Performance of p16<sup>INK4a</sup>/Ki-67 immunocytochemistry for identifying CIN2+ in atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion specimens

a Japanese Gynecologic Oncology Group study

Takuma Fujii, Miyuki Saito, Toshihiko Hasegawa, Takashi Iwata, Hiroyuki Kuramoto, Kaneyuki Kubushiro, Mineo Ohmura, Kazunori Ochiai, Hiroharu Arai, Masaru Sakamoto, Teiichi Motoyama, Daisuke Aoki

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: p16<sup>INK4a</sup> immunohistochemistry has revealed a high rate of positivity in cervical intraepithelial neoplasia grade 2 (CIN2) and more severe conditions (CIN2+). The Lower Anogenital Squamous Terminology Standardization project proposed p16<sup>INK4a</sup> immunohistochemistry as an ancillary test for CIN. Immunocytochemistry involving dual staining for p16<sup>INK4a</sup> and Ki-67 in the triage of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) is reported to be useful in the identification of CIN2+. However, it is unclear whether p16<sup>INK4a</sup>/Ki-67 immunocytochemistry is of practical relevance for the triage of ASCUS and LSIL in the Japanese screening system. Methods: From 427 women fulfilling the eligibility criteria, 188 ASCUS and 239 LSIL specimens were analyzed. The accuracy of p16<sup>INK4a</sup>/Ki-67 immunocytochemistry and genotyping of high-risk human papillomaviruses (HPVs) in detecting CIN2+ were compared. Results: p16<sup>INK4a</sup>/Ki-67 immunocytochemistry was positive in 33.5 % (63/188) of ASCUS, and 36.8 % (88/239) of LSIL specimens. The sensitivity and specificity of p16<sup>INK4a</sup>/Ki-67 immunocytochemistry was 87.3 % (95 % confidence interval 78.0–93.8 %) and 76.4 % (71.6–80.8 %), respectively. The positive and negative predictive values were 45.7 % (37.6–54.0 %) and 96.4 % (93.4–98.3 %), respectively; positive and negative likelihood ratios were 3.71 and 0.17, respectively. Using the McNemar test, p16<sup>INK4a</sup>/Ki-67 immunocytochemistry showed equivalent sensitivity but higher specificity than the HPV genotyping test Conclusions: Compared with high-risk HPV genotyping, p16<sup>INK4a</sup>/Ki-67 immunocytochemistry was a more accurate triage test for identifying CIN2+ in ASCUS and LSIL specimens.

Original languageEnglish
Pages (from-to)134-142
Number of pages9
JournalInternational Journal of Clinical Oncology
Volume20
Issue number1
DOIs
Publication statusPublished - 2015

Fingerprint

Cervical Intraepithelial Neoplasia
Immunohistochemistry
Triage
Squamous Intraepithelial Lesions of the Cervix
Atypical Squamous Cells of the Cervix
Sensitivity and Specificity
Terminology
Confidence Intervals
Staining and Labeling

Keywords

  • Biomarker
  • Cervical cancer screening
  • Human papillomavirus
  • Liquid-based cytology
  • p16 immunocytochemistry

ASJC Scopus subject areas

  • Oncology
  • Surgery
  • Hematology

Cite this

Performance of p16<sup>INK4a</sup>/Ki-67 immunocytochemistry for identifying CIN2+ in atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion specimens : a Japanese Gynecologic Oncology Group study. / Fujii, Takuma; Saito, Miyuki; Hasegawa, Toshihiko; Iwata, Takashi; Kuramoto, Hiroyuki; Kubushiro, Kaneyuki; Ohmura, Mineo; Ochiai, Kazunori; Arai, Hiroharu; Sakamoto, Masaru; Motoyama, Teiichi; Aoki, Daisuke.

In: International Journal of Clinical Oncology, Vol. 20, No. 1, 2015, p. 134-142.

Research output: Contribution to journalArticle

Fujii, Takuma ; Saito, Miyuki ; Hasegawa, Toshihiko ; Iwata, Takashi ; Kuramoto, Hiroyuki ; Kubushiro, Kaneyuki ; Ohmura, Mineo ; Ochiai, Kazunori ; Arai, Hiroharu ; Sakamoto, Masaru ; Motoyama, Teiichi ; Aoki, Daisuke. / Performance of p16<sup>INK4a</sup>/Ki-67 immunocytochemistry for identifying CIN2+ in atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion specimens : a Japanese Gynecologic Oncology Group study. In: International Journal of Clinical Oncology. 2015 ; Vol. 20, No. 1. pp. 134-142.
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abstract = "Background: p16INK4a immunohistochemistry has revealed a high rate of positivity in cervical intraepithelial neoplasia grade 2 (CIN2) and more severe conditions (CIN2+). The Lower Anogenital Squamous Terminology Standardization project proposed p16INK4a immunohistochemistry as an ancillary test for CIN. Immunocytochemistry involving dual staining for p16INK4a and Ki-67 in the triage of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) is reported to be useful in the identification of CIN2+. However, it is unclear whether p16INK4a/Ki-67 immunocytochemistry is of practical relevance for the triage of ASCUS and LSIL in the Japanese screening system. Methods: From 427 women fulfilling the eligibility criteria, 188 ASCUS and 239 LSIL specimens were analyzed. The accuracy of p16INK4a/Ki-67 immunocytochemistry and genotyping of high-risk human papillomaviruses (HPVs) in detecting CIN2+ were compared. Results: p16INK4a/Ki-67 immunocytochemistry was positive in 33.5 {\%} (63/188) of ASCUS, and 36.8 {\%} (88/239) of LSIL specimens. The sensitivity and specificity of p16INK4a/Ki-67 immunocytochemistry was 87.3 {\%} (95 {\%} confidence interval 78.0–93.8 {\%}) and 76.4 {\%} (71.6–80.8 {\%}), respectively. The positive and negative predictive values were 45.7 {\%} (37.6–54.0 {\%}) and 96.4 {\%} (93.4–98.3 {\%}), respectively; positive and negative likelihood ratios were 3.71 and 0.17, respectively. Using the McNemar test, p16INK4a/Ki-67 immunocytochemistry showed equivalent sensitivity but higher specificity than the HPV genotyping test Conclusions: Compared with high-risk HPV genotyping, p16INK4a/Ki-67 immunocytochemistry was a more accurate triage test for identifying CIN2+ in ASCUS and LSIL specimens.",
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author = "Takuma Fujii and Miyuki Saito and Toshihiko Hasegawa and Takashi Iwata and Hiroyuki Kuramoto and Kaneyuki Kubushiro and Mineo Ohmura and Kazunori Ochiai and Hiroharu Arai and Masaru Sakamoto and Teiichi Motoyama and Daisuke Aoki",
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T1 - Performance of p16INK4a/Ki-67 immunocytochemistry for identifying CIN2+ in atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion specimens

