Prognostic value of p16-INK4A protein in women with negative or CIN1 histology result: A follow-up study

Alberto Pacchiarotti, Francesca Ferrari, Paola Bellardini, Francesco Chini, Guido Collina, Paolo Dalla Palma, Bruno Ghiringhello, Vincenzo MacCallini, Fabio Musolino, Giovanni Negri, Roberto Pisa, Ilaria Sabatucci, Paolo Giorgi Rossi

Research output: Contribution to journalArticle

Abstract

P16-INK4A overexpression has been proposed as a prognostic marker to manage the follow up of women with positive cytology and/or HPV test but without high-grade cervical intraepithelial neoplasia (CIN2+). This study measures the relative risk (RR) of CIN2+ of p16 positive versus negative in these women. All the women referred to colposcopy from October 2008 to September 2010 with negative or CIN1 colposcopy-guided biopsy were included in the study; women surgically treated or having a CIN2-3 were excluded. All baseline biopsies were dyed with hematoxylin and eosin and p16. Women were followed up according to screening protocols, with cytology or colposcopy at 6 or 12 months. CIN2/3 RRs and 95% confidence intervals (95%CI) were computed. Of 442 eligible women, 369 (83.5%) had at least one follow-up episode. At baseline, 113 (30.6%) were CIN1, 248 (67.2%) negative, and 8 (2.2%) inadequate histology; 293 (79.4%) were p16-negative, 64 (17.3%) p16 positive and 12 (3.2%) not valid. During follow up, we found ten CIN2 and three CIN3; of these, six were p16 positive (sensitivity 46%, 95% CI 19-75). The absolute risk among p16 positives was 9.4/100 compared to 1.7/100 of the p16 negatives (RR 5.5; 95% CI 1.7-17.4). The risk was also higher for CIN1 than for histologically negative women (RR 4.4; 95% CI 1.3-14.3). The RR for p16 in CIN1 did not change (RR 5.2; 95% CI 0.6-47.5). P16 overexpression is a good candidate for modulating follow-up intensity after a negative colposcopy but is limited by its low prospective sensitivity. What's new? Women with low-grade cervical intraepithelial neoplasia 1 (CIN1) detected by positive Pap smear but accompanied by negative colposcopic biopsy present unique challenges for follow-up, especially since CIN1 is known to often regress. The situation could be helped in part through the use of a biomarker for CIN1 progression, such as p16 overexpression. This study shows that p16 has low prognostic sensitivity for patients with CIN2+ (CIN2 or worse) but is associated with elevated risk for these advanced conditions. The data suggest that p16 overexpression may be useful in evaluating the intensity of follow-up needed after a negative colposcopy.

Original languageEnglish
Pages (from-to)897-904
Number of pages8
JournalInternational Journal of Cancer
Volume134
Issue number4
DOIs
Publication statusPublished - Feb 15 2014

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Cyclin-Dependent Kinase Inhibitor p16
Cervical Intraepithelial Neoplasia
Histology
Colposcopy
Biopsy
Cell Biology
Papanicolaou Test
Hematoxylin
Eosine Yellowish-(YS)
Biomarkers
Confidence Intervals

Keywords

  • cervical cancer
  • cervical intraepithelial neoplasia
  • cohort study
  • colposcopy
  • p16
  • prognostic value
  • screening

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Prognostic value of p16-INK4A protein in women with negative or CIN1 histology result : A follow-up study. / Pacchiarotti, Alberto; Ferrari, Francesca; Bellardini, Paola; Chini, Francesco; Collina, Guido; Dalla Palma, Paolo; Ghiringhello, Bruno; MacCallini, Vincenzo; Musolino, Fabio; Negri, Giovanni; Pisa, Roberto; Sabatucci, Ilaria; Giorgi Rossi, Paolo.

In: International Journal of Cancer, Vol. 134, No. 4, 15.02.2014, p. 897-904.

