Download PDF
Horm Metab Res 2011; 43(12): 832-837
DOI: 10.1055/s-0031-1287794
Review
© Georg Thieme Verlag KG Stuttgart · New York

Biomarkers and Molecular Imaging in Gastroenteropancreatic Neuroendocrine Tumors

D. P. Lindholm
1   Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden
,
K. Öberg
1   Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden
› Author Affiliations
Further Information

Publication History

received 22 March 2011

accepted 30 August 2011

Publication Date:
18 October 2011 (online)

Also available at
    Permissions and Reprints

Abstract

Neuroendocrine gastrointestinal and pancreatic tumors (GEP-NETs) are a heterogenous group of cancers with various clinical expressions. All tumors produce and secret various amines and peptides, which can be used as tissue and circulating markers. Chromogranin A (CgA) is a general tumor marker stored in secretory granules within the tumor cell and released upon stimulation. CgA is the best general tumor marker at the moment, expressed in 80–90% in all patients with GEP-NETs. CgA and NSE are used as tissue markers for the delineation of the neuroendocrine features of the tumors, but recently also the proliferation marker Ki-67 has been included in the standard procedure for evaluation of the proliferation. GEP-NETs are classified into well differentiated neuroendocrine tumors (Ki-67<2%), well-differentiated neuroendocrine carcinoma (Ki-67 2–20%), poorly differentiated neuroendocrine carcinoma (Ki-67>20%). The molecular imaging of NETs is based on the ability of these tumor cells to express somatostatin receptors as well as the APUD features. Octreoscan has been applied for imaging and staging of the disease for more than 2 decades and will nowadays be replaced by 68Ga-DOTA-Octreotate, with higher specificity and sensitivity. 18Fluoro-DOPA and 11C-5HTP are specific tracers for NETs with high specificity and selectivity. A new potential biomarker is auto-antibodies to paraneoplastic antigen MA2, which might indicate early recurrence of carcinoids after surgery with a curative intent. Circulating tumor cells (CTC) have been applied in GEP-NETs quite recently. There is still an unmet need for new markers.

