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Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors

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Abstract

Small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs) often present with liver metastases. Although liver biopsy establishes a neuroendocrine diagnosis, the primary tumor site is frequently unknown without exploratory surgery. Gene expression differences in metastases may distinguish primary SBNETs and PNETs. This study sought to determine expression differences of four genes in neuroendocrine metastases and to create a gene expression algorithm to distinguish the primary site. Nodal and liver metastases from SBNETs and PNETs (n = 136) were collected at surgery under an Institutional Review Board-approved protocol. Quantitative PCR measured expression of bombesin-like receptor-3, opioid receptor kappa-1, oxytocin receptor, and secretin receptor in metastases. Logistic regression models defined an algorithm predicting the primary tumor site. Models were developed on a training set of 21 nodal metastases and performance was validated on an independent set of nodal and liver metastases. Expression of all four genes was significantly different in SBNET compared to PNET metastases. The optimal model employed expression of bombesin-like receptor-3 and opioid receptor kappa-1. When these genes did not amplify, the algorithm used oxytocin receptor and secretin receptor expression, which allowed classification of all 136 metastases with 94.1 % accuracy. In the independent liver metastasis validation set, 52/56 (92.9 %) were correctly classified. Positive predictive values were 92.5 % for SBNETs and 93.8 % for PNETs. This validated algorithm accurately distinguishes SBNET and PNET metastases based on their expression of four genes. High accuracy in liver metastases demonstrates applicability to the clinical setting. Studies assessing this algorithm’s utility in prospective clinical decision-making are warranted.

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Abbreviations

SBNETs:

Small bowel neuroendocrine tumors

PNETs:

Pancreatic neuroendocrine tumors

NETs:

Neuroendocrine tumors

mTOR:

Mammalian target of rapamycin

IHC:

Immunohistochemistry

OXTR:

Oxytocin receptor

SCTR:

Secretin receptor

GIPR:

Gastric inhibitory polypeptide receptor

BRS3:

Bombesin-like receptor-3

OPRK1:

Opioid receptor kappa-1

Ct:

Threshold cycles

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

POLR2A:

Polymerase (RNA) II polypeptide A

dCT:

Delta threshold cycles

PFS:

Progression-free survival

OS:

Overall survival

CDX2:

Caudal type homeobox 2

ISL1:

Insulin gene enhancer binding protein 1

PR:

Progesterone receptor

PAX6:

Paired box gene 6

IQR:

Interquartile range

CI:

Confidence interval

PPV:

Positive predictive value

References

  1. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB (2008) One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26(18):3063–3072. doi:10.1200/JCO.2007.15.4377

    Article  PubMed  Google Scholar 

  2. Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A (2008) Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 9(1):61–72. doi:10.1016/S1470-2045(07)70410-2

    Article  CAS  PubMed  Google Scholar 

  3. Wang SC, Parekh JR, Zuraek MB, Venook AP, Bergsland EK, Warren RS, Nakakura EK (2010) Identification of unknown primary tumors in patients with neuroendocrine liver metastases. Arch Surg 145(3):276–280. doi:10.1001/archsurg.2010.10

    Article  PubMed  Google Scholar 

  4. Oberg K, Knigge U, Kwekkeboom D, Perren A (2012) Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 23(Suppl 7):vii124–130. doi:10.1093/annonc/mds295

  5. Dahdaleh FS, Lorenzen A, Rajput M, Carr JC, Liao J, Menda Y, O’Dorisio TM, Howe JR (2013) The value of preoperative imaging in small bowel neuroendocrine tumors. Ann Surg Oncol 20(6):1912–1917. doi:10.1245/s10434-012-2836-y

    Article  PubMed  Google Scholar 

  6. Prasad V, Ambrosini V, Hommann M, Hoersch D, Fanti S, Baum RP (2010) Detection of unknown primary neuroendocrine tumours (CUP-NET) using (68)Ga-DOTA-NOC receptor PET/CT. Eur J Nucl Med Mol Imaging 37(1):67–77. doi:10.1007/s00259-009-1205-y

