Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Diagnostic Pathology
Published in: Diagnostic Pathology 1/2015

Open Access 01-12-2015 | Research

Comparison of digital image analysis and visual scoring of KI-67 in prostate cancer prognosis after prostatectomy

Authors: Patrice Desmeules, Hélène Hovington, Molière Nguilé-Makao, Caroline Léger, André Caron, Louis Lacombe, Yves Fradet, Bernard Têtu, Vincent Fradet

Published in: Diagnostic Pathology | Issue 1/2015

Login to get access

Abstract

Background

The tumor proliferative index marker Ki-67 was shown to be associated with clinically significant outcomes in prostate cancer, but its clinical application has limitations due to lack of uniformity and consistency in quantification. Our objective was to compare the measurements obtained with digital image analysis (DIA) versus virtual microscopy (visual scoring (VS)).

Methods

To do so, we compared the measurement distributions of each technique and their ability to predict clinically useful endpoints. A tissue microarray series from a cohort of 225 men who underwent radical prostatectomy was immunostained for Ki-67. The percentage of Ki-67 positive nuclei in malignant cells was assessed both by VS and DIA, and a H–score was calculated. The distribution and predictive ability of these scoring methods to predict biochemical recurrence (BCR) and death from prostate cancer (DPCa) were compared using Mann–Whitney test and C-index.

Results

The measurements obtained with VS were similar to the DIA measurements (p = 0.73) but dissimilar to the H-score (p < 0.001). Cox regression models showed that Ki-67 was associated with BCR (HR 1.46, 95 % CI 1.10-1.94) and DPCa (HR 1.26, 95 % CI 1.06-1.50). C-indexes revealed that Ki-67 was a better predictor of DPCa (0.803, 0.8059 and 0.789; VS, DIA and H-score, respectively) than of BCR (0.625, 0.632 and 0.604; VS, DIA and H-score, respectively).

Conclusion

The measurement distributions and the predictive abilities of VS and DIA were similar and presented the same predictive behaviour in our cohort, supporting the role of Ki-67 proliferative index as an important prognostic factor of BCR and DPCa in prostate cancer post RP.

