Skip to main content
SpringerLink
Log in

Tumor budding as a prognostic factor in pancreatic ductal adenocarcinoma

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

In this retrospective study, we analyzed the association between tumor budding and perineural invasion as well as their prognostic role in pancreatic ductal adenocarcinoma. A total of N = 119 patients resected for pancreatic ductal carcinoma from 1996 to 2015 were included. Clinical and standard histopathological parameters were retrieved from the patient’s records. One representative hematoxylin and eosin section from the tumor region was examined for perineural invasion and tumor budding using light microscopy. Tumor budding was assessed independently using two different methods: in the first approach, the number of buds was counted over three fields of 0.237 mm2 at 40-fold magnification; in the second approach, tumor budding was quantified according to the recommendation of the International Tumor Budding Consensus Conference (ITBCC) over a field of 0.785 mm2 at 20-fold magnification. Linear and logistic regression was applied to delineate association between perineural invasion, tumor budding, and other parameters; Kaplan-Meier and Cox regression were used in the survival analysis. Regardless of the quantification approach, high tumor budding was a significant negative prognostic factor in the univariable Cox regression (> 5 buds/0.237 mm2, hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.06–2.61, p = 0.027; ≥ 10 buds/0.785 mm2, HR 1.68, 95% CI 1.07–2.64, p = 0.024). In the multivariable model adjusting for stage and standard histopathological parameters, lymph vessel invasion (HR = 2.43, 95% CI 1.47–4.03, p = 0.001) and tumor budding > 5 buds/0.237 mm2 (HR = 1.70, 95% CI 1.07–2.7, p = 0.026) were independent negative prognostic factors, while adjuvant therapy was a positive prognostic factor (HR = 0.54, 95% CI 0.33–0.86, p = 0.009). No significant prognostic value could be delineated for perineural invasion. In conclusion, tumor budding is an independent negative prognostic factor in pancreatic ductal adenocarcinoma associated with lymph node metastasis. The prognostic role of perineural invasion remains uncertain.

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

Similar content being viewed by others

References

  1. Cienfuegos JA, Martínez P, Baixauli J, Beorlegui C, Rosenstone S, Sola JJ, Rodríguez J, Hernández-Lizoáin JL (2017) Perineural invasion is a major prognostic and predictive factor of response to adjuvant chemotherapy in stage I-II colon cancer. Ann Surg Oncol 24:1077–1084

    Article  CAS  Google Scholar 

  2. Ryu YJ, Kang SJ, Cho JS et al (2018) Lymphovascular invasion can be better than pathologic complete response to predict prognosis in breast cancer treated with neoadjuvant chemotherapy. Medicine 97:e11647

    Article  Google Scholar 

  3. Saeter T, Bogaard M, Vlatkovic L et al (2015) The relationship between perineural invasion, tumor grade, reactive stroma and prostate cancer-specific mortality: a clinicopathologic study on a population-based cohort. Prostate 76:207–214

    Article  Google Scholar 

  4. Prall F (2007) Tumour budding in colorectal carcinoma. Histopathology 50:151–162

    Article  CAS  Google Scholar 

  5. Bronsert P, Enderle-Ammour K, Bader M, Timme S, Kuehs M, Csanadi A, Kayser G, Kohler I, Bausch D, Hoeppner J, Hopt UT, Keck T, Stickeler E, Passlick B, Schilling O, Reiss CP, Vashist Y, Brabletz T, Berger J, Lotz J, Olesch J, Werner M, Wellner UF (2014) Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface. J Pathol 234:410–422

    Article  CAS  Google Scholar 

  6. Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol 15:178–196

    Article  CAS  Google Scholar 

  7. Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H, el Zimaity H, Fléjou JF, Hansen TP, Hartmann A, Kakar S, Langner C, Nagtegaal I, Puppa G, Riddell R, Ristimäki A, Sheahan K, Smyrk T, Sugihara K, Terris B, Ueno H, Vieth M, Zlobec I, Quirke P (2017) Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol 30:1299–1311

    Article  Google Scholar 

  8. Chouat E, Zehani A, Chelly I, Njima M, Maghrebi H, Bani MA, Njim L, Zakhama A, Haouet S, Kchir N (2018) Tumor budding is a prognostic factor linked to epithelial mesenchymal transition in pancreatic ductal adenocarcinoma. Study report and literature review. Pancreatology 18:79–84

    Article  Google Scholar 

  9. Kohler I, Bronsert P, Timme S et al (2015) Detailed analysis of epithelial-mesenchymal transition and tumor budding identifies predictors of long-term survival in pancreatic ductal adenocarcinoma. J Gastroenterol Hepatol 30(Suppl 1):78–84

    Article  CAS  Google Scholar 

  10. Lawlor RT, Veronese N, Nottegar A et al (2019) Prognostic role of high-grade tumor budding in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis with a focus on epithelial to mesenchymal transition. Cancers 11

