title: Assessment of the Ki67 labeling index: a Japanese validation ring study.
abstract: BACKGROUND
  A lack of consistent methods to evaluate Ki67 expression is problematic in terms of accurately predicting prognosis in breast cancer. Accordingly, this study aimed to identify the causes of discrepancies in Ki67 labeling index measurements by different observers under different conditions using breast cancer samples.
  
  
  METHODS
  This Japanese study group compared and assessed immunohistochemical (IHC) analysis of the Ki67 labeling index when measured by different pathologists. Six pathologists (pathologists A-F) in Japan participated in this ring study. One hundred and ten surgical cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative invasive breast cancer treated in 2007 were identified from the breast cancer database of Tokai University Hospital and were included in this study.
  
  
  RESULTS
  For all 6 pathologists, the Ki67 labeling index were significantly different between grade 3 and grade 1 cases and between grade 3 and grade 2 cases, whereas the index tended to be different between grade 1 and grade 2 cases. Further, the Ki67 labeling indexes measured by the 6 pathologists were strongly correlated (ρ: 0.73-0.88). The IHC scores recorded by pathologist A were in moderate to good agreement with those recorded by the others in patients with a Ki67 labeling index of <13.25 % and in those with a Ki67 labeling index of >13.25 % (κ = 0.429-0.660). The Ki67 low and high concordance rates between pathologist A and the others were 0.452-0.778 and 0.862-0.979, respectively. The most pertinent reason for discrepancy in scores seemed to be the selection of the area for counting and the quality of nuclear staining.
  
  
  CONCLUSIONS
  The Ki67 labeling index measured by 6 pathologists without method standardization was in fair to good agreement. We plan to undertake a second ring study, pending recommendations by the international Ki67 panel.
authors.affiliation: Department of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan. niikura@is.icc.u-tokai.ac.jp.|Study Group of Standard Measurement of Ki67, The Japanese Society of Breast Cancer, Tokyo, Japan. niikura@is.icc.u-tokai.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Niikura
authors.affiliation: Study Group of Standard Measurement of Ki67, The Japanese Society of Breast Cancer, Tokyo, Japan.|Department of Pathology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakatani
authors.affiliation: Study Group of Standard Measurement of Ki67, The Japanese Society of Breast Cancer, Tokyo, Japan.|Department of Pathology, Kumamoto City Hospital, Kumamoto, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Arima
authors.affiliation: Study Group of Standard Measurement of Ki67, The Japanese Society of Breast Cancer, Tokyo, Japan.|Department of Pathology, Hakuaikai Medical Corporation, Sagara Hospital, Kagoshima, Japan.
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Ohi
authors.affiliation: Study Group of Standard Measurement of Ki67, The Japanese Society of Breast Cancer, Tokyo, Japan.|Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Honma
authors.affiliation: Study Group of Standard Measurement of Ki67, The Japanese Society of Breast Cancer, Tokyo, Japan.|Department of Pathology, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanomata
authors.affiliation: Study Group of Standard Measurement of Ki67, The Japanese Society of Breast Cancer, Tokyo, Japan.|Breast Center, Northern Fukushima Medical Center, Fukushima, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Study Group of Standard Measurement of Ki67, The Japanese Society of Breast Cancer, Tokyo, Japan.|Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kadoya
authors.affiliation: Study Group of Standard Measurement of Ki67, The Japanese Society of Breast Cancer, Tokyo, Japan.|Department of Breast Surgery, Nahanishi Clinic, Okinawa, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tamaki
authors.affiliation: Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Nobue
authors.initials: N
authors.lastname: Kumaki
authors.affiliation: Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iwamoto
authors.affiliation: Department of Breast Surgery, Kansai Medical University Hirakata Hospital, Hirakata, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Sugie
authors.affiliation: Study Group of Standard Measurement of Ki67, The Japanese Society of Breast Cancer, Tokyo, Japan.|Department of Pathology, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Moriya
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007564:Japan; D019394:Ki-67 Antigen / Q000378:metabolism*; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D015588:Observer Variation; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human
keywords: Breast cancer; Ki67; Proliferation; Ring study