Tumor Biology

, Volume 34, Issue 5, pp 2881–2889 | Cite as

Expression of CK19 and KIT in resectable pancreatic neuroendocrine tumors

Research Article


The objectives of this study were to validate the immunohistochemical expression patterns of CK19 and KIT in primary pancreatic neuroendocrine tumors (pNETs) and to verify the potential biomarkers that can be used to predict the clinical behaviors and postoperative outcomes. The immunohistochemical expressions of CK19 and KIT were determined in normal pancreatic islets and resectable pNETs. Associations of the immunohistochemical features with the clinicopathologic features and prognosis were evaluated. All 20 samples from the normal control group were negative for both KIT and CK19 in normal pancreatic islets. Positive rates for KIT and CK19 in pNETs were 49.5 % (45/91) and 70.0 % (70/100), respectively. The percentages of G1, G2, and G3 tumors were 54.9, 42.9, and 2.2 %, respectively. Ki-67 index was significantly higher in the KIT-positive subgroup than in the KIT-negative subgroup (p < 0.05); however, no statistically significant difference of the Ki-67 index was found between the CK19-positive and the CK19-negative subgroups (p = 0.656). The positive CK19 expression was significantly associated with non-functioning tumors, regional lymph nodes metastases, and advanced tumor node metastasis (TNM) stage (p < 0.05). Meanwhile, the positive KIT expression was significantly associated with advanced TNM grade (p < 0.05). In univariate analysis, the overall survival in patients with positive CK19 expression was significantly lower than that in patients with CK19-negative expression (p < 0.05). Also, patients with negative KIT expression showed a tendency of longer survival duration compared with those with positive KIT expression (p = 0.188). The high-risk subgroup (2.1 ± 2.9) might have a higher Ki-67 index than the low-risk subgroup (1.0 ± 1.7, p = 0.208). There was a significant difference in functioning status among the three risk levels (p < 0.05). Pairwise comparison prompted that patients at high risk were more prone to have regional lymph nodes metastases, distant metastases, and/or recurrences. In conclusion, the expressions of CK19 and KIT are associated with aggressive clinical behaviors in patients with resectable pNETs. CK19 and KIT may play a role in tumor progression and metastases.


