Skip to main content
SpringerLink
Log in

Hyperglycemia is associated with adverse prognosis in patients with pancreatic neuroendocrine neoplasms

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Background

Although glucose has a well-recognized protumoral role and the pancreas is a critical organ in adjusting glucose metabolism, the clinical value of hyperglycemia in pancreatic neuroendocrine neoplasms (pNENs) remains largely unidentified.

Methods

A retrospective study including 335 patients with pathologically confirmed pNENs was conducted. A baseline fasting blood glucose concentration ≥5.6 mmol/L was defined as hyperglycemia (otherwise, normal). Survival and regression analyses were performed.

Results

Compared with patients with normal glucose, patients with hyperglycemia (47.8%) had a higher proportion of preexisting diabetes mellitus (DM) (36.9% vs. 4.6%, p < 0.001), lymph node involvement (31.0% vs. 14.6%, p = 0.002), distant metastasis (34.4% vs. 22.9%, p = 0.019), and carbohydrate antigen 19-9 (CA19-9) ≥ 37 U/mL (16.6% vs. 7.2%, p = 0.009). Hyperglycemia was associated with CA19-9 ≥ 37 U/mL (Odds Ratio (OR) = 3.19, 95% CI: 1.11–9.17, p = 0.031), lymph node involvement (OR = 2.32, 95% CI: 1.02–5.28, p = 0.045), nonfunctional tumors (OR = 9.90, 95% CI: 2.11–46.34, p = 0.004), and preexisting diabetes (OR = 18.24, 95% CI: 4.06–81.95, p < 0.001). Hyperglycemia was an independent determinant for overall survival in the multivariate analysis (hazard ratio (HR) = 2.65, 95% CI: 1.31–5.34, p = 0.006).

Conclusion

Hyperglycemia is an independent predictor of overall survival and is associated with preexisting DM or lymphatic metastasis in patients with pNENs. Patients with hyperglycemia and resectable pNENs may benefit from radical resection with dissection of regional lymph nodes.

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. J.C. Yao, et al., One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J. Clin. Oncol.: Off. J. Am. Soc. Clin. Oncol. 26(18), 3063–72 (2008). https://doi.org/10.1200/JCO.2007.15.4377

    Article  Google Scholar 

  2. A.K. Lam, H. Ishida, Pancreatic neuroendocrine neoplasms: Clinicopathological features and pathological staging. Histol. Histopathol. 36(4), 367–382 (2021). https://doi.org/10.14670/HH-18-288

    Article  CAS  PubMed  Google Scholar 

  3. H. Ishida, A. K. Lam, Pancreatic neuroendocrine neoplasms: The latest surgical and medical treatment strategies based on the current World Health Organization classification. Crit. Rev. Oncol. Hematol. 145,102835 (2020). https://doi.org/10.1016/j.critrevonc.2019.102835

  4. R.E. Rosenblum et al. Predictors of recurrence and survival in patients with surgically resected pancreatic neuroendocrine tumors. Pancreas 49(2), 249–254 (2020). https://doi.org/10.1097/MPA.0000000000001477

    Article  PubMed  Google Scholar 

  5. W.Q. Wang et al. A novel risk factor panel predicts early recurrence in resected pancreatic neuroendocrine tumors. J. Gastroenterol. 56(4), 395–405 (2021). https://doi.org/10.1007/s00535-021-01777-0

    Article  CAS  PubMed  Google Scholar 

  6. J.D. Mizrahi, R. Surana, J.W. Valle, R.T. Shroff, Pancreatic cancer. Lancet 395(10242), 2008–2020 (2020). https://doi.org/10.1016/S0140-6736(20)30974-0

    Article  CAS  PubMed  Google Scholar 

  7. G. Luo, K. Jin, S. Deng, H. Cheng, Z. Fan, Y. Gong, Y. Qian, Q. Huang, Q. Ni, C. Liu, X. Yu, Roles of CA19-9 in pancreatic cancer: Biomarker, predictor and promoter. Biochim. Biophys Acta Rev. Cancer 1875(2), 188409 (2021). https://doi.org/10.1016/j.bbcan.2020.188409. Reviews on cancer

