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Pathology and Surgical Treatment of High-Grade Pancreatic Neuroendocrine Carcinoma: an Evolving Landscape

  • Sven-Petter HaugvikEmail author
  • Daniel Kaemmerer
  • Sebastien Gaujoux
  • Knut Jørgen Labori
  • Caroline Sophie Verbeke
  • Ivar Prydz Gladhaug
Gastrointestinal Cancers (J Meyer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Gastrointestinal Cancers

Abstract

Pancreatic neuroendocrine neoplasms (PNENs) are rare, accounting for less than 5 % of all pancreatic tumors. High-grade pancreatic neuroendocrine carcinomas (hgPNECs) represent about 5 % of all PNENs. They show highly aggressive behavior with dismal prognosis. Throughout the last two decades, there has been a notable progress in basic and clinical research of PNENs and a therapeutic trend towards both more aggressive and minimally invasive surgery. Despite these advances, hgPNECs as a distinct clinical entity remains largely unexplored among surgeons. This review of current development in pathology reporting and surgical treatment of hgPNECs aims at increasing the awareness of an evolving field in pancreatic surgery.

Keywords

Neuroendocrine tumor Neuroendocrine neoplasm Gastroenteropancreatic neuroendocrine tumor Neuroendocrine carcinoma Pancreas Pancreatic neoplasm Pancreatic surgery Pancreatic cancer Review 