    Article  CAS  PubMed  Google Scholar 

  7. Bartlett EK, Roses RE, Gupta M, Shah PK, Shah KK, Zaheer S, Wachtel H, Kelz RR, Karakousis GC, Fraker DL (2013) Surgery for metastatic neuroendocrine tumors with occult primaries. J Surg Res 184(1):221–227. doi:10.1016/j.jss.2013.04.008

    Article  PubMed  Google Scholar 

  8. Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Blaker M, Harder J, Arnold C, Gress T, Arnold R (2009) Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 27(28):4656–4663. doi:10.1200/JCO.2009.22.8510

    Article  CAS  PubMed  Google Scholar 

  9. Korse CM, Taal BG, van Velthuysen ML, Visser O (2013) Incidence and survival of neuroendocrine tumours in the Netherlands according to histological grade: experience of two decades of cancer registry. Eur J Cancer 49(8):1975–1983. doi:10.1016/j.ejca.2012.12.022

    Article  PubMed  Google Scholar 

  10. Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM, Que FG (2003) Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg 197(1):29–37. doi:10.1016/S1072-7515(03)00230-8

    Article  PubMed  Google Scholar 

  11. Mayo SC, de Jong MC, Pulitano C, Clary BM, Reddy SK, Gamblin TC, Celinksi SA, Kooby DA, Staley CA, Stokes JB, Chu CK, Ferrero A, Schulick RD, Choti MA, Mentha G, Strub J, Bauer TW, Adams RB, Aldrighetti L, Capussotti L, Pawlik TM (2010) Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol 17(12):3129–3136. doi:10.1245/s10434-010-1154-5

    Article  PubMed  Google Scholar 

  12. Zaknun JJ, Bodei L, Mueller-Brand J, Pavel ME, Baum RP, Horsch D, O’Dorisio MS, O’Dorisiol TM, Howe JR, Cremonesi M, Kwekkeboom DJ (2013) The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 40(5):800–816. doi:10.1007/s00259-012-2330-6

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Givi B, Pommier SJ, Thompson AK, Diggs BS, Pommier RF (2006) Operative resection of primary carcinoid neoplasms in patients with liver metastases yields significantly better survival. Surgery 140 (6):891–897; discussion 897–898. doi:10.1016/j.surg.2006.07.033

  14. Hill JS, McPhee JT, McDade TP, Zhou Z, Sullivan ME, Whalen GF, Tseng JF (2009) Pancreatic neuroendocrine tumors: the impact of surgical resection on survival. Cancer 115(4):741–751. doi:10.1002/cncr.24065

    Article  PubMed  Google Scholar 

  15. Capurso G, Bettini R, Rinzivillo M, Boninsegna L, Delle Fave G, Falconi M (2011) Role of resection of the primary pancreatic neuroendocrine tumour only in patients with unresectable metastatic liver disease: a systematic review. Neuroendocrinology 93(4):223–229. doi:10.1159/000324770

    Article  CAS  PubMed  Google Scholar 

  16. Capurso G, Rinzivillo M, Bettini R, Boninsegna L, Delle Fave G, Falconi M (2012) Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases. Br J Surg 99(11):1480–1486. doi:10.1002/bjs.8842

    Article  CAS  PubMed  Google Scholar 

  17. Strosberg JR (2013) Systemic treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): current approaches and future options. Endocr Pract 20(2):167–175. doi:10.4158/EP13262.RA

    Article  Google Scholar 

  18. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364(6):514–523. doi:10.1056/NEJMoa1009290

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Horsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364(6):501–513. doi:10.1056/NEJMoa1003825

