Skip to main content
SpringerLink
Log in

Evaluation of diagnostic and prognostic significance of Ki-67 index in pulmonary carcinoid tumours

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

Pulmonary carcinoid (PC) tumours are classified as either typical (TC) or atypical (AC) according to mitotic index (MI) and presence of necrosis. The aim of this study was to analyse the diagnostic and prognostic values of the Ki-67 index in PC.

Methods/patients

Between January 2001 and March 2015, we evaluated 94 consecutive patients with a confirmed diagnosis of TC (n = 75) or AC (n = 19) at our institution. Diagnostic histology was centrally reviewed by a local expert neuroendocrine pathologist, with assessment of Ki-67, MI, and necrosis.

Results

Median patient follow-up was 35 months. Eighty-four patients who underwent curative surgical resection were included in the survival analysis for identification of prognostic factors. Ki-67 index showed high diagnostic accuracy to predict histological subtype when assessed by receiver operator characteristic curves with an area under the curve of 0.923 (95% CI 0.852–0.995, p < 0.001). Multivariate analysis showed that MI, Ki-67 index, and the presence or absence of necrosis were independent prognostic factors for relapse-free survival. Combination of MI, Ki-67, and necrosis led to the classification of patients into four different prognostic groups (very low, low, intermediate, and high risks of relapse).

Conclusions

The current study proposes the incorporation of Ki-67 index in the prognostic classification of PC tumours. Due to the limited number of patients and length of follow-up, the current model needs validation by larger cohort studies. Nevertheless, our results suggest that Ki-67 index and MI have continuous effect on prognosis. Prognostic models incorporating multiple cutoffs of Ki-67 and MI might better predict outcome and inform clinical decisions.

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
Fig. 4

Similar content being viewed by others

References

  1. Travis WD. Lung tumours with neuroendocrine differentiation. Eur J Cancer. 2009;45(Suppl 1):251–66.

    Article  PubMed  Google Scholar 

  2. Rekhtman N. Neuroendocrine tumours of the lung: an update. Arch Pathol Lab Med. 2010;134:1628–38.

    PubMed  Google Scholar 

  3. Chen LC, Travis WD, Krug LM. Pulmonary neuroendocrine tumours: what (little) do we know? J Natl Compr Canc Netw. 2006;4:623–30.

    PubMed  Google Scholar 

  4. Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC. World Health Organisation Classification of Tumours. Pathol Genet Tumours Lung Pleura Thymus Heart, 4th edn. Geneva: WHO; 2004.

  5. Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, Oberg K, Pelosi G, Perren A, Rossi RE, Travis WD, ENETS consensus conference participants. Pulmonary neuroendocrine (carcinoid) tumours: European Neuroendocrine Tumour Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26:1604–20.

    Article  CAS  PubMed  Google Scholar 

  6. Fink G, Krelbaum T, Yellin A, Bendayan D, Saute M, Glazer M, Kramer MR. Pulmonary carcinoid: Presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest. 2001;119:1647–51.

    Article  CAS  PubMed  Google Scholar 

  7. Travis WD. Advances in neuroendocrine lung tumours. Ann Oncol. 2010;21(Suppl 7):vii65–vii71.

  8. Travis WD. The concept of pulmonary neuroendocrine tumours. In: Travis WD, Brambilla E, Müller-Hermelink HK et al., editors. World Health Organisation Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. 4th edn. Geneva: WHO; 2004. p. 19–20.

  9. Warth A, Fink L, Fisseler-Eckhoff A, et al. Interobserver agreement of proliferation index (Ki-67) outperforms mitotic count in pulmonary carcinoids. Virchows Arch. 2013;462:507–13.

    Article  CAS  PubMed  Google Scholar 

  10. Travis WD, Rush W, Flieder DB, Falk R, Fleming MV, Gal AA, Koss MN. Survival analysis of 200 pulmonary neuroendocrine tumours with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol. 1998;22:934–44.

    Article  CAS  PubMed  Google Scholar 

  11. Skov BG, Holm B, Erreboe A, Skov T, Mellemgaard A. ERCC1 and Ki67 in small cell lung carcinoma and other neuroendocrine tumours of the lung: distribution and impact on survival. J Thorac Oncol. 2010;5:453–9.

    Article  PubMed  Google Scholar 

  12. Rindi G, Klöppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumours: a consensus proposal including a grading system. Virchows Arch. 2006;449:395–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rindi G, Falconi M, Klersy C, 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.

    Article  CAS  PubMed  Google Scholar 

  14. Granberg D, Wilander E, Oberg K, Skogseid B. Prognostic markers in patients with typical bronchial carcinoid tumours. J Clin Endocrinol Metab. 2000;85:3425–30.

