Semi‑automated evaluation of Ki‑67 index in invasive ductal carcinoma of the breast

Suciu,Cristian; Muresan,Anca; Cornea,Remus; Suciu,Oana; Dema,Alis; Raica,Marius

doi:10.3892/ol.2013.1654

Semi‑automated evaluation of Ki‑67 index in invasive ductal carcinoma of the breast

Authors:
- Cristian Suciu
- Anca Muresan
- Remus Cornea
- Oana Suciu
- Alis Dema
- Marius Raica
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Affiliations: Department of Microscopic Morphology, ‘Victor Babes’ University of Medicine and Pharmacy, Timișoara, Timiș 300041, Romania, Department of Rehabilitation, ‘Victor Babes’ University of Medicine and Pharmacy Timișoara, Timișoara, Timiș 300041, Romania
Published online on: November 4, 2013 https://doi.org/10.3892/ol.2013.1654
Pages: 107-114

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Abstract

A significant factor that affects the value of the Ki‑67 proliferation index (IK) is the interpretation and implementation approach. This method is based on visual or automated methods to count tumor nuclei labeled with Ki‑67 antigen, and is prone to errors. Detection of Ki‑67 is a useful tool in breast cancer and contributes to its molecular classification. The current study proposes a method for the quantification of Ki‑67‑positive tumor nuclei, which allows for the determination of the exact IK value that is required for tumor stratification based on the proliferation rate. The IK was assessed in 81 successive cases of diagnosed invasive ductal breast carcinoma using a semi‑automated method that accurately identifies positive tumor cell nuclei. This method prevents the inclusion of other possible positive cells, including lymphoid, normal epithelia and hyperplastic. In small specimens with increased cell density, where the nucleus/cytoplasm ratio is markedly in favor of the nucleus and the distance between nuclei is small, the method allows precise quantification of the nuclei, even when the limits between nuclei are difficult to identify. In addition, images may be stored in a database, including the assessments, and easily accessed when required. We hypothesize that the semi‑automated method for counting nuclei offers the most accurate method of assessing the IK and avoids counting errors that may occur through other methods.