    Article  CAS  PubMed  Google Scholar 

  8. T. Feola, G. Puliani, F. Sesti, R. Modica, R. Centello, R. Minotta, G. Cannavale, S. Di Meglio, V. Di Vito, R. Lauretta, M. Appetecchia, A. Colao, A. Lenzi, A.M. Isidori, A. Faggiano, E. Giannetta, Risk factors for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a three-centric case-control study. J. Endocrinol. Invest. 45(4), 849–857 (2022). https://doi.org/10.1007/s40618-021-01715-0

    Article  CAS  PubMed  Google Scholar 

  9. M. Gallo, R.M. Ruggeri, G. Muscogiuri, G. Pizza, A. Faggiano, A. Colao, N. Group, Diabetes and pancreatic neuroendocrine tumours: Which interplays, if any? Cancer Treat. Rev. 67,1–9 (2018). https://doi.org/10.1016/j.ctrv.2018.04.013

  10. E. Leoncini, G. Carioli, C. La Vecchia, S. Boccia, G. Rindi, Risk factors for neuroendocrine neoplasms: a systematic review and meta-analysis. Ann. Oncol.: Off. J. Eur. Soc. Med. Oncol. 27(1), 68–81 (2016). https://doi.org/10.1093/annonc/mdv505

    Article  CAS  Google Scholar 

  11. X. Zhuge, Y. Wang, X. Chen, C. Guo, Diabetes in patients with pancreatic neuroendocrine neoplasms. Front Endocrinol. 11, 615082 (2020). https://doi.org/10.3389/fendo.2020.615082

  12. L. de Mestier, A.L. Vedie, M. Faron, J. Cros, V. Rebours, O. Hentic, C. Do Cao, P. Bardet, P. Levy, A. Sauvanet, P. Ruszniewski, P. Hammel, The postoperative occurrence or worsening of diabetes mellitus may increase the risk of recurrence in resected pancreatic neuroendocrine tumors. Neuroendocrinology 110(11–12), 967–976 (2020). https://doi.org/10.1159/000505158

    Article  CAS  PubMed  Google Scholar 

  13. Y. Gong, Z. Fan, P. Zhang, Y. Qian, Q. Huang, S. Deng, G. Luo, H. Cheng, K. Jin, Q. Ni, X. Yu, C. Liu, High pre-operative fasting blood glucose levels predict a poor prognosis in patients with pancreatic neuroendocrine tumour. Endocrine 71(2), 494–501 (2021). https://doi.org/10.1007/s12020-020-02469-0

    Article  CAS  PubMed  Google Scholar 

  14. G. Muscogiuri, B. Altieri, M. Albertelli, A. Dotto, R. Modica, L. Barrea, G. Fanciulli, T. Feola, R. Baldelli, R.M. Ruggeri, M. Gallo, V. Guarnotta, P. Malandrino, E. Messina, M.A. Venneri, E. Giannetta, D. Ferone, A. Colao, A. Faggiano; N. group, Epidemiology of pancreatic neuroendocrine neoplasms: a gender perspective. Endocrine 69(2), 441–450 (2020). https://doi.org/10.1007/s12020-020-02331-3

    Article  CAS  PubMed  Google Scholar 

  15. G. Luo, C. Liu, M. Guo, H. Cheng, Y. Lu, K. Jin, L. Liu, J. Long, J. Xu, R. Lu, Q. Ni, X. Yu, Potential biomarkers in lewis negative patients with pancreatic cancer. Ann. Surg. 265(4), 800–805 (2017). https://doi.org/10.1097/SLA.0000000000001741

    Article  PubMed  Google Scholar 

  16. G. Luo 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.: Off. J. Am. Soc. Clin. Oncol. 35(3), 274–280 (2017). https://doi.org/10.1200/JCO.2016.67.8193

    Article  Google Scholar 

  17. I.D. Nagtegaal, R.D. Odze, D. Klimstra, V. Paradis, M. Rugge, P. Schirmacher, K.M. Washington, F. Carneiro, I.A. Cree; W.H.O.C.o.T.E. Board, The 2019 WHO classification of tumours of the digestive system. Histopathology 76(2), 182–188 (2020). https://doi.org/10.1111/his.13975

    Article  PubMed  Google Scholar 

  18. C. American Diabetes Association Professional Practice, 2, Classification and diagnosis of diabetes: standards of medical care in diabetes-2022. Diabetes Care 45(Suppl 1), S17–S38 (2022). https://doi.org/10.2337/dc22-S002

