Skip to main content

Advertisement

SpringerLink
Log in

A novel risk factor panel predicts early recurrence in resected pancreatic neuroendocrine tumors

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Pancreatic neuroendocrine tumors (PanNETs) are indolent pancreatic tumors derived from neuroendocrine cells in pancreatic islets. To date, reliable predictors for identifying patients at high risk for recurrence after curative cancer resection are lacking. We aimed to determine independent predictors for high-risk PanNETs and patient outcomes after surgery.

Methods

We analyzed relevant clinicopathological parameters in 319 consecutive patients of derivation cohort 1 and 106 patients of validation cohort 2 who underwent pancreatectomy and were diagnosed with PanNETs. Association of tumor characteristics with recurrence-free survival (RFS) and overall survival (OS) was evaluated using Cox regression.

Results

PanNET grade 3 (G3), pancreatic duct dilatation, and perineural invasion were independent prognostic factors for RFS and were significantly associated with early recurrence (within 1.5 years) of PanNETs after curative resection (P = 0.019, P < 0.001, and P < 0.001, respectively). Using these factors, we established a novel risk factor panel (R-panel), which predicted early recurrence (P < 0.001, HR = 15.02, 95% CI 5.76–39.19). Predictive accuracy of this R-panel was favorable, with a C-index of 0.853, higher than AJCC TNM staging (0.713). We further built an integrated staging system combining R-panel scoring and TNM staging, which improved predictive probability of TNM staging. Finally, we showed that adjuvant therapy with long-acting somatostatin analogs (SSAs) significantly reduced postoperative recurrence (P < 0.001) and prolonged long-term survival (P = 0.021) in patients with the above risk factors.

Conclusion

We identified a novel risk factor panel, which includes PanNET G3, pancreatic duct dilatation, and perineural invasion; this panel predicted early recurrence of PanNETs after curative resection. Patients with these risk factors can benefit from adjuvant therapy with SSAs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an international agency for research on cancer (IARC) and world health organization (WHO) expert consensus proposal. Mod Pathol. 2018;31:1770–86.

    Article  Google Scholar 

  2. Lloyd RV, Osamura R, Kloppel G, et al. WHO classification of tumours of endocrine organs. Lyon, France: IARC Press; 2017.

    Google Scholar 

  3. Cives M, Strosberg JR. Gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin. 2018;68:471–87.

    Article  Google Scholar 

  4. Partelli S, Bartsch DK, Capdevila J, et al. ENETS consensus guidelines for standard of care in neuroendocrine tumours: surgery for small intestinal and pancreatic neuroendocrine tumours. Neuroendocrinology. 2017;105:255–65.

    Article  CAS  Google Scholar 

  5. Luo G, Javed A, Strosberg JR, et al. Modified staging classification for pancreatic neuroendocrine tumors on the basis of the American joint committee on cancer and european neuroendocrine tumor society systems. J Clin Oncol. 2017;35:274–80.

    Article  Google Scholar 

  6. Knigge U, Capdevila J, Bartsch DK, et al. ENETS consensus recommendations for the standards of care in neuroendocrine neoplasms: follow-up and documentation. Neuroendocrinology. 2017;105:310–9.

    Article  CAS  Google Scholar 

  7. National comprehensive cancer network clinical practice guidelines in oncology (NCCN guidelines®). Neuroendocrine and adrenal tumors. Version 1.2019. http://www.nccn.org. Accessed 20 June 2020

  8. Genc CG, Jilesen AP, Partelli S, et al. A new scoring system to predict recurrent disease in grade 1 and 2 nonfunctional pancreatic neuroendocrine tumors. Ann Surg. 2018;267:1148–54.

    Article  Google Scholar 

  9. Sallinen VJ, Le Large TYS, Tieftrunk E, et al. Prognosis of sporadic resected small (≤ 2 cm) nonfunctional pancreatic neuroendocrine tumors—a multi-institutional study. HPB (Oxford). 2018;20:251–9.

    Article  Google Scholar 

  10. Nanno Y, Matsumoto I, Zen Y, et al. Pancreatic duct involvement in well-differentiated neuroendocrine tumors is an independent poor prognostic factor. Ann Surg Oncol. 2017;24:1127–33.