Notes

Compliance with Ethical Standards

Conflict of Interest

Sven-Petter Haugvik, Daniel Kaemmerer, Sebastien Gaujoux, Knut Jørgen Labori, Caroline Sophie Verbeke, and Ivar Prydz Gladhaug declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Milan SA, Yeo CJ. Neuroendocrine tumors of the pancreas. Curr Opin Oncol. 2012;24:46–55.CrossRefPubMedGoogle Scholar
  2. 2.
    Fitzgerald TL, Hickner ZJ, Schmitz M, Kort EJ. Changing incidence of pancreatic neoplasms: a 16-year review of statewide tumor registry. Pancreas. 2008;37:134–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Bosman FT, Carneiro F, Hruban RH. WHO classification of tumours of the digestive system. Lyon: International Agency for Research on Cancer (IARC); 2010.Google Scholar
  4. 4.
    Boyar CR, Aagnes B, Thiis-Evensen E, Tretli S, Bergestuen DS, Hansen S: Trends in incidence of neuroendocrine neoplasms in Norway: a report of 16,075 cases from 1993 through 2010. Neuroendocrinology 2015.Google Scholar
  5. 5.••
    Basturk O, Tang L, Hruban RH, Adsay V, Yang Z, Krasinskas AM, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol. 2014;38:437–47. Most hgPNECs are diagnosed in patients around 60 years of age with a male predilection and predominance of tumors located in the pancreatic head. hgPNECs are often misdiagnosed by pathologists. Google Scholar
  6. 6.••
    Haugvik SP, Janson ET, Osterlund P, Langer SW, Falk RS, Labori KJ, et al: Surgical treatment as a principle for patients with high-grade pancreatic neuroendocrine carcinoma: a Nordic multicenter comparative study. Ann.Surg.Oncol. 2015. Resection of the primary tumor is an independent prognostic factor of improved survival for patients with hgPNEC at different disease stages. Patients selected for combined treatment with surgery and chemotherapy had better survival than chemotherapy alone. Google Scholar
  7. 7.
    Chabot J: Pancreatic neuroendocrine tumors: Primum non nocere. Surgery 2015.Google Scholar
  8. 8.
    Kulke MH. Are neuroendocrine tumors going mainstream? J Clin Oncol. 2013;31:404–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Norton JA, Harris EJ, Chen Y, Visser BC, Poultsides GA, Kunz PC, et al. Pancreatic endocrine tumors with major vascular abutment, involvement, or encasement and indication for resection. Arch Surg. 2011;146:724–32.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bertani E, Fazio N, Botteri E, Chiappa A, Falconi M, Grana C, et al. Resection of the primary pancreatic neuroendocrine tumor in patients with unresectable liver metastases: possible indications for a multimodal approach. Surgery. 2014;155:607–14.CrossRefPubMedGoogle Scholar
  11. 11.
    Fernandez-Cruz L, Molina V, Vallejos R, Jimenez CE, Lopez-Boado MA, Ferrer J. Outcome after laparoscopic enucleation for non-functional neuroendocrine pancreatic tumours. HPB (Oxford). 2012;14:171–6.CrossRefGoogle Scholar
  12. 12.
    Haugvik SP, Labori KJ, Edwin B, Mathisen O, Gladhaug IP. Surgical treatment of sporadic pancreatic neuroendocrine tumors: a state of the art review. Sci World J. 2012;2012:357475.CrossRefGoogle Scholar
  13. 13.
    Huttner FJ, Schneider L, Tarantino I, Warschkow R, Schmied BM, Hackert T, et al. Palliative resection of the primary tumor in 442 metastasized neuroendocrine tumors of the pancreas: a population-based, propensity score-matched survival analysis. Langenbecks Arch Surg. 2015;400:715–23.CrossRefPubMedGoogle Scholar
  14. 14.••
    Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol. 2015;39:683–90. PNENs with a mitotic rate within the G2 area and a Ki-67 index within the G3 represent a distinct subgroup of hgPNEC.CrossRefPubMedGoogle Scholar
  15. 15.
    Campbell F, Verbeke CS. Pathology of the pancreas: a practical approach. London: Springer; 2013.CrossRefGoogle Scholar
  16. 16.
    Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2012;36:173–84.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.••
    Tang LH, Untch BR, Reidy DL, Eileen OE, Dhall D, Jih L, et al: Well differentiated neuroendocrine tumors with a morphologically apparent high grade component: a pathway distinct from poorly differentiated neuroendocrine carcinomas. Clin Cancer Res 2015. The etiology of PNETs (G1 and G2) is genetically different from that of hgPNEC. Google Scholar
  18. 18.