Neuroendocrine tumor Pancreas CK19 KIT 


Conflict of interest



  1. 1.
    Oberg K, Eriksson B. Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol. 2005;19:753–81.CrossRefPubMedGoogle Scholar
  2. 2.
    Clawson GA. From devils to jobs: tracking neuroendocrine tumors. Transl Cancer Res. 2013;2:3–5.Google Scholar
  3. 3.
    Schurr PG, Strate T, Rese K, et al. Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience. Ann Surg. 2007;245:273–81.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Niederle MB, Hackl M, Kaserer K, Niederle B. Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters. Endocrinol Relat Cancer. 2010;17:909–18.CrossRefGoogle Scholar
  5. 5.
    Chen M, Van Ness M, Guo Y, et al. Molecular pathology of pancreatic neuroendocrine tumors. J Gastrointest Oncol. 2012;3:182–8.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Chen WQ, Zeng HM, Zheng RS, Zhang SW, He J. Cancer incidence and mortality in China, 2007. Chin J Cancer Res. 2012;24:1–8.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–23.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13.CrossRefPubMedGoogle Scholar
  9. 9.
    Zhang L, Smyrk TC, Oliveira AM, et al. KIT is an independent prognostic marker for pancreatic endocrine tumors: a finding derived from analysis of islet cell differentiation markers. Am J Surg Pathol. 2009;33:1562–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Saeed A, Buell JF, Kandil E. Surgical treatment of liver metastases in patients with neuroendocrine tumors. Ann Transl Med. 2013;1:6.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Oliver-Krasinski JM, Stoffers DA. On the origin of the beta cell. Genes Dev. 2008;22:1998–2021.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Ashman LK. The biology of stem cell factor and its receptor c-kit. Int J Biochem Cell Biol. 1999;31:1037–51.CrossRefPubMedGoogle Scholar
  13. 13.
    Linnekin D, Keller JR, Ferris DK, et al. Stem cell factor induces phosphorylation of a 200 kDa protein which associates with c-kit. Growth Factors. 1995;12:57–67.CrossRefPubMedGoogle Scholar
  14. 14.
    Li J, Quirt J, Do HQ, et al. Expression of c-Kit receptor tyrosine kinase and effect on beta-cell development in the human fetal pancreas. Am J Physiol Endocrinol Metab. 2007;293:E475–83.CrossRefPubMedGoogle Scholar
  15. 15.
    Bouwens L, Lu WG, De Krijger R. Proliferation and differentiation in the human fetal endocrine pancreas. Diabetologia. 1997;40:398–404.CrossRefPubMedGoogle Scholar
  16. 16.
    Piper K, Brickwood S, Turnpenny LW, et al. Beta cell differentiation during early human pancreas development. J Endocrinol. 2004;181:11–23.CrossRefPubMedGoogle Scholar
  17. 17.
    Bouwens L. Cytokeratins and cell differentiation in the pancreas. J Pathol. 1998;184:234–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Real FX, Vila MR, Skoudy A, et al. Intermediate filaments as differentiation markers of exocrine pancreas. II. Expression of cytokeratins of complex and stratified epithelia in normal pancreas and in pancreas cancer. Int J Cancer. 1993;54:720–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Deshpande V, Fernandez-del Castillo C, Muzikansky A, et al. Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. Am J Surg Pathol. 2004;28:1145–53.CrossRefPubMedGoogle Scholar
  20. 20.
    La Rosa S, Rigoli E, Uccella S, et al. Prognostic and biological significance of cytokeratin 19 in pancreatic endocrine tumours. Histopathology. 2007;50:597–606.CrossRefPubMedGoogle Scholar
  21. 21.
    Crippa S, Partelli S, Boninsegna L, et al. Implications of the new histological classification (WHO 2010) for pancreatic neuroendocrine neoplasms. Ann Oncol. 2012;23:1928.CrossRefPubMedGoogle Scholar
  22. 22.
    Rindi G, Klöppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006;449:395–401.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Yasuda A, Sawai H, Takahashi H, et al. The stem cell factor/c-kit receptor pathway enhances proliferation and invasion of pancreatic cancer cells. Mol Cancer. 2006;5:46.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Sammarco I, Capurso G, Coppola L, et al. Expression of the protooncogene c-KIT in normal and tumor tissues from colorectal carcinoma patients. Int J Color Dis. 2004;19:545–53.CrossRefGoogle Scholar
  25. 25.
    Nio Y, Omori H, Hashimoto K, et al. Immunohistochemical expression of receptor-tyrosine kinase c-kit protein and TGF-beta1 in invasive ductal carcinoma of the pancreas. Anticancer Res. 2005;25:3523–9.PubMedGoogle Scholar
  26. 26.
    Hong SM, Hwang I, Song DE, et al. Clinical and prognostic significances of nuclear and cytoplasmic KIT expressions in extrahepatic bile duct carcinomas. Mod Pathol. 2007;20:562–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Strosberg JR, Cheema A, Weber JM, et al. Relapse-free survival in patients with nonmetastatic, surgically resected pancreatic neuroendocrine tumors: an analysis of the AJCC and ENETS staging classifications. Ann Surg. 2012;256:321–5.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Xu Han
    • 1
  • Jing Zhao
    • 2
  • Yuan Ji
    • 2
  • Xuefeng Xu
    • 1
  • Wenhui Lou
    • 1
  1. 1.Department of Pancreatic Surgery, ZhongShan HospitalFudan UniversityShanghaiChina
  2. 2.Department of Pathology, ZhongShan HospitalFudan UniversityShanghaiChina

Personalised recommendations