Biomarker expression in cervical intraepithelial neoplasia: potential progression predictive factors for low-grade lesions

Ozaki, Satoru; Zen, Yoh; Inoue, Masakí

doi:10.1016/j.humpath.2010.10.021

Cited by 60 publications

(41 citation statements)

References 22 publications

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“…However, previous studies using either cytology or biopsy have shown no effect of the biopsy on the short-term evolution of LSIL/ CIN1 lesions. 30 Besides this, in our study the rate of outcome diagnosis of HSIL/CIN2-3 was 17%, being slightly higher than that shown in other series 5,10,18,21,25,31 and suggesting that the effect of the biopsy procedure on increasing the rate of regression is very low if not null. A final possible limitation is related to the accuracy of colposcopy to guide biopsy sampling, 32 which might miss an underlying HSIL/CIN2-3 at initial evaluation in a proportion of women.…”

Section: Discussioncontrasting

confidence: 48%

“…Some of these studies do not include hrHPV testing, 4,16 have a short follow-up, 21 or include a very limited number of patients with LSIL/CIN1. 25,26 Other studies analyze specific groups, which were retrospectively selected based on the outcome.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, prospective, longitudinal studies focused on the prognostic value of p16 immunostaining in patients with biopsies showing LSIL/CIN1 are needed before definitive conclusions can be drawn. 5,16,[18][19][20][21][22] The aim of this study was to evaluate the usefulness of p16 staining in predicting the outcome of biopsy proven LSIL/CIN1 lesions, in a large prospective series of patients recruited at a single institution and who were strictly followed over a long period of time.…”

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confidence: 99%

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p16 staining has limited value in predicting the outcome of histological low-grade squamous intraepithelial lesions of the cervix

et al. 2016

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In order to evaluate the usefulness of p16 staining in predicting the outcome of histological low-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 1 (LSIL/CIN1) we prospectively recruited all the patients referred to colposcopy from 2003 to 2011 due to abnormal screening test results and diagnosed with LSIL/CIN1 at biopsy (n = 507). All biopsies were stained for p16 and re-evaluated after three years by the same gynecological pathologist using the LAST criteria. Follow-up was conducted every 6 months and included a Pap test (liquid-based cytology), high-risk human papillomavirus testing (Hybrid Capture 2 test), and colposcopy. The mean follow-up was 28 months. An outcome diagnosis of HSIL was defined as a histological diagnosis of highgrade SIL/CIN (HSIL/CIN2-3). The diagnosis of LSIL/CIN1 was confirmed in 416 out of 507 biopsies (82%), whereas 58 (11%) were reclassified as negative and 33 (6%) as HSIL/CIN2-3. During follow-up, 86/507 women initially diagnosed with LSIL/CIN1 (17%) showed an outcome diagnosis of HSIL/CIN2-3, with the rate of HSIL final diagnosis of 3% (2/58) in the women with biopsies reclassified as negative, 17% (70/416) in the group with confirmed LSIL and 42% (14/33) in the women with biopsies reclassified as HSIL (Po 0.001). p16 was positive in 245/507 patients (48%) and in 210/416 patients (50%) with confirmed LSIL/CIN1 at re-evaluation. Although positive p16 immunostaining was associated with risk of HSIL/CIN2-3 outcome in the multivariate analysis (Hazard ratio (HR) 1.9; 95% confidence interval (CI): 1.2-3.1; P = 0.009) in the overall group of patients with LSIL/CIN1, this association was not verified in the subset of patients with confirmed LSIL/CIN1 after re-evaluation (HR: 1.6; 95% CI: 0.9-2.6; P = 0.095). In conclusion, in LSIL/CIN1 lesions p16 should be limited to equivocal cases in which HSIL/CIN2 is included in the differential diagnosis since it has low value in clinical practice as a marker of progression of LSIL/CIN1.

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Section: Discussioncontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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p16 staining has limited value in predicting the outcome of histological low-grade squamous intraepithelial lesions of the cervix

et al. 2016

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“…Overuse in unequivocal cases of -IN 1 might lead some pathologists to inappropriately overinterpret such cases as high-grade (-IN 2), leading to the potential for overtreatment. As noted above, the natural history of p16-positive -IN 1 is not well known, and although some evidence exists to support it as a higher risk category, the evidence is insufficient at this time to alter clinical management from that based on the histologic assessment alone [172][173][174]. In addition, the natural history of p16-negative -IN 3 is uncertain, and hence, the use of p16 to downgrade an unequivocal example of -IN 3 is not recommended.…”

Section: Wg4 Recommendation Nomentioning

confidence: 99%

“…There are 3 studies that provide data regarding this question [172][173][174]. In these studies, the presence of strong and diffuse block-positive p16 immunostaining in CIN 1 was associated with increased ''progression'' or precancer outcomes on follow-up.…”

Section: Additional Findings From Wg4mentioning

confidence: 99%

The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: Background and Consensus Recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology

Darragh

Colgan

Cox

et al. 2012

Archives of Pathology &Amp; Laboratory Medicine

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372

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The terminology for human papillomavirus (HPV)–associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) Project was cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology and included 5 working groups; 3 work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted on at the consensus meeting. The final, approved recommendations standardize biologically relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

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

Pacchiarotti

Ferrari

Bellardini³

et al. 2013

Intl Journal of Cancer

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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 (CIN21). This study measures the relative risk (RR) of CIN21 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.Cervical cancer is the third most common cancer in women worldwide, and the seventh overall, with an estimated 530,000 new cases in 2008. However, while persistent infection of the cervix with oncogenic human papillomavirus types-the most common sexually contracted infection in humans-is its necessary cause, 1-3 cervical cancer is in fact rare; only a very small proportion of infected women will develop a high-grade intraepithelial lesion (CIN21) and even fewer will develop cancer. 4More than 85% of the global cervical cancer burden occurs in developing countries, where it accounts for 13% of all female cancers. 5 In fact, cervical cancer is a wellKey words: cervical cancer, screening, cervical intraepithelial neoplasia, p16, colposcopy, cohort study, prognostic value Novelty and impact: P16 overexpression has been proposed as a prognostic marker for CIN progression, but a few prospective studies tested the prognostic value of histological p16 in post-colposcopy follow up. In a 2 years cohort study, we found low prognostic sensitivity for CIN21 (6/13), but a 5.5 relative risk (95% CI 1.7-17.4) for women p16 positive at baseline compared to negative. P16 overexpression is a good candidate for modulating follow up intensity after a negative colposcopy.

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Biomarker expression in cervical intraepithelial neoplasia: potential progression predictive factors for low-grade lesions

Cited by 60 publications

References 22 publications

p16 staining has limited value in predicting the outcome of histological low-grade squamous intraepithelial lesions of the cervix

p16 staining has limited value in predicting the outcome of histological low-grade squamous intraepithelial lesions of the cervix

The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: Background and Consensus Recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology

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

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