    Khan MS, Luong TV, Watkins J, Toumpanakis C, Caplin ME, Meyer T. A comparison of Ki-67 and mitotic count as prognostic markers for metastatic pancreatic and midgut neuroendocrine neoplasms. Br J Cancer. 2013;108:1838–45.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    La RS, Sessa F. High-grade poorly differentiated neuroendocrine carcinomas of the gastroenteropancreatic system: from morphology to proliferation and back. Endocr Pathol. 2014;25:193–8.CrossRefGoogle Scholar
  20. 20.••
    Velayoudom-Cephise FL, Duvillard P, Foucan L, Hadoux J, Chougnet CN, Leboulleux S, et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer. 2013;20:649–57. PNENs with a mitotic rate within the G2 area and a Ki-67 index within the G3 represent a distinct subgroup of hgPNEC.CrossRefPubMedGoogle Scholar
  21. 21.••
    Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013;24:152–60. Gastroenteropancreatic NECs with a Ki-67 value > 55% behave clinically differently than those with a Ki-67 value < 55%.CrossRefPubMedGoogle Scholar
  22. 22.
    Sorbye H, Strosberg J, Baudin E, Klimstra DS, Yao JC. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer. 2014;120:2814–23.CrossRefPubMedGoogle Scholar
  23. 23.
    Rindi G. The ENETS guidelines: the new TNM classification system. Tumori. 2010;96:806–9.PubMedGoogle Scholar
  24. 24.
    Rindi G, Kloppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, et al. TNM staging of foregut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006;449:395–401.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sobin LH, Gospodarowicz MK, Wittekind C. UICC: TNM classification of malignant tumours, edn 7th. edn. Oxford: Wiley-Blackwell; 2009.Google Scholar
  26. 26.
    Ellison TA, Wolfgang CL, Shi C, Cameron JL, Murakami P, Mun LJ, et al. A single institution’s 26-year experience with nonfunctional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram. Ann Surg. 2014;259:204–12.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW, et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst. 2012;104:764–77.CrossRefPubMedGoogle Scholar
  28. 28.
    Qadan M, Ma Y, Visser BC, Kunz PL, Fisher GA, Norton JA, et al. Reassessment of the current American Joint Committee on Cancer staging system for pancreatic neuroendocrine tumors. J Am Coll Surg. 2014;218:188–95.CrossRefPubMedGoogle Scholar
  29. 29.
    Kloppel G, Rindi G, Perren A, Komminoth P, Klimstra DS. The ENETS and AJCC/UICC TNM classifications of the neuroendocrine tumors of the gastrointestinal tract and the pancreas: a statement. Virchows Arch. 2010;456:595–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Adesoye T, Daleo MA, Loeffler AG, Winslow ER, Weber SM, Cho CS. Discordance of histologic grade between primary and metastatic neuroendocrine carcinomas. Ann Surg Oncol. 2015;22(3):817–21.CrossRefGoogle Scholar
  31. 31.
    Tang LH, Gonen M, Hedvat C, Modlin IM, Klimstra DS. Objective quantification of the Ki67 proliferative index in neuroendocrine tumors of the gastroenteropancreatic system: a comparison of digital image analysis with manual methods. Am J Surg Pathol. 2012;36:1761–70.CrossRefPubMedGoogle Scholar
  32. 32.••
    Crippa S, Partelli S, Bassi C, Berardi R, Capelli P, Scarpa A, et al: Long-term outcomes and prognostic factors in neuroendocrine carcinomas of the pancreas: morphology matters. Surgery 2015. Radical resection of nonmetastatic hgPNEC is associated with improved survival compared with no resection. R0/R1 resections of hgPNEC is associated with better oncologic outcome than R2 resections. Google Scholar
  33. 33.
    Fischer L, Bergmann F, Schimmack S, Hinz U, Priess S, Muller-Stich BP, et al. Outcome of surgery for pancreatic neuroendocrine neoplasms. Br J Surg. 2014;101:1405–12.CrossRefPubMedGoogle Scholar
  34. 34.
    Sharpe SM, In H, Winchester DJ, Talamonti MS, Baker MS. Surgical resection provides an overall survival benefit for patients with small pancreatic neuroendocrine tumors. J Gastrointest Surg. 2015;19:117–23.CrossRefPubMedGoogle Scholar
  35. 35.••
    Garcia-Carbonero R, Sorbye H, Baudin E, Raymond E, Wiedenmann B, Niederle B, et al: Consensus guidelines for high grade gastro-entero-pancreatic (gep) neuroendocrine tumours and neuroendocrine carcinomas (nec). Neuroendocrinology 2016. The current guidelines of the European Neuroendocrine Tumor Society represent the most comprehensive of existing guidelines in the management of patients with gastroenteropancreatic NECs. Google Scholar
  36. 36.
    Heetfeld M, Chougnet CN, Olsen IH, Rinke A, Borbath I, Crespo G, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2015;22:657–64.CrossRefPubMedGoogle Scholar