    Article  Google Scholar 

  19. S. Bose, A. Le, Glucose metabolism in cancer. Adv Exp Med Biol. 10633, 3–12 (2018). https://doi.org/10.1007/978-3-319-77736-8_1

  20. N. Hay, Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat. Rev. Cancer 16(10), 635–49 (2016). https://doi.org/10.1038/nrc.2016.77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. M. Elgendy et al. Combination of hypoglycemia and metformin impairs tumor metabolic plasticity and growth by modulating the PP2A-GSK3beta-MCL-1 axis. Cancer cell 35(5), 798–815 e5 (2019). https://doi.org/10.1016/j.ccell.2019.03.007

    Article  CAS  PubMed  Google Scholar 

  22. G.W. Krampitz, J.A. Norton, G.A. Poultsides, B.C. Visser, L. Sun, R.T. Jensen, Lymph nodes and survival in pancreatic neuroendocrine tumors. Arch. Surg. 147(9), 820–7 (2012). https://doi.org/10.1001/archsurg.2012.1261

    Article  PubMed  PubMed Central  Google Scholar 

  23. X.F. Zhang, F. Xue, D.H. Dong, A.G. Lopez-Aguiar, G. Poultsides, E. Makris, F. Rocha, Z. Kanji, S. Weber, A. Fisher, R. Fields, B.A. Krasnick, K. Idrees, P.M. Smith, C. Cho, M. Beems, Y. Lv, S.K. Maithel, T.M. Pawlik, New nodal staging for primary pancreatic neuroendocrine tumors: a multi-institutional and national data analysis. Ann. Surg. 274(1), e28–e35 (2021). https://doi.org/10.1097/SLA.0000000000003478

    Article  PubMed  Google Scholar 

  24. Y.M. Hashim, K.M. Trinkaus, D.C. Linehan, S.S. Strasberg, R.C. Fields, D. Cao, W.G. Hawkins, Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann. Surg. 259(2), 197–203 (2014). https://doi.org/10.1097/SLA.0000000000000348

    Article  PubMed  Google Scholar 

  25. Z. Zhang, M. Liu, S. Ji, G. Luo, W. Xu, W. Liu, Q. Hu, Q. Sun, Z. Ye, Y. Qin, G. Fan, X. Yu, X. Xu, Prognostic value and clinical predictors of lymph node metastases in pancreatic neuroendocrine tumors. Pancreas 49(3), 381–386 (2020). https://doi.org/10.1097/MPA.0000000000001493

    Article  CAS  PubMed  Google Scholar 

  26. G. Luo, K. Jin, H. Cheng, C. Liu, M. Guo, Y. Lu, C. Yang, J. Xu, W. Wang, H. Gao, S. Zhang, J. Long, J. Xu, Q. Ni, J. Chen, X. Yu, Carbohydrate antigen 19-9 as a prognostic biomarker in pancreatic neuroendocrine tumors. Oncol. Lett. 14(6), 6795–6800 (2017). https://doi.org/10.3892/ol.2017.7071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. L. Chen, Y. Zhang, M. Chen, J. Chen, Prognostic value of carcinoembryonic antigen, alpha fetoprotein, carbohydrate antigen 125 and carbohydrate antigen 19-9 in gastroenteropancreatic neuroendocrine neoplasms. Chin. J. Gastrointest. Surg. 20(9), 1002–1008 (2017)

    Google Scholar 

  28. J. Murai, S. Soga, H. Saito, M. Otsuki, T. Kitada, Y. Saisho, H. Nakamura, S. Kasayama, M. Koga, Study on the mechanism causing elevation of serum CA19-9 levels in diabetic patients. Endocr. J. 60(7), 885–91 (2013). https://doi.org/10.1507/endocrj.ej12-0364

    Article  CAS  PubMed  Google Scholar 

  29. H. Yu, R. Li, L. Zhang, H. Chen, Y. Bao, W. Jia, Serum CA19-9 level associated with metabolic control and pancreatic beta cell function in diabetic patients. Exp. Diabetes Res. 2012, 745189 (2012). https://doi.org/10.1155/2012/745189

  30. S.H. Kim, C.O. Baek, K.A. Lee, T.S. Park, H.S. Baek, H.Y. Jin, Clinical implication of elevated CA 19-9 level and the relationship with glucose control state in patients with type 2 diabetes. Endocrine 46(2), 249–55 (2014). https://doi.org/10.1007/s12020-013-0058-0