Key words

11C-5HTP - 68 GA-DOTATOC PET - PNMA 2 - CTC - MGMT - PLA - GEP-NETs - biomarkers
 

  • References

  • 1 Klöppel G, Couvelard A, Perren A, Komminoth P, McNicol AM, Nilsson O, Scarpa A, Scoazec JY, Wiedenmann B, Papotti M, Rindi G, Plöckinger U. Mallorca Consensus Conference participants; European Neuroendocrine Tumor Society . ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification. Neuroendocrinology 2009; 90: 162-166
    CrossrefPubMedGoogle Scholar
  • 2 Sawyers CL. The cancer biomarker problem. Nature 2008; 452 (7187) 548-552
    CrossrefPubMedGoogle Scholar
  • 3 O’Connor DT. Chromogranin: widespread immunoreactivity in polypeptide hormone producing tissues and in serum. Regul Pept 1983; 6: 263-280
    CrossrefPubMedGoogle Scholar
  • 4 O’Connor DT, Deftos LJ. Secretion of chromogranin A by peptide-producing endocrine neoplasms. N Engl J Med 1986; 314: 1145-1151
    CrossrefPubMedGoogle Scholar
  • 5 Eriksson B, Arnberg H, Oberg K, Hellman U, Lundqvist G, Wernstedt C, Wilander E. Chromogranins – new sensitive markers for neuro­endocrine tumors. Acta Oncologica (Stockholm, Sweden) 1989; 28: 325-329
    CrossrefPubMedGoogle Scholar
  • 6 Arnold R, Wilke A, Rinke A, Mayer C, Kann PH, Klose KJ, Scherag A, Hahmann M, Müller HH, Barth P. Plasma chromogranin A as marker for survival in patients with metastatic endocrine gastroenteropancreatic tumors. Clin Gastroenterol Hepatol 2008; 6: 820-827
    CrossrefPubMedGoogle Scholar
  • 7 Welin S, Stridsberg M, Cunnigham J, Granberg D, Skogseid B, Oberg K, Eriksson B, Janson ET. Elevated Plasma Chromogranin A Is the First Indication of Recurrence in Radically Operated Midgut Carcinoid Tumors. Neuroendocrinology 2009; 89: 302-307
    CrossrefPubMedGoogle Scholar
  • 8 Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008; 26: 4311-4318
    CrossrefPubMedGoogle Scholar
  • 9 Korse C, Taal BG, de Groot CA, Bakker RH, Bonfrer JMG. Chromogranin-A and N-Terminal Pro-Brain Natriuretic Peptide: An Excellent Pair of Biomarkers for Diagnostics in Patients With Neuroendocrine Tumor. J Clin Oncol 2009; 27: 4293-4299
    CrossrefPubMedGoogle Scholar
  • 10 Sanduleanu S, Stridsberg M, Jonkers D, Hameeteman W, Biemond I, Lundqvist G, Lamers C, Stockbrügger RW. Serum gastrin and chromogranin A during medium- and long-term acid suppressive therapy: a case-control study. Aliment Pharmacol Ther 1999; 13: 145-153
    CrossrefPubMedGoogle Scholar
  • 11 Sidhu R, McAlindon ME, Leeds JS, Skilling J, Sanders DS. The role of serum chromogranin A in diarrhoea predominant irritable bowel syndrome. J Gastrointestin Liver Dis 2009; 18: 23-26
    PubMedGoogle Scholar
  • 12 Sciola V, Massironi S, Conte D, Caprioli F, Ferrero S, Ciafardini C, Peracchi M, Bardella MT, Piodi L. Plasma chromogranin a in patients with inflammatory bowel disease. Inflamm Bowel Dis 2009; 15: 867-871
    PubMedGoogle Scholar
  • 13 Molina R, Alvarez E, Aniel-Quiroga A, Borque M, Candás B, Leon A, Poyatos RM, Gelabert M. Evaluation of chromogranin A determined by three different procedures in patients with benign diseases, neuroendocrine tumors and other malignancies. Tumour Biol 2011; 32: 13-22
    CrossrefPubMedGoogle Scholar
  • 14 Oberg K, Stridsberg M. Neuroendocrine Tumors in Tumor Markers. In Diamandis EP, Fritsche HA, Lilja H, Chan DW, Schwartz MK. (eds.) 2002. AACC Press; Washington: 339-349
    Google Scholar
  • 15 Plöckinger U, Rindi G, Arnold R, Eriksson B, Krenning EP, de Herder WW, Goede A, Caplin M, Oberg K, Reubi JC, Nilsson O, Delle Fave G, Ruszniewski P, Ahlman H, Wiedenmann B. European Neuroendocrine Tumour ­Society . Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology 2004; 80: 394-424
    CrossrefPubMedGoogle Scholar
  • 16 Boudreaux JP, Klimstra DS, Hassan MM, Woltering EA, Jensen RT, Goldsmith SJ, Nutting C, Bushnell DL, Caplin ME, Yao JC. North American Neuroendocrine Tumor Society (NANETS) . The NANETS Consensus Guideline for the Diagnosis and Management of Neuroendocrine Tumors: Well-Differentiated Neuroendocrine Tumors of the Jejunum, Ileum, Appendix, and Cecum. Pancreas 2010; 39: 753-766