Research output: Contribution to journalArticle

Pacchiarotti, A, Ferrari, F, Bellardini, P, Chini, F, Collina, G, Dalla Palma, P, Ghiringhello, B, MacCallini, V, Musolino, F, Negri, G, Pisa, R, Sabatucci, I & Giorgi Rossi, P 2014, 'Prognostic value of p16-INK4A protein in women with negative or CIN1 histology result: A follow-up study', International Journal of Cancer, vol. 134, no. 4, pp. 897-904. https://doi.org/10.1002/ijc.28407
Pacchiarotti A, Ferrari F, Bellardini P, Chini F, Collina G, Dalla Palma P et al. Prognostic value of p16-INK4A protein in women with negative or CIN1 histology result: A follow-up study. International Journal of Cancer. 2014 Feb 15;134(4):897-904. https://doi.org/10.1002/ijc.28407
Pacchiarotti, Alberto ; Ferrari, Francesca ; Bellardini, Paola ; Chini, Francesco ; Collina, Guido ; Dalla Palma, Paolo ; Ghiringhello, Bruno ; MacCallini, Vincenzo ; Musolino, Fabio ; Negri, Giovanni ; Pisa, Roberto ; Sabatucci, Ilaria ; Giorgi Rossi, Paolo. / Prognostic value of p16-INK4A protein in women with negative or CIN1 histology result : A follow-up study. In: International Journal of Cancer. 2014 ; Vol. 134, No. 4. pp. 897-904.
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AU - Bellardini, Paola

AU - Chini, Francesco

AU - Collina, Guido

AU - Dalla Palma, Paolo

AU - Ghiringhello, Bruno

AU - MacCallini, Vincenzo

AU - Musolino, Fabio

AU - Negri, Giovanni

AU - Pisa, Roberto

AU - Sabatucci, Ilaria

AU - Giorgi Rossi, Paolo

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N2 - P16-INK4A overexpression has been proposed as a prognostic marker to manage the follow up of women with positive cytology and/or HPV test but without high-grade cervical intraepithelial neoplasia (CIN2+). This study measures the relative risk (RR) of CIN2+ of p16 positive versus negative in these women. All the women referred to colposcopy from October 2008 to September 2010 with negative or CIN1 colposcopy-guided biopsy were included in the study; women surgically treated or having a CIN2-3 were excluded. All baseline biopsies were dyed with hematoxylin and eosin and p16. Women were followed up according to screening protocols, with cytology or colposcopy at 6 or 12 months. CIN2/3 RRs and 95% confidence intervals (95%CI) were computed. Of 442 eligible women, 369 (83.5%) had at least one follow-up episode. At baseline, 113 (30.6%) were CIN1, 248 (67.2%) negative, and 8 (2.2%) inadequate histology; 293 (79.4%) were p16-negative, 64 (17.3%) p16 positive and 12 (3.2%) not valid. During follow up, we found ten CIN2 and three CIN3; of these, six were p16 positive (sensitivity 46%, 95% CI 19-75). The absolute risk among p16 positives was 9.4/100 compared to 1.7/100 of the p16 negatives (RR 5.5; 95% CI 1.7-17.4). The risk was also higher for CIN1 than for histologically negative women (RR 4.4; 95% CI 1.3-14.3). The RR for p16 in CIN1 did not change (RR 5.2; 95% CI 0.6-47.5). P16 overexpression is a good candidate for modulating follow-up intensity after a negative colposcopy but is limited by its low prospective sensitivity. What's new? Women with low-grade cervical intraepithelial neoplasia 1 (CIN1) detected by positive Pap smear but accompanied by negative colposcopic biopsy present unique challenges for follow-up, especially since CIN1 is known to often regress. The situation could be helped in part through the use of a biomarker for CIN1 progression, such as p16 overexpression. This study shows that p16 has low prognostic sensitivity for patients with CIN2+ (CIN2 or worse) but is associated with elevated risk for these advanced conditions. The data suggest that p16 overexpression may be useful in evaluating the intensity of follow-up needed after a negative colposcopy.

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