    Article  CAS  PubMed  Google Scholar 

  20. Oberg K, Casanovas O, Castano JP, Chung D, Delle Fave G, Denefle P, Harris P, Khan MS, Kulke MH, Scarpa A, Tang LH, Wiedenmann B (2013) Molecular pathogenesis of neuroendocrine tumors: implications for current and future therapeutic approaches. Clin Cancer Res 19(11):2842–2849. doi:10.1158/1078-0432.CCR-12-3458

    Article  CAS  PubMed  Google Scholar 

  21. Ganetsky A, Bhatt V (2012) Gastroenteropancreatic neuroendocrine tumors: update on therapeutics. Ann Pharmacother 46(6):851–862. doi:10.1345/aph.1Q729

    Article  PubMed  Google Scholar 

  22. Sherman SK, Howe JR (2013) Translational research in endocrine surgery. Surg Oncol Clin N Am 22(4):857–884. doi:10.1016/j.soc.2013.06.012

    Article  PubMed Central  PubMed  Google Scholar 

  23. Bellizzi AM (2013) Assigning site of origin in metastatic neuroendocrine neoplasms: a clinically significant application of diagnostic immunohistochemistry. Adv Anat Pathol 20(5):285–314. doi:10.1097/PAP.0b013e3182a2dc67

    Article  CAS  PubMed  Google Scholar 

  24. Koo J, Mertens RB, Mirocha JM, Wang HL, Dhall D (2012) Value of Islet 1 and PAX8 in identifying metastatic neuroendocrine tumors of pancreatic origin. Mod Pathol 25(6):893–901. doi:10.1038/modpathol.2012.34

    Article  CAS  PubMed  Google Scholar 

  25. Kerr SE, Schnabel CA, Sullivan PS, Zhang Y, Huang VJ, Erlander MG, Brachtel EF, Dry SM (2013) A 92-gene cancer classifier predicts the site of origin for neuroendocrine tumors. Mod Pathol. doi:10.1038/modpathol.2013.105

    PubMed  Google Scholar 

  26. Kerr SE, Schnabel CA, Sullivan PS, Zhang Y, Singh V, Carey B, Erlander MG, Highsmith WE, Dry SM, Brachtel EF (2012) Multisite validation study to determine performance characteristics of a 92-gene molecular cancer classifier. Clin Cancer Res 18(14):3952–3960. doi:10.1158/1078-0432.CCR-12-0920

    Article  CAS  PubMed  Google Scholar 

  27. Posorski N, Kaemmerer D, Ernst G, Grabowski P, Hoersch D, Hommann M, von Eggeling F (2011) Localization of sporadic neuroendocrine tumors by gene expression analysis of their metastases. Clin Exp Metastasis 28(7):637–647. doi:10.1007/s10585-011-9397-5

    Article  CAS  PubMed  Google Scholar 

  28. Carr JC, Boese EA, Spanheimer PM, Dahdaleh FS, Martin M, Calva D, Schafer B, Thole DM, Braun T, O’Dorisio TM, O’Dorisio MS, Howe JR (2012) Differentiation of small bowel and pancreatic neuroendocrine tumors by gene-expression profiling. Surgery 152(6):998–1007. doi:10.1016/j.surg.2012.08.040

    Article  PubMed Central  PubMed  Google Scholar 

  29. Carr JC, Sherman SK, Wang D, Dahdaleh FS, Bellizzi AM, O’Dorisio MS, O’Dorisio TM, Howe JR (2013) Overexpression of membrane proteins in primary and metastatic gastrointestinal neuroendocrine tumors. Ann Surg Oncol 20(Suppl 3):739–746. doi:10.1245/s10434-013-3318-6

    Article  Google Scholar 

  30. Sherman SK, Carr JC, Wang D, O’Dorisio MS, O’Dorisio TM, Howe JR (2013) Gastric inhibitory polypeptide receptor (GIPR) is a promising target for imaging and therapy in neuroendocrine tumors. Surgery 154(6):1206–1214. doi:10.1016/j.surg.2013.04.052