Virtual Slides

The virtual slide(s) for this article can be found here: http://​www.​diagnosticpathol​ogy.​diagnomx.​eu/​vs/​6656878501536663​
Appendix
Available only for authorised users
Literature
1.
2.
Shariat SF, Karakiewicz PI, Margulis V, Kattan MW. Inventory of prostate cancer predictive tools. Curr Opin Urol. 2008;18:279–96.PubMedCrossRef
3.
4.
Li R, Wheeler T, Dai H, Frolov A, Thompson T, Ayala G. High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence-free survival in prostate: cancer patients treated with radical prostatectomy. Am J Surg Path. 2004;28:928–34.PubMedCrossRef
5.
Bubendorf L, Sauter G, Moch H, Jordan P, Blochlinger A, Gasser TC, et al. Prognostic significance of Bcl-2 in clinically localized prostate cancer. Am J Surg Path. 1996;148:1557–65.
6.
Viola MV, Fromowitz F, Oravez S, Deb S, Finkel G, Lundy J, et al. Expression of ras oncogene p21 in prostate cancer. N Engl J Med. 1986;314:133–7.PubMedCrossRef
7.
Bookstein R, MacGrogan D, Hilsenbeck SG, Sharkey F, Allred DC. p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res. 1993;53:3369–73.PubMed
8.
Gerdes J, Li L, Schlueter C, Duchrow M, Wohlenberg C, Gerlach C, et al. Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am J Surg Path. 1991;138:867–73.
9.
10.
Adsay V. Ki67 labeling index in neuroendocrine tumors of the gastrointestinal and pancreatobiliary tract: to count or not to count is not the question, but rather how to count. Am J Surg Path. 2012;36:1743–6.PubMedCrossRef
11.
Fasanella S, Leonardi E, Cantaloni C, Eccher C, Bazzanella I, Aldovini D, et al. Proliferative activity in human breast cancer: Ki-67 automated evaluation and the influence of different Ki-67 equivalent antibodies. Diagn Pathol. 2011;6(1):S7.PubMedCentralPubMedCrossRef
12.
Yang Z, Tang LH, Klimstra DS. Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification. Am J Surg Path. 2011;35:853–60.PubMedCrossRef
13.
Young HT, Carr NJ, Green B, Tilley C, Bhargava V, Pearce N. Accuracy of visual assessments of proliferation indices in gastroenteropancreatic neuroendocrine tumours. J Clin Pathol. 2013;66:700–4.PubMedCrossRef
14.
Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 2010;11:174–83.PubMedCrossRef
15.
Jamali M, Chetty R. Predicting prognosis in gastroentero-pancreatic neuroendocrine tumors: an overview and the value of Ki-67 immunostaining. Endocr Pathol. 2008;19:282–8.PubMedCrossRef
16.
Aaltomaa S, Karja V, Lipponen P, Isotalo T, Kankkunen JP, Talja M, et al. Expression of Ki-67, cyclin D1 and apoptosis markers correlated with survival in prostate cancer patients treated by radical prostatectomy. Anticancer Res. 2006;26:4873–8.PubMed
17.
Berney DM, Gopalan A, Kudahetti S, Fisher G, Ambroisine L, Foster CS, et al. Ki-67 and outcome in clinically localised prostate cancer: analysis of conservatively treated prostate cancer patients from the Trans-Atlantic Prostate Group study. Br J Cancer. 2009;100:888–93.PubMedCentralPubMedCrossRef
18.
Jhavar S, Bartlett J, Kovacs G, Corbishley C, Dearnaley D, Eeles R, et al. Biopsy tissue microarray study of Ki-67 expression in untreated, localized prostate cancer managed by active surveillance. Prostate Cancer Prostatic Dis. 2009;12:143–7.PubMedCrossRef
19.
Khatami A, Hugosson J, Wang W, Damber JE. Ki-67 in screen-detected, low-grade, low-stage prostate cancer, relation to prostate-specific antigen doubling time, Gleason score and prostate-specific antigen relapse after radical prostatectomy. Scand J Urol Nephrol. 2009;43:12.PubMedCrossRef
20.
Laitinen S, Martikainen PM, Tolonen T, Isola J, Tammela TL, Visakorpi T. EZH2, Ki-67 and MCM7 are prognostic markers in prostatectomy treated patients. Int J Cancer. 2008;122:595–602.PubMedCrossRef
21.
Revelos K, Petraki C, Gregorakis A, Scorilas A, Papanastasiou P, Tenta R, et al. p27(kip1) and Ki-67 (MIB1) immunohistochemical expression in radical prostatectomy specimens of patients with clinically localized prostate cancer. In Vivo. 2005;19(5):911–20.PubMed
22.