    Article  Google Scholar 

  11. Gao H, Liu L, Wang W, et al. Novel recurrence risk stratification of resected pancreatic neuroendocrine tumor. Cancer Lett. 2018;412:188–93.

    Article  CAS  Google Scholar 

  12. Cai L, Michelakos T, Deshpande V, et al. Role of tumor-associated macrophages in the clinical course of pancreatic neuroendocrine tumors (PanNETs). Clin Cancer Res. 2019;25:2644–55.

    Article  CAS  Google Scholar 

  13. Xu JZ, Wang WQ, Zhang SR, et al. Intrinsic contact between T and N classifications in resected well-moderately differentiated locoregional pancreatic neuroendocrine neoplasms. Ann Surg Oncol. 2018;25:647–54.

    Article  Google Scholar 

  14. Amin MB, Edge SB, Greene FL, et al. AJCC cancer staging manual. 8th ed. New York: Springer; 2018.

    Google Scholar 

  15. WHO Classification of Tumours Editorial Board. Digestive system tumours, WHO classification of tumours. 5th ed. Lyon, France: IARC Press; 2019.

    Google Scholar 

  16. Tang LH, Basturk O, Sue JJ, et al. A practical approach to the classification of WHO grade 3 (G3) well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol. 2016;40:1192–202.

    Article  Google Scholar 

  17. Pavel M, Oberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31:844–60.

    Article  CAS  Google Scholar 

  18. Shrier I, Platt RW. Reducing bias through directed acyclic graphs. BMC Med Res Methodol. 2008;8:70.

    Article  Google Scholar 

  19. Wang WQ, Liu L, Xu HX, et al. Infiltrating immune cells and gene mutations in pancreatic ductal adenocarcinoma. Br J Surg. 2016;103:1189–99.

    Article  CAS  Google Scholar 

  20. Lee MR, Harris C, Baeg KJ, et al. Incidence trends of gastroenteropancreatic neuroendocrine tumors in the United States. Clin Gastroenterol Hepatol. 2018;17(11):2212–7.

    Article  Google Scholar 

  21. Fan JH, Zhang YQ, Shi SS, et al. A nation-wide retrospective epidemiological study of gastroenteropancreatic neuroendocrine neoplasms in China. Oncotarget. 2017;8:71699–708.

    Article  Google Scholar 

  22. Velayoudom-Cephise FL, Duvillard P, Foucan L, et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer. 2013;20:649–57.

    Article  Google Scholar 

  23. Basturk O, Yang Z, Tang LH, 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.

    Article  Google Scholar 

  24. Fazio N, Milione M. Heterogeneity of grade 3 gastroenteropancreatic neuroendocrine carcinomas: new insights and treatment implications. Cancer Treat Rev. 2016;50:61–7.

    Article  Google Scholar 

  25. Nunez-Valdovinos B, Carmona-Bayonas A, Jimenez-Fonseca P, et al. Neuroendocrine tumor heterogeneity adds uncertainty to the world health organization 2010 classification: real-world data from the spanish tumor registry (R-GETNE). Oncologist. 2018;23:422–32.

    Article  Google Scholar 

  26. Rinke A, Gress TM. Neuroendocrine cancer, therapeutic strategies in G3 cancers. Digestion. 2017;95:109–14.

    Article  CAS  Google Scholar 

  27. Bettini R, Partelli S, Boninsegna L, et al. Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery. 2011;150:75–82.

    Article  Google Scholar 

  28. Wong J, Fulp WJ, Strosberg JR, et al. Predictors of lymph node metastases and impact on survival in resected pancreatic neuroendocrine tumors: a single-center experience. Am J Surg. 2014;208:775–80.

    Article  Google Scholar 

  29. Ausania F, Senra Del Rio P, Gomez-Bravo MA, et al. Can we predict recurrence in WHO G1–G2 pancreatic neuroendocrine neoplasms? Results from a multi-institutional Spanish study. Pancreatology. 2019;19:367–71.

    Article  CAS  Google Scholar 

  30. Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012;2:270–87.

    Article  CAS  Google Scholar 

  31. Kasajima A, Papotti M, Ito W, et al. High interlaboratory and interobserver agreement of somatostatin receptor immunohistochemical determination and correlation with response to somatostatin analogs. Hum Pathol. 2018;72:144–52.