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1	Siegel R, Naishadham D and Jemal A: Cancer Statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar
2	Cianfrocca M and Goldstein LJ: Prognostic and predictive factors in early-stage breast cancer. Oncologist. 9:606–616. 2004. View Article : Google Scholar
3	Tavassoli FA and Devilee P: TNM classification of carcinomas of the breast. World Health Classification of Tumours Pathology and Genetics of Tumours of the Breast and Female Genital Organs. IARC Press; Lyon: pp. 11–12. 2003
4	Rosen PP: Invasive duct carcinoma: assessment of prognosis, morphologic prognostic markers, and tumor growth rate. Rosen’s Breast Pathology. 3rd edition. Lippincott Williams & Wilkins; Philadelphia, PA: pp. 358–404. 2009
5	Perou CM, Sørlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature. 406:747–752. 2000. View Article : Google Scholar : PubMed/NCBI
6	Goldhirsch A, Wood WC, Coates AS, et al: Panel members: Strategies for subtypes - dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncology. 22:1736–1747. 2011. View Article : Google Scholar
7	Carey L, Perou CM, Livasy CA, et al: Race, breast cancer subtypes and survival in the Carolina Breast Cancer Study. JAMA. 295:2492–2502. 2006. View Article : Google Scholar : PubMed/NCBI
8	Mullan PB and Millikan RC: Molecular subtyping of breast cancer: opportunities for new therapeutic approaches. Cell Mol Life Sci. 64:3219–3232. 2007.PubMed/NCBI
9	Dowsett M, Nielsen OT, A’Hern R, et al; International Ki-67 in Breast Cancer Working Group. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 103:1656–1664. 2011. View Article : Google Scholar
10	Urruticoechea A, Smith IE and Dowsett M: Proliferation marker Ki-67 in early breast cancer. J Clin Oncol. 23:7212–7220. 2005. View Article : Google Scholar : PubMed/NCBI
11	Goldhirsch A, Ingle JN, Gelber RD, et al: Panel members: Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol. 20:1319–1329. 2009. View Article : Google Scholar
12	Yerushalmi R, Woods R, Ravdin PM, et al: Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 11:174–183. 2010. View Article : Google Scholar : PubMed/NCBI
13	Varga Z, Diebold J, Dommann-Scherrer C, et al: How reliable is Ki-67 immunohistochemistry in grade 2 breast carcinomas? A QA study of the Swiss Working Group of Breast- and Gynecopathologists. PLoS One. 7:e373792012. View Article : Google Scholar
14	Fitzgibbons PL, Page DL, Weaver D, et al: Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 124:966–978. 2000.PubMed/NCBI
15	Edge SB, Byrd DR, Compton CC, et al: Breast. AJCC Cancer Staging Manual. 7th edition. Springer; New York, NY: pp. 345–376. 2010
16	Derek AC: Breast carcinoma. Histopathology Reporting Guidelines for Surgical Cancer. Springer-Verlag; London: pp. 213–235. 2006
17	Moinfair F: Infiltrating ductal carcinoma (NOS type). Essentials of Diagnostic Breast Pathology. A Practical Approach. Springer; Berlin Heidelberg, New York, NY: pp. 180–181. 2007
18	Rakha EA, Reis-Filho JS, Baehner F, et al: Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 12:2072010.PubMed/NCBI
19	Elston CW and Ellis IO: Pathological prognostic factors in breast cancer. I The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 19:403–410. 1991. View Article : Google Scholar
20	Dunne B and Going JJ: Scoring nuclear pleomorphism in breast cancer. Histopathology. 39:259–265. 2001. View Article : Google Scholar : PubMed/NCBI
21	Elston CW and Ellis IO: Assessment of histological gradee. Systemic Pathology. The Breast. 13. 3rd edition. Churchill Livingstone; Philadelphia, PA: pp. 365–384. 1998
22	Rampaul RS, Pinder SE, Elston CW and Ellis IO; Nottingham Breast Team. Prognostic and predictive factors in primary breast cancer and their role in patient management: The Nottingham Breast Team. Eur J Surg Oncol. 27:229–238. 2001. View Article : Google Scholar : PubMed/NCBI
23	Wolff AC, Hammond HE, Schwartz JN, et al; American Society of Clinical Oncology; College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 25:118–145. 2007. View Article : Google Scholar
24	Rakha EA, Elsheikh SE, Aleskandarany MA, et al: Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res. 15:2302–2310. 2009. View Article : Google Scholar
25	Gerdes J, Schwab U, Lemke H and Stein H: Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer. 31:13–20. 1983. View Article : Google Scholar
26	Beresford MJ, Wilson GD and Makris A: Measuring proliferation in breast cancer: practicalities and applications. Breast Cancer Res. 8:2162006. View Article : Google Scholar : PubMed/NCBI
27	Gerdes J, Li L, Schlueter 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 Pathol. 138:867–873. 1991.
28	du Manoir S, Guillaud P, Camus E, et al: Ki-67 labeling in postmitotic cells defines different Ki-67 pathways within the 2c compartment. Cytometry. 12:455–463. 1991.PubMed/NCBI
29	Bruno S and Darzynkiewicz Z: Cell cycle dependent expression and stability of the nuclear protein detected by Ki-67 antibody in HL-60 cells. Cell Prolif. 25:31–40. 1992. View Article : Google Scholar
30	Gerdes J, Lemke H, Baisch H, et al: Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 133:1710–1715. 1984.
31	Park D, Kåresen R, Noren T and Sauer T: Ki-67 expression in primary breast carcinomas and their axillary lymph node metastases: clinical implications. Virchows Arch. 451:11–18. 2007. View Article : Google Scholar : PubMed/NCBI
32	Aleskandarany MA, Green AR, Benhasouna AA, et al: Prognostic value of proliferation assay in the luminal, HER2-positive and triple-negative biologic classes of breast cancer. Breast Cancer Res. 14:R32012. View Article : Google Scholar
33	Luporsi E, André F, Spyratos F, et al: Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review. Breast Cancer Res Treat. 132:895–915. 2012. View Article : Google Scholar
34	Cheang MC, Chia SK, Voduc D, et al: Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 101:736–750. 2009. View Article : Google Scholar
35	Yamaguchi T and Mukai H: Ki-67 index guided selection of preoperative chemotherapy for HER2-positive breast cancer: a randomized phase II trial. Jpn J Clin Oncol. 42:1211–1214. 2012. View Article : Google Scholar
36	Jalava P, Kuopio T, Juntti-Patinen L, et al: Ki67 immunohistochemistry: a valuable marker in prognostication but with a risk of misclassification: proliferation subgroups formed based on Ki67 immunoreactivity and standardized mitotic index. Histopathology. 48:674–682. 2006. View Article : Google Scholar
37	Arber DA: Effect of prolonged formalin fixation on the immunohistochemical reactivity of breast markers. Appl Immunohistochem Mol Morphol. 10:183–186. 2002. View Article : Google Scholar : PubMed/NCBI
38	Camp RL, Charette LA and Rimm DL: Validation of tissue microarray technology in breast carcinoma. Lab Invest. 80:1943–1949. 2000. View Article : Google Scholar : PubMed/NCBI
39	DiVito KA, Charette LA, Rimm DL and Camp RL: Long-term preservation of antigenicity on tissue microarrays. Lab Invest. 84:1071–1078. 2004. View Article : Google Scholar : PubMed/NCBI
40	Boon ME: Microwave-antigen retrieval: the importance of pH of the retrieval solution for MIB-1 staining. Eur J Morphol. 34:375–379. 1996. View Article : Google Scholar : PubMed/NCBI
41	Mengel M, von Wasielewski R, Wiese B, et al: Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labelling index in a large multi-centre trial. J Pathol. 198:292–299. 2002. View Article : Google Scholar
42	Faratian D, Munro A, Twelves C and Bartlett JM: Membranous and cytoplasmic staining of Ki67 is associated with HER2 and ER status in invasive breast carcinoma. Histopathology. 54:254–257. 2009. View Article : Google Scholar : PubMed/NCBI
43	Tawfik O, Kimler BF, Davis M, et al: Grading invasive ductal carcinoma of the breast: advantages of using automated proliferation index instead of mitotic count. Virchows Arch. 450:627–636. 2007. View Article : Google Scholar
44	Viale G, Giobbie-Hurder A, Regan MM, et al; Breast International Group Trial 1-98. Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol. 26:5569–5575. 2008. View Article : Google Scholar
45	Mohammed ZM, McMillan DC, Elsberger B, et al: Comparison of visual and automated assessment of Ki-67 proliferative activity and their impact on outcome in primary operable invasive ductal breast cancer. Br J Cancer. 106:383–388. 2012. View Article : Google Scholar