    Article  CAS  PubMed  Google Scholar 

  31. Z. Fan, Y. Gong, Q. Huang, C. Yang, H. Cheng, K. Jin, K. Fan, Q. Ni, X. Yu, G. Luo, C. Liu, Diabetes is associated with the metastasis of pancreatic neuroendocrine tumors. Pancreas 49(6), 751–756 (2020). https://doi.org/10.1097/MPA.0000000000001564

    Article  CAS  PubMed  Google Scholar 

  32. S. Pusceddu et al. Metformin with everolimus and octreotide in pancreatic neuroendocrine tumor patients with diabetes. Future Oncol. 12(10), 1251–60 (2016). https://doi.org/10.2217/fon-2015-0077

    Article  CAS  PubMed  Google Scholar 

  33. S. Pusceddu et al. Impact of diabetes and metformin use on enteropancreatic neuroendocrine tumors: post hoc analysis of the CLARINET study. Cancers 14(1), 69 (2021). https://doi.org/10.3390/cancers14010069

  34. S. Pusceddu et al. Metformin use is associated with longer progression-free survival of patients with diabetes and pancreatic neuroendocrine tumors receiving everolimus and/or somatostatin analogues. Gastroenterology 155(2), 479–489 e7 (2018). https://doi.org/10.1053/j.gastro.2018.04.010

    Article  CAS  PubMed  Google Scholar 

  35. N. Sadeghi, J.L. Abbruzzese, S.C. Yeung, M. Hassan, D. Li, Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res. 18(10), 2905–12 (2012). https://doi.org/10.1158/1078-0432.CCR-11-2994

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank American Journal Experts (www.aje.com) for English language editing.

Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 81625016, 81871940, 81902417), the Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057), Clinical and Scientific Innovation Project of Shanghai Hospital Development Center (SHDC12018109), the Shanghai Natural Science Foundation (grant number 17ZR1406300), the Shanghai Cancer Center Foundation for Distinguished Young Scholars (grant number YJJQ201803), and the Fudan University Personalized Project for “Double Top” Original Research (grant number XM03190633).

Author information

Author notes

  1. These authors contributed equally: Pin Zhang, Zhiwen Xiao, Huaxiang Xu

Authors and Affiliations

  1. Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Pin Zhang, Zhiwen Xiao, Huaxiang Xu, Xinzhe Zhu, Yun Liang, Quanxing Ni, Jie Chen, Xianjun Yu & Guopei Luo

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Pin Zhang, Zhiwen Xiao, Huaxiang Xu, Xinzhe Zhu, Lei Wang, Dan Huang, Yun Liang, Quanxing Ni, Jie Chen, Xianjun Yu & Guopei Luo

  3. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China

    Pin Zhang, Zhiwen Xiao, Huaxiang Xu, Xinzhe Zhu, Quanxing Ni, Xianjun Yu & Guopei Luo

  4. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China

    Pin Zhang, Zhiwen Xiao, Huaxiang Xu, Xinzhe Zhu, Quanxing Ni, Xianjun Yu & Guopei Luo

  5. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Pin Zhang, Zhiwen Xiao, Huaxiang Xu, Xinzhe Zhu, Quanxing Ni, Xianjun Yu & Guopei Luo

  6. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Lei Wang & Dan Huang

  7. Department of Head & Neck tumors and Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Yun Liang & Jie Chen

Authors
  1. Pin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiwen Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huaxiang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xinzhe Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yun Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Quanxing Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xianjun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Guopei Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. G.L. and X.Y.: conceptualization and funding acquisition. P.Z., Z.X., and H.X.: resources and investigation and data curation. G.L. and X.Y.: project administration. G.L. and Q.N.: review and editing. P.Z., Z.X., and H.X.: formal analysis and software and writing—original draft. All authors read and approved the final paper.

Corresponding authors

Correspondence to Xianjun Yu or Guopei Luo.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

The study was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, P., Xiao, Z., Xu, H. et al. Hyperglycemia is associated with adverse prognosis in patients with pancreatic neuroendocrine neoplasms. Endocrine 77, 262–271 (2022). https://doi.org/10.1007/s12020-022-03100-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-022-03100-0

Keywords

Search

Navigation