    Article  PubMed  Google Scholar 

  31. Dahdaleh FS, Calva-Cerqueira D, Carr JC, Liao J, Mezhir JJ, O’Dorisio TM, Howe JR (2012) Comparison of clinicopathologic factors in 122 patients with resected pancreatic and ileal neuroendocrine tumors from a single institution. Ann Surg Oncol 19(3):966–972. doi:10.1245/s10434-011-1997-4

    Article  PubMed  Google Scholar 

  32. Begum N, Hubold C, Buchmann I, Thorns C, Bouchard R, Lubienski A, Schloricke E, Zimmermann M, Lehnert H, Bruch HP, Burk CG (2013) Diagnostics and therapy for neuroendocrine neoplasia of an unknown primary—a plea for open exploration. Zentralbl Chir. doi:10.1055/s-0032-1327962

    Google Scholar 

  33. Taner T, Atwell TD, Zhang L, Oberg TN, Harmsen WS, Slettedahl SW, Kendrick ML, Nagorney DM, Que FG (2013) Adjunctive radiofrequency ablation of metastatic neuroendocrine cancer to the liver complements surgical resection. HPB (Oxford) 15(3):190–195. doi:10.1111/j.1477-2574.2012.00528.x

    Article  Google Scholar 

  34. Eriksson J, Stalberg P, Nilsson A, Krause J, Lundberg C, Skogseid B, Granberg D, Eriksson B, Akerstrom G, Hellman P (2008) Surgery and radiofrequency ablation for treatment of liver metastases from midgut and foregut carcinoids and endocrine pancreatic tumors. World J Surg 32(5):930–938. doi:10.1007/s00268-008-9510-3

    Article  PubMed  Google Scholar 

  35. Falconi M, Bartsch DK, Eriksson B, Kloppel G, Lopes JM, O’Connor JM, Salazar R, Taal BG, Vullierme MP, O’Toole D (2012) ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors. Neuroendocrinology 95(2):120–134. doi:10.1159/000335587

    Article  CAS  PubMed  Google Scholar 

  36. Pape UF, Perren A, Niederle B, Gross D, Gress T, Costa F, Arnold R, Denecke T, Plockinger U, Salazar R, Grossman A (2012) ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology 95(2):135–156. doi:10.1159/000335629

    Article  CAS  PubMed  Google Scholar 

  37. Kuo EJ, Salem RR (2013) Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size. Ann Surg Oncol 20(9):2815–2821. doi:10.1245/s10434-013-3005-7

    Article  PubMed  Google Scholar 

  38. Lee LC, Grant CS, Salomao DR, Fletcher JG, Takahashi N, Fidler JL, Levy MJ, Huebner M (2012) Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): role for nonoperative management. Surgery 152(6):965–974. doi:10.1016/j.surg.2012.08.038

    Article  PubMed  Google Scholar 

  39. Pavel M, Baudin E, Couvelard A, Krenning E, Oberg K, Steinmuller T, Anlauf M, Wiedenmann B, Salazar R (2012) ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 95(2):157–176. doi:10.1159/000335597

    Article  CAS  PubMed  Google Scholar 

  40. Stashek KM, Czeczok TW, Bellizzi AM (2014) Extensive evaluation of immunohistochemistry to assign site of origin in well-differentiated neuroendocrine tumors: a study of 10 markers in 265 tumors. Mod Pathol 27(Suppl 2):160A

    Google Scholar 

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Acknowledgments

We gratefully acknowledge our patients for participating in this research. Supported by NIH 5T32#CA148062-03 (SKS, JEM, JCC)

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Correspondence to James R. Howe.

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Sherman, S.K., Maxwell, J.E., Carr, J.C. et al. Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors. Clin Exp Metastasis 31, 935–944 (2014). https://doi.org/10.1007/s10585-014-9681-2

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  • DOI: https://doi.org/10.1007/s10585-014-9681-2

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