T2 - a Japanese Gynecologic Oncology Group study

AU - Fujii, Takuma

AU - Saito, Miyuki

AU - Hasegawa, Toshihiko

AU - Iwata, Takashi

AU - Kuramoto, Hiroyuki

AU - Kubushiro, Kaneyuki

AU - Ohmura, Mineo

AU - Ochiai, Kazunori

AU - Arai, Hiroharu

AU - Sakamoto, Masaru

AU - Motoyama, Teiichi

AU - Aoki, Daisuke

PY - 2015

Y1 - 2015

N2 - Background: p16INK4a immunohistochemistry has revealed a high rate of positivity in cervical intraepithelial neoplasia grade 2 (CIN2) and more severe conditions (CIN2+). The Lower Anogenital Squamous Terminology Standardization project proposed p16INK4a immunohistochemistry as an ancillary test for CIN. Immunocytochemistry involving dual staining for p16INK4a and Ki-67 in the triage of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) is reported to be useful in the identification of CIN2+. However, it is unclear whether p16INK4a/Ki-67 immunocytochemistry is of practical relevance for the triage of ASCUS and LSIL in the Japanese screening system. Methods: From 427 women fulfilling the eligibility criteria, 188 ASCUS and 239 LSIL specimens were analyzed. The accuracy of p16INK4a/Ki-67 immunocytochemistry and genotyping of high-risk human papillomaviruses (HPVs) in detecting CIN2+ were compared. Results: p16INK4a/Ki-67 immunocytochemistry was positive in 33.5 % (63/188) of ASCUS, and 36.8 % (88/239) of LSIL specimens. The sensitivity and specificity of p16INK4a/Ki-67 immunocytochemistry was 87.3 % (95 % confidence interval 78.0–93.8 %) and 76.4 % (71.6–80.8 %), respectively. The positive and negative predictive values were 45.7 % (37.6–54.0 %) and 96.4 % (93.4–98.3 %), respectively; positive and negative likelihood ratios were 3.71 and 0.17, respectively. Using the McNemar test, p16INK4a/Ki-67 immunocytochemistry showed equivalent sensitivity but higher specificity than the HPV genotyping test Conclusions: Compared with high-risk HPV genotyping, p16INK4a/Ki-67 immunocytochemistry was a more accurate triage test for identifying CIN2+ in ASCUS and LSIL specimens.

AB - Background: p16INK4a immunohistochemistry has revealed a high rate of positivity in cervical intraepithelial neoplasia grade 2 (CIN2) and more severe conditions (CIN2+). The Lower Anogenital Squamous Terminology Standardization project proposed p16INK4a immunohistochemistry as an ancillary test for CIN. Immunocytochemistry involving dual staining for p16INK4a and Ki-67 in the triage of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) is reported to be useful in the identification of CIN2+. However, it is unclear whether p16INK4a/Ki-67 immunocytochemistry is of practical relevance for the triage of ASCUS and LSIL in the Japanese screening system. Methods: From 427 women fulfilling the eligibility criteria, 188 ASCUS and 239 LSIL specimens were analyzed. The accuracy of p16INK4a/Ki-67 immunocytochemistry and genotyping of high-risk human papillomaviruses (HPVs) in detecting CIN2+ were compared. Results: p16INK4a/Ki-67 immunocytochemistry was positive in 33.5 % (63/188) of ASCUS, and 36.8 % (88/239) of LSIL specimens. The sensitivity and specificity of p16INK4a/Ki-67 immunocytochemistry was 87.3 % (95 % confidence interval 78.0–93.8 %) and 76.4 % (71.6–80.8 %), respectively. The positive and negative predictive values were 45.7 % (37.6–54.0 %) and 96.4 % (93.4–98.3 %), respectively; positive and negative likelihood ratios were 3.71 and 0.17, respectively. Using the McNemar test, p16INK4a/Ki-67 immunocytochemistry showed equivalent sensitivity but higher specificity than the HPV genotyping test Conclusions: Compared with high-risk HPV genotyping, p16INK4a/Ki-67 immunocytochemistry was a more accurate triage test for identifying CIN2+ in ASCUS and LSIL specimens.

KW - Biomarker

KW - Cervical cancer screening

KW - Human papillomavirus

KW - Liquid-based cytology

KW - p16 immunocytochemistry

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