    CAS  PubMed  Google Scholar 

  15. Rugge M, Fassan M, Clemente R, Rizzardi G, Giacomelli L, Pennelli G, Mescoli C, Segat D, Rea F. Bronchopulmonary carcinoid: phenotype and long-term outcome in a single-institution series of Italian patients. Clin Cancer Res. 2008;14:149–54.

    Article  CAS  PubMed  Google Scholar 

  16. Santinelli A, Ranaldi R, Baccarini M, Mannello B, Bearzi I. Ploidy, proliferative activity, p53 and bcl-2 expression in bronchopulmonary carcinoids: relationship with prognosis. Pathol Res Pract. 1999;195:467–74.

    Article  CAS  PubMed  Google Scholar 

  17. Costes V, Marty-Ané C, Picot MC, Serre I, Pujol JL, Mary H, Baldet P. Typical and atypical bronchopulmonary carcinoid tumours: a clinicopathologic and KI-67-labeling study. Hum Pathol. 1995;26:740–5.

    Article  CAS  PubMed  Google Scholar 

  18. Grimaldi F, Muser D, Beltrami C, et al. Partitioning of bronchopulmonary carcinoids in two different prognostic categories by Ki-67 score. Front Endocrinol (Lausanne). 2011;2:20.

    Google Scholar 

  19. Swarts DR, van Suylen RJ, den Bakker MA, et al. Interobserver variability for the WHO classification of pulmonary carcinoids. Am J Surg Pathol. 2014;38:1429–36.

    Article  PubMed  Google Scholar 

  20. Zahel T, Krysa S, Herpel E, Stenzinger A, Goeppert B, Schirmacher P, Hoffmann H, Schnabel PA, Warth A. Phenotyping of pulmonary carcinoids and a Ki-67-based grading approach. Virchows Arch. 2012;460:299–308.

    Article  CAS  PubMed  Google Scholar 

  21. Walts AE, Ines D, Marchevsky AM. Limited role of Ki-67 proliferative index in predicting overall short-term survival in patients with typical and atypical pulmonary carcinoid tumours. Mod Pathol. 2012;25:1258–64.

    Article  PubMed  Google Scholar 

  22. Rindi G, Klersy C, Inzani F, et al. Grading the neuroendocrine tumours of the lung: an evidence-based proposal. Endocr Relat Cancer. 2013;21:1–16.

    Article  PubMed  Google Scholar 

  23. Rekhtman N. Neuroendocrine tumours of the lung: an update. Arch Pathol Lab Med. 2010;134:1628–38.

    PubMed  Google Scholar 

  24. Pelosi G, Rindi G, Travis WD, Papotti M. Ki-67 antigen in lung neuroendocrine tumours: unraveling a role in clinical practice. J Thorac Oncol. 2014;9:273–84.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

G.P. has been awarded a Grant from the Hellenic Society of Medical Oncology (HeSMO). A.L. is part-funded by an SEOM (Spanish Society of Medical Oncology) Translational Research Fellowship Award.

Author information

Author notes

    Authors and Affiliations

    1. Department of Medical Oncology, The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester, M20 4BX, UK

      V. Clay, G. Papaxoinis, B. Sanderson, J. W. Valle, M. Howell, A. Lamarca & W. Mansoor

    2. Institute of Cancer Studies, University of Manchester, Manchester, UK

      V. Clay, J. W. Valle, D. Nonaka & W. Mansoor

    3. Department of Cardiothoracic Surgery, University Hospital of South Manchester, Manchester, M23 9LT, UK

      P. Krysiak

    4. Department of Thoracic Pathology, University Hospital of South Manchester, Manchester, M23 9LT, UK

      P. Bishop

    5. Department of Histopathology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK

      D. Nonaka

    Authors
    1. V. Clay
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. G. Papaxoinis
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. B. Sanderson
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. J. W. Valle
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. M. Howell
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. A. Lamarca
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. P. Krysiak
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. P. Bishop
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. D. Nonaka
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. W. Mansoor
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to W. Mansoor.

    Ethics declarations

    Conflict of interest

    JWV: Honoraria—Novartis; Consulting or Advisory Role—Novartis; Research Funding—Novartis (to institute). The other authors have nothing to disclose.

    Ethical statement

    For this type of study (retrospective), formal consent was not required.

    Additional information

    V. Clay and G. Papaxoinis have equally contributed to the manuscript (joint first authors).

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (PDF 407 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Clay, V., Papaxoinis, G., Sanderson, B. et al. Evaluation of diagnostic and prognostic significance of Ki-67 index in pulmonary carcinoid tumours. Clin Transl Oncol 19, 579–586 (2017). https://doi.org/10.1007/s12094-016-1568-z

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12094-016-1568-z

    Keywords

    Search

    Navigation