  11. Schorn S, Demir IE, Haller B, Scheufele F, Reyes CM, Tieftrunk E, Sargut M, Goess R, Friess H, Ceyhan GO (2017) The influence of neural invasion on survival and tumor recurrence in pancreatic ductal adenocarcinoma - a systematic review and meta-analysis. Surg Oncol 26:105–115

    Article  Google Scholar 

  12. Lohneis P, Sinn M, Klein F, Bischoff S, Striefler JK, Wislocka L, Sinn BV, Pelzer U, Oettle H, Riess H, Denkert C, Bläker H, Jühling A (2018) Tumour buds determine prognosis in resected pancreatic ductal adenocarcinoma. Br J Cancer 118:1485–1491

    Article  CAS  Google Scholar 

  13. Liebl F, Demir IE, Mayer K et al (2014) The impact of neural invasion severity in gastrointestinal malignancies: a clinicopathological study. Ann Surg 260:900–907 discussion 907-908

    Article  Google Scholar 

  14. Gospodarowicz MK, Brierley JD, Wittekind C (2017) TNM Classification of Malignant Tumours. John Wiley & Sons

  15. O’Connor K, Li-Chang HH, Kalloger SE et al (2015) Tumor budding is an independent adverse prognostic factor in pancreatic ductal adenocarcinoma. Am J Surg Pathol 39:472–478

    Article  Google Scholar 

  16. Cappellesso R, Luchini C, Veronese N, Lo Mele M, Rosa-Rizzotto E, Guido E, de Lazzari F, Pilati P, Farinati F, Realdon S, Solmi M, Fassan M, Rugge M (2017) Tumor budding as a risk factor for nodal metastasis in pT1 colorectal cancers: a meta-analysis. Hum Pathol 65:62–70

    Article  CAS  Google Scholar 

  17. Karamitopoulou E, Zlobec I, Born D, Kondi-Pafiti A, Lykoudis P, Mellou A, Gennatas K, Gloor B, Lugli A (2013) Tumour budding is a strong and independent prognostic factor in pancreatic cancer. Eur J Cancer 49:1032–1039

    Article  CAS  Google Scholar 

  18. Karamitopoulou E, Wartenberg M, Zlobec I, Cibin S, Worni M, Gloor B, Lugli A (2018) Tumour budding in pancreatic cancer revisited: validation of the ITBCC scoring system. Histopathology 73:137–146

    Article  Google Scholar 

  19. Chen SH, Zhang BY, Zhou B, Zhu CZ, Sun LQ, Feng YJ (2019) Perineural invasion of cancer: a complex crosstalk between cells and molecules in the perineural niche. Am J Cancer Res 1:1–21

    Google Scholar 

  20. Fujii-Nishimura Y, Yamazaki K, Masugi Y, Douguchi J, Kurebayashi Y, Kubota N, Ojima H, Kitago M, Shinoda M, Hashiguchi A, Sakamoto M (2018) Mesenchymal-epithelial transition of pancreatic cancer cells at perineural invasion sites is induced by Schwann cells. Pathol Int 68:214–223

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany

    Ekaterina Petrova, Verena Zielinski, Louisa Bolm, Dirk Bausch, Tobias Keck & Ulrich Wellner

  2. Institute of Pathology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany

    Cleopatra Schreiber, Juliana Knief, Christoph Thorns & Sven Perner

  3. Institute of Pathology, Katholisches Marienkrankenhaus Hamburg gGmbH, Hamburg, Germany

    Juliana Knief & Christoph Thorns

  4. Institute for Surgical Pathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Peter Bronsert & Sylvia Timme-Bronsert

  5. Tumorbank Comprehensive Cancer Center Freiburg, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Peter Bronsert & Sylvia Timme-Bronsert

  6. Pathology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany

    Sven Perner

Authors
  1. Ekaterina Petrova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Verena Zielinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Louisa Bolm
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cleopatra Schreiber
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juliana Knief
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christoph Thorns
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter Bronsert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sylvia Timme-Bronsert
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dirk Bausch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sven Perner
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tobias Keck
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ulrich Wellner
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E Petrova integrated the data, performed the statistical analysis, and wrote the manuscript; V Zielinski performed histological analysis and drafted the manuscript; C Schreiber and S Perner acquired data from histopathological records and revised the manuscript; J Knief and C Thorns performed histological analysis and revised the manuscript; L Bolm, D Bausch, and T Keck acquired clinical data and revised the manuscript; S Timme-Bronsert, P Brosert, and U Wellner conceived and designed the study, and revised the manuscript. All authors approved the final manuscript for submission. U Wellner takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

Corresponding author

Correspondence to Ulrich Wellner.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was conducted with the approval of the ethics committee of the University of Lübeck, Germany (Reference number 17-118A).

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

Petrova, E., Zielinski, V., Bolm, L. et al. Tumor budding as a prognostic factor in pancreatic ductal adenocarcinoma. Virchows Arch 476, 561–568 (2020). https://doi.org/10.1007/s00428-019-02719-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-019-02719-1

Keywords

Search

Navigation