    CrossrefPubMedGoogle Scholar
  • 17 Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 2002; 419 (6903) 135-141
    CrossrefPubMedGoogle Scholar
  • 18 Pelosi G, Bresaola E, Bogina G, Pasini F, Rodella S, Castelli P, Iacono C, Serio G, Zamboni G. Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables. Hum Pathol 1996; 27: 1124-1134
    CrossrefPubMedGoogle Scholar
  • 19 Clarke MR, Baker EE, Weyant RJ, Hill L, Carty SE. Proliferative Activity in Pancreatic Endocrine Tumors: Association with Function, Metastases, and Survival. Endocr Pathol 1997; 8: 181-187
    CrossrefPubMedGoogle Scholar
  • 20 Gentil Perret A, Mosnier JF, Buono JP, Berthelot P, Chipponi J, Balique JG, Cuilleret J, Dechelotte P, Boucheron S. The relationship between MIB-1 proliferation index and outcome in pancreatic neuroendocrine tumors. Am J Clin Pathol 1998; 109: 286-293
    PubMedGoogle Scholar
  • 21 Rigaud G, Missiaglia E, Moore PS, Zamboni G, Falconi M, Talamini G, Pesci A, Baron A, Lissandrini D, Rindi G, Grigolato P, Pederzoli P, Scarpa A. High resolution allelotype of nonfunctional pancreatic endocrine tumors: identification of two molecular subgroups with clinical implications. Cancer Res 2001; 61: 285-292
    PubMedGoogle Scholar
  • 22 Hochwald SN, Zee S, Conlon KC, Colleoni R, Louie O, Brennan MF, Klimstra DS. Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol 2002; 20: 2633-2642
    CrossrefPubMedGoogle Scholar
  • 23 Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res 2008; 14: 7798-7803
    CrossrefPubMedGoogle Scholar
  • 24 Granberg D, Wilander E, Oberg K, Skogseid B. Prognostic markers in patients with typical bronchial carcinoid tumors. J Clin Endocrinol Metab 2000; 85: 3425-3430
    CrossrefPubMedGoogle Scholar
  • 25 Cunningham JL, Grimelius L, Sundin A, Agarwal S, Janson ET. Malignant ileocaecal serotonin-producing carcinoid tumours: the presence of a solid growth pattern and/or Ki67 index above 1% identifies patients with a poorer prognosis. Acta oncologica (Stockholm, Sweden) 2007; 46: 747-756
    CrossrefPubMedGoogle Scholar
  • 26 Bergestuen DS, Aabakken L, Holm K, Vatn M, Thiis-Evensen E. Small intestinal neuroendocrine tumors: Prognostic factors and survival. Scand J Gastroenterol 2009; 1-8
    PubMedGoogle Scholar
  • 27 Viale G, Giobbie-Hurder A, Regan MM, Coates AS, Mastropasqua MG, Dell’Orto P, Maiorano E, MacGrogan G, Braye SG, Ohlschlegel C, Neven P, Orosz Z, Olszewski WP, Knox F, Thürlimann B, Price KN, Castiglione-Gertsch M, Gelber RD, Gusterson BA, Goldhirsch A. Breast International Group Trial 1-98 . Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol 2008; 26: 5569-5575
    CrossrefPubMedGoogle Scholar
  • 28 Krausz Y, Freedman N, Rubinstein R, Lavie E, Orevi M, Tshori S, Salmon A, Glaser B, Chisin R, Mishani EJ, Gross D. Ga-DOTA-NOC PET/CT imaging of neuroendocrine tumors: comparison with (1)(1)(1)In-DTPA-octreotide (OctreoScan(R)). Mol Imaging Biol 2011; 13: 583-593
    CrossrefPubMedGoogle Scholar
  • 29 Ruf J, Schiefer J, Furth C, Kosiek O, Kropf S, Heuck F, Denecke T, Pavel M, Pascher A, Wiedenmann B, Amthauer H. 68Ga-DOTATOC PET/CT of neuroendocrine tumors: spotlight on the CT phases of a triple-phase protocol. J Nucl Med 52: 697-704
    PubMedGoogle Scholar
  • 30 Gabriel M, Decristoforo C, Kendler D, Dobrozemsky G, Heute D, Uprimny C, Kovacs P, Von Guggenberg E, Bale R, Virgolini IJ. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med 2007; 48: 508-518
    CrossrefPubMedGoogle Scholar
  • 31 Koopmans KP, Neels OC, Kema IP, Elsinga PH, Sluiter WJ, Vanghillewe K, Brouwers AH, Jager PL, de Vries EG. Improved staging of patients with carcinoid and islet cell tumors with 18F-dihydroxy-phenyl-alanine and 11C-5-hydroxy-tryptophan positron emission tomography. J Clin Oncol 2008; 26: 1489-1495
    CrossrefPubMedGoogle Scholar