    Article  CAS  Google Scholar 

  32. Kaemmerer D, Peter L, Lupp A, et al. Molecular imaging with 68Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2011;38:1659–68.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Prof. Jie Chen (Department of Gastroenterology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China), Prof. Cheng-Hao Shao (Department of Pancreatic-Biliary Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China), and Prof. Jian Wang (Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China), three senior members of the Chinese Study Group for Neuroendocrine Tumor, for providing study materials. We also thank Dr. Kai-Zhou Jin, Ying Yang, and Ms. Huan-Yu Xia (Fudan University Shanghai Cancer Centre) for their assistance in collecting patient data. We thank Prof. Wei-Qi Sheng (Department of Pathology, Fudan University Shanghai Cancer Centre, China) and Prof. Hai-Ying Zeng (Department of Pathology, Zhongshan Hospital, Fudan University, China) for their assistance in the pathological diagnosis of PanNETs in all enrolled patients. Lastly, we thank Prof. Hai-Tao Chen (School of Public Health, Fudan University, China) and Dr. Miao Mo (Department of Clinical Statistics, Fudan University Shanghai Cancer Centre, China) for their assistance with statistical analyses.

Funding

This work was supported by grants from the National Science Foundation for Distinguished Young Scholars of China (81625016), the National Natural Science Foundation of China (81871941, 81872366, 81827807, 81802675, 81701630 and 81702341), the Outstanding Academic Leader Program of the “Technological Innovation Action Plan” in Shanghai Science and Technology Commission (18XD1401200), the Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057), the Natural Science Foundation of Shanghai (19ZR1410800), Clinical and Scientific Innovation Project of Shanghai Hospital Development Center (SHDC12018109), and the Young Talented Specialist Training Program of Shanghai.

Author information

Author notes

  1. Wen-Quan Wang, Wu-Hu Zhang, and He-Li Gao contributed equally to this work.

Authors and Affiliations

  1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

    Wen-Quan Wang, Wu-Hu Zhang, He-Li Gao, Hua-Xiang Xu, Shuo Li, Tian-Jiao Li, Shuai-Shuai Xu, Hao Li, Jiang Long, Long-Yun Ye, Chun-Tao Wu, Xuan Han, Liang Liu & Xian-Jun Yu

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Wen-Quan Wang, Wu-Hu Zhang, He-Li Gao, Dan Huang, Hua-Xiang Xu, Shuo Li, Tian-Jiao Li, Shuai-Shuai Xu, Hao Li, Jiang Long, Long-Yun Ye, Chun-Tao Wu, Xuan Han, Xiao-Hong Wang, Liang Liu & Xian-Jun Yu

  3. Shanghai Pancreatic Cancer Institute, Shanghai, China

    Wen-Quan Wang, Wu-Hu Zhang, He-Li Gao, Hua-Xiang Xu, Shuo Li, Tian-Jiao Li, Shuai-Shuai Xu, Hao Li, Jiang Long, Long-Yun Ye, Chun-Tao Wu, Xuan Han, Liang Liu & Xian-Jun Yu

  4. Pancreatic Cancer Institute, Fudan University, Shanghai, China

    Wen-Quan Wang, Wu-Hu Zhang, He-Li Gao, Hua-Xiang Xu, Shuo Li, Tian-Jiao Li, Shuai-Shuai Xu, Hao Li, Jiang Long, Long-Yun Ye, Chun-Tao Wu, Xuan Han, Liang Liu & Xian-Jun Yu

  5. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China

    Dan Huang

  6. Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China

    Xiao-Hong Wang

Authors
  1. Wen-Quan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wu-Hu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. He-Li Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hua-Xiang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tian-Jiao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shuai-Shuai Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiang Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Long-Yun Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Chun-Tao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xuan Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xiao-Hong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Liang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Xian-Jun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Liang Liu or Xian-Jun Yu.

Ethics declarations

Conflict of interest

None reported.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, WQ., Zhang, WH., Gao, HL. et al. A novel risk factor panel predicts early recurrence in resected pancreatic neuroendocrine tumors. J Gastroenterol 56, 395–405 (2021). https://doi.org/10.1007/s00535-021-01777-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-021-01777-0

Keywords

Search

Navigation