        Diagnostic accuracy of EUS-FNA in the evaluation of pancreatic neuroendocrine neoplasms grading: possible clinical impact of misclassification.
        Endosc Ultrasound. 2021; 10: 372-380
        • Vitali F.
        • Pfeifer L.
        • Janson C.
        • et al.
        Quantitative perfusion analysis in pancreatic contrast enhanced ultrasound (DCE-US): a promising tool for the differentiation between autoimmune pancreatitis and pancreatic cancer.
        Z Gastroenterol. 2015; 53: 1175-1181