  • 32 Orlefors H, Sundin A, Garske U, Juhlin C, Oberg K, Skogseid B, Langstrom B, Bergstrom M, Eriksson B. Whole-body (11)C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and computed tomography. J Clin Endocrinol Metab 2005; 90: 3392-3400
    CrossrefPubMedGoogle Scholar
  • 33 Binderup T, Knigge U, Loft A, Federspiel B, Kjaer A. 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors. Clin Cancer Res 2010; 16: 978-985
    CrossrefPubMedGoogle Scholar
  • 34 Del Vecchio S, Zannetti A, Fonti R, Iommelli F, Pizzuti LM, Lettieri A, Salvatore M. PET/CT in cancer research: from preclinical to clinical applications. Contrast Media Mol Imaging 2010; 5: 190-200
    CrossrefPubMedGoogle Scholar
  • 35 Barwick T, Bencherif B, Mountz JM, Avril N. Molecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: a comprehensive evaluation. Nucl Med Commun 2009; 30: 908-917
    CrossrefPubMedGoogle Scholar
  • 36 Cui T, Hurtig M, Elgue G, Li SC, Veronesi G, Essaghir A, Demoulin JB, Pelosi G, Alimohammadi M, Öberg K, Giandomenico V. Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors. PLoS One 2010; 5: e16010
    CrossrefPubMedGoogle Scholar
  • 37 Khan MS, Tsigani T, Rashid M, Rabouhans Js, Yu D, Luong TV, Caplin M, Meyer T. Circulating tumor cells and EpCAM expression in neuroendocrine tumors. Clin Cancer Res 2010; 17: 337-345
    PubMedGoogle Scholar
  • 38 Kulke MH, Hornick JL, Frauenhoffer C, Hooshmand S, Ryan DP, Enzinger PC, Meyerhardt JA, Clark JW, Stuart K, Fuchs CS, Redston MS. O6-methyl­guanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 2009; 15: 338-345
    CrossrefPubMedGoogle Scholar
  • 39 Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, della Peruta M, Piemonti L, Capurso G, Di Florio A, delle Fave G, Pederzoli P, Croce CM, Scarpa A. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 2010; 28: 245-255
    CrossrefPubMedGoogle Scholar
  • 40 Söderberg O, Leuchowius KJ, Kamali-Moghaddam M, Jarvius M, Gustafsdottir S, Schallmeiner E, Gullberg M, Jarvius J, Landegren U. Proximity ligation: a specific and versatile tool for the proteomic era. Genet Eng (NY) 2007; 28: 85-93
    PubMedGoogle Scholar
  • 41 Schallmeiner E, Oksanen E, Ericsson O, Spångberg L, Eriksson S, Stenman UH, Pettersson K, Landegren U. Sensitive protein detection via triple-binder proximity ligation assays. Nat Meth 2007; 4: 135-137
    CrossrefPubMedGoogle Scholar
  • 42 Fredriksson S, Gullberg M, Jarvius J, Olsson C, Pietras K, Gústafsdóttir SM, Ostman A, Landegren U. Protein detection using proximity-dependent DNA ligation assays. Nat Biotechnol 2002; 20: 473-477
    CrossrefPubMedGoogle Scholar
  • 43 Gullberg M, Gústafsdóttir SM, Schallmeiner E, Jarvius J, Bjarnegård M, Betsholtz C, Landegren U, Fredriksson S. Cytokine detection by antibody-based proximity ligation. Proc Natl Acad Sci USA 2004; 101: 8420-8424
    CrossrefPubMedGoogle Scholar
  • 44 Darmanis S, Nong RY, Hammond M, Gu J, Alderborn A, Vänelid J, Siegbahn A, Gustafsdottir S, Ericsson O, Landegren U, Kamali-Moghaddam M. Sensitive plasma protein analysis by microparticle-based proximity ligation assays. Mol Cell Proteomics 2010; 9: 327-335
    PubMedGoogle Scholar
  • 45 Rindi G Leiter AB, Kopin AS, Bordi C, Solcia E. The “normal” endocrine cell odddddf the gut: changing concepts and new evidences. Ann NY Acad Sci 2004; 1014: 1-12
    CrossrefPubMedGoogle Scholar
  • 46 Berezovski MV, Lechmann M, Musheev MU, Mak TW, Krylov SN. Aptamer-facilitated biomarker discovery (AptaBiD). J Am Chem Soc 2008; 130: 9137-9143
    CrossrefPubMedGoogle Scholar
  • 47 Andersson T, Lundquist M, Dolphin GT, Enander K, Jonsson BH, Nilsson JW, Baltzer L. The binding of human carbonic anhydrase II by functionalized folded polypeptide receptors. Chem Biol 2005; 12: 1245-1252
    CrossrefPubMedGoogle Scholar
  • 48 Pu Y, Zhu Z, Liu H, Zhang J, Liu J, Tan W. Using aptamers to visualize and capture cancer cells. Anal Bioanal Chem 397: 3225-3233
    PubMedGoogle Scholar
  • 49 Vinik AI, Silva MP, Woltering EA, Go VL, Warner R, Caplin M. Biochemical testing for neuroendocrine tumors. Pancreas 2009; 38: 876-889
    CrossrefPubMedGoogle Scholar