Rubio J, Ramos D, Lopez-Guerrero JA, Iborra I, Collado A, Solsona E, et al. Immunohistochemical expression of Ki-67 antigen, cox-2 and Bax/Bcl-2 in prostate cancer; prognostic value in biopsies and radical prostatectomy specimens. Eur Urol. 2005;48:745–51.PubMedCrossRef
23.
Zellweger T, Gunther S, Zlobec I, Savic S, Sauter G, Moch H, et al. Tumour growth fraction measured by immunohistochemical staining of Ki67 is an independent prognostic factor in preoperative prostate biopsies with small-volume or low-grade prostate cancer. Int J Cancer. 2009;124:2116–23.PubMedCrossRef
24.
Cheng L, Pisansky TM, Sebo TJ, Leibovich BC, Ramnani DM, Weaver AL, et al. Cell proliferation in prostate cancer patients with lymph node metastasis: a marker for progression. Clin Cancer. 1999;5:2820–3.
25.
Sebo TJ, Cheville JC, Riehle DL, Lohse CM, Pankratz VS, Myers RP, et al. Perineural invasion and MIB-1 positivity in addition to Gleason score are significant preoperative predictors of progression after radical retropubic prostatectomy for prostate cancer. Am J Surg Path. 2002;26:431–9.PubMedCrossRef
26.
Tollefson MK, Karnes RJ, Kwon ED, Lohse CM, Rangel LJ, Mynderse LA, et al. Prostate cancer Ki-67 (MIB-1) expression, perineural invasion, and gleason score as biopsy-based predictors of prostate cancer mortality: the Mayo model. Mayo Clin Proc. 2014;89:308–18.PubMedCrossRef
27.
Riber-Hansen R, Vainer B, Steiniche T. Digital image analysis: a review of reproducibility, stability and basic requirements for optimal results. APMIS. 2012;120:276–89.PubMedCrossRef
28.
Walker RA. Quantification of immunohistochemistry–issues concerning methods, utility and semiquantitative assessment I. Histopathol. 2006;49:406–10.CrossRef
29.
Dowsett M, Nielsen TO, A'Hern R, Bartlett J, Coombes RC, Cuzick J, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011;103:1656–64.PubMedCentralPubMedCrossRef
30.
Clark BZ, Dabbs DJ, Cooper KL, Bhargava R. Impact of progesterone receptor semiquantitative immunohistochemical result on Oncotype DX recurrence score: a quality assurance study of 1074 cases. Appl Immunohistochem Mol Morphol. 2013;21:287–91.PubMedCrossRef
31.
Gudlaugsson E, Skaland I, Janssen EA, Smaaland R, Shao Z, Malpica A, et al. Comparison of the effect of different techniques for measurement of Ki67 proliferation on reproducibility and prognosis prediction accuracy in breast cancer. Histopathol. 2012;61:1134–44.CrossRef
32.
Bettencourt MC, Bauer JJ, Sesterhenn IA, Mostofi FK, McLeod DG, Moul JW. Ki-67 expression is a prognostic marker of prostate cancer recurrence after radical prostatectomy. J Urol. 1996;156:1064–8.PubMedCrossRef
33.
Bubendorf L, Sauter G, Moch H, Schmid HP, Gasser TC, Jordan P, et al. Ki67 labelling index: an independent predictor of progression in prostate cancer treated by radical prostatectomy. J Pathol. 1996;178:437–41.PubMedCrossRef
34.
Inoue T, Segawa T, Shiraishi T, Yoshida T, Toda Y, Yamada T, et al. Androgen receptor, Ki67, and p53 expression in radical prostatectomy specimens predict treatment failure in Japanese population. Urology. 2005;66:332–7.PubMedCrossRef
35.
Mathieu R, Shariat SF, Seitz C, Karakiewicz PI, Fajkovic H, Sun M, et al. Multi-institutional validation of the prognostic value of Ki-67 labeling index in patients treated with radical prostatectomy. World J Urol. 2014. doi:10.1007/s00345-014-1421-3
36.
Malhotra S, Lapointe J, Salari K, Higgins JP, Ferrari M, Montgomery K, et al. A tri-marker proliferation index predicts biochemical recurrence after surgery for prostate cancer. PLoS One. 2011;6, e20293.PubMedCentralPubMedCrossRef
37.
Karnes RJ, Cheville JC, Ida CM, Sebo TJ, Nair AA, Tang H, et al. The ability of biomarkers to predict systemic progression in men with high-risk prostate cancer treated surgically is dependent on ERG status. Cancer Res. 2010;70:8994–9002.PubMedCrossRef
38.
Vis AN, van Rhijn BW, Noordzij MA, Schroder FH, van der Kwast TH. Value of tissue markers p27(kip1), MIB-1, and CD44s for the pre-operative prediction of tumour features in screen-detected prostate cancer. J Pathol. 2002;197:148–54.PubMedCrossRef
39.