  37. 37.
    Curran T, Pockaj BA, Gray RJ, Halfdanarson TR, Wasif N. Importance of lymph node involvement in pancreatic neuroendocrine tumors: impact on survival and implications for surgical resection. J Gastrointest Surg. 2015;19:152–60.CrossRefPubMedGoogle Scholar
  38. 38.
    Hashim YM, Trinkaus KM, Linehan DC, Strasberg SS, Fields RC, Cao D, et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg. 2014;259:197–203.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ferrone CR. Lymphadenectomy for pancreatic neuroendocrine tumors: is that the relevant debate? Ann Surg. 2014;259:213–4.CrossRefPubMedGoogle Scholar
  40. 40.
    Ricci C, Casadei R, Taffurelli G, Buscemi S, D’Ambra M, Monari F, et al. The role of lymph node ratio in recurrence after curative surgery for pancreatic endocrine tumours. Pancreatology. 2013;13:589–93.CrossRefPubMedGoogle Scholar
  41. 41.
    Stabile BE. When pNETs bust out of their shells. Arch Surg. 2012;147:828.CrossRefPubMedGoogle Scholar
  42. 42.
    Krampitz GW, Norton JA, Poultsides GA, Visser BC, Sun L, Jensen RT. Lymph nodes and survival in pancreatic neuroendocrine tumors. Arch Surg. 2012;147:820–7.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Yoo YJ, Yang SJ, Hwang HK, Kang CM, Kim H, Lee WJ. Overestimated oncologic significance of lymph node metastasis in G1 nonfunctioning neuroendocrine tumor in the left side of the pancreas. Medicine (Baltimore). 2015;94, e1404.CrossRefGoogle Scholar
  44. 44.
    Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42:557–77.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Shiba S, Morizane C, Hiraoka N, Sasaki M, Koga F, Sakamoto Y, et al: Pancreatic neuroendocrine tumors: a single-center 20-year experience with 100 patients. Pancreatology. 2015.Google Scholar
  46. 46.
    Janson ET, Sorbye H, Welin S, Federspiel B, Gronbaek H, Hellman P, et al. Nordic guidelines 2014 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. Acta Oncol. 2014;53:1284–97.CrossRefPubMedGoogle Scholar
  47. 47.
    Frilling A, Modlin IM, Kidd M, Russell C, Breitenstein S, Salem R, et al. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol. 2014;15:e8–e21.CrossRefPubMedGoogle Scholar
  48. 48.
    Partelli S, Inama M, Rinke A, Begum N, Valente R, Fendrich V, et al. Long-term outcomes of surgical management of pancreatic neuroendocrine tumors with synchronous liver metastases. Neuroendocrinology. 2015;102:68–76.CrossRefPubMedGoogle Scholar
  49. 49.
    Keutgen XM, Nilubol N, Glanville J, Sadowski SM, Liewehr DJ, Venzon DJ, et al: Resection of primary tumor site is associated with prolonged survival in metastatic nonfunctioning pancreatic neuroendocrine tumors. Surgery 2015.Google Scholar
  50. 50.••
    Du S, Ni J, Weng L, Ma F, Li S, Wang W, et al. Aggressive locoregional treatment improves the outcome of liver metastases from grade 3 gastroenteropancreatic neuroendocrine tumors. Medicine (Baltimore). 2015;94:e1429. Combined surgical treatment and chemotherapy of metastatic gastroenteropancreatic NECs may improve survival compared with chemotherapy alone.CrossRefGoogle Scholar
  51. 51.
    Labori KJ, Haugvik SP, Line PD. Letter to the editor: Multidisciplinary management of pancreatic neuroendocrine tumors—the importance of an aggressive surgical approach. Scand J Gastroenterol. 2016;51:383–4.CrossRefPubMedGoogle Scholar
  52. 52.
    Kulke MH, Siu LL, Tepper JE, Fisher G, Jaffe D, Haller DG, et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin Oncol. 2011;29:934–43.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Sven-Petter Haugvik
    • 1
    • 2
    • 3
    Email author
  • Daniel Kaemmerer
    • 4
  • Sebastien Gaujoux
    • 5
  • Knut Jørgen Labori
    • 1
  • Caroline Sophie Verbeke
    • 2
    • 6
  • Ivar Prydz Gladhaug
    • 1
    • 2
  1. 1.Department of Hepato-Pancreato-Biliary SurgeryOslo University HospitalNydalenNorway
  2. 2.Institute of Clinical MedicineUniversity of OsloBlindernNorway
  3. 3.Department of Surgery, Drammen HospitalVestre Viken Hospital TrustDrammenNorway
  4. 4.Department of General and Visceral SurgeryZentralklinik Bad BerkaBad BerkaGermany
  5. 5.Department of Digestive and Endocrine Surgery, Cochin Hospital, APHPUniversité Paris DescartesParisFrance
  6. 6.Department of PathologyOslo University HospitalNydalenNorway

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