Bubendorf L, Tapia C, Gasser TC, Casella R, Grunder B, Moch H, et al. Ki67 labeling index in core needle biopsies independently predicts tumor-specific survival in prostate cancer. Hum Pathol. 1998;29:949–54.PubMedCrossRef
40.
Masuda M, Takano Y, Iki M, Asakura T, Hashiba T, Noguchi S, et al. Prognostic significance of Ki-67, p53, and Bcl-2 expression in prostate cancer patients with lymph node metastases: a retrospective immunohistochemical analysis. Pathol Int. 1998;48:41–6.PubMedCrossRef
41.
Stattin P, Damber JE, Karlberg L, Bergh A. Cell proliferation assessed by Ki-67 immunoreactivity on formalin fixed tissues is a predictive factor for survival in prostate cancer. J Urol. 1997;157:219–22.PubMedCrossRef
42.
Fisher G, Yang ZH, Kudahetti S, Moller H, Scardino P, Cuzick J, et al. Prognostic value of Ki-67 for prostate cancer death in a conservatively managed cohort. Br J Cancer. 2013;108:271–7.PubMedCentralPubMedCrossRef
43.
Tang LH, Gonen M, Hedvat C, Modlin IM, Klimstra DS. Objective quantification of the Ki67 proliferative index in neuroendocrine tumors of the gastroenteropancreatic system: a comparison of digital image analysis with manual methods. Am J Surg Path. 2012;36:1761–70.PubMedCrossRef
44.
Klimowicz AC, Bose P, Nakoneshny SC, Dean M, Huang L, Chandarana S, et al. Basal Ki67 expression measured by digital image analysis is optimal for prognostication in oral squamous cell carcinoma. Eur J Cancer. 2012;48:2166–74.PubMedCrossRef
45.
Nielsen PS, Riber-Hansen R, Jensen TO, Schmidt H, Steiniche T. Proliferation indices of phosphohistone H3 and Ki67: strong prognostic markers in a consecutive cohort with stage I/II melanoma. Modern Pathol. 2013;26:404–13.CrossRef
46.
Nielsen PS, Riber-Hansen R, Raundahl J, Steiniche T. Automated quantification of MART1-verified Ki67 indices by digital image analysis in melanocytic lesions. Arch Pathol Lab Med. 2012;136:627–34.PubMedCrossRef
47.
Wagner D, Trudel D, Van der Kwast T, Nonn L, Giangreco AA, Li D, et al. Randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and ki67 labeling in prostate cancer patients. J Clin Endocrinol Metab. 2013;98:1498–507.PubMedCrossRef
48.
Verhoven B, Yan Y, Ritter M, Khor LY, Hammond E, Jones C, et al. Ki-67 is an independent predictor of metastasis and cause-specific mortality for prostate cancer patients treated on Radiation Therapy Oncology Group (RTOG) 94–08. Int J Radiat Oncol Biol Phys. 2013;86:317–23.PubMedCentralPubMedCrossRef
49.
Trudel D, Desmeules P, Turcotte S, Plante M, Gregoire J, Renaud MC, et al. Visual and automated assessment of matrix metalloproteinase-14 tissue expression for the evaluation of ovarian cancer prognosis. Modern Pathol. 2014;27:1394–404.CrossRef
50.
Rubin MA, Dunn R, Strawderman M, Pienta KJ. Tissue microarray sampling strategy for prostate cancer biomarker analysis. Am J Surg Pathol. 2002;26:312–9.PubMedCrossRef
Metadata
Title
Comparison of digital image analysis and visual scoring of KI-67 in prostate cancer prognosis after prostatectomy
Authors
Patrice Desmeules
Hélène Hovington
Molière Nguilé-Makao
Caroline Léger
André Caron
Louis Lacombe
Yves Fradet
Bernard Têtu
Vincent Fradet
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2015
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/s13000-015-0294-0

Other articles of this Issue 1/2015

Diagnostic Pathology 1/2015 Go to the issue

Research

Calreticulin down-regulation inhibits the cell growth, invasion and cell cycle progression of human hepatocellular carcinoma cells

Research

Decreased functional activity of multidrug resistance protein in primary colorectal cancer

Research

Differential expression of Mediator complex subunit MED15 in testicular germ cell tumors

Research

Cyclin D1 in well differentiated thyroid tumour of uncertain malignant potential

Research

Association of C5aR1genetic polymorphisms with coronary artery disease in a Han population in Xinjiang, China

Hypothesis

A promising hypothesis of c-KIT methylation/ expression paradox in c-KIT (+) squamous cell carcinoma of uterine cervix ----- CTCF transcriptional repressor regulates c-KIT proto-oncogene expression