Conjunctive p16INK4a Testing Significantly Increases Accuracy in Diagnosing High-Grade Cervical Intraepithelial Neoplasia

Bergeron, Christine; Ordi, Jaume; Schmidt, Dietmar; Trunk, Marcus J.; Keller, Thomas; Ridder, Ruediger

doi:10.1309/ajcpxsvcdz3d5mzm

Cited by 202 publications

(144 citation statements)

References 30 publications

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“…Inter-and intraobserver variability is a known inherent limitation of morphological diagnosis. 2,12 A diagnosis of HSIL in the re-evaluation was associated with progression, suggesting that these women indeed had high-grade lesions which had been underdiagnosed in the first evaluation. This study has some possible limitations.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

“…[11][12][13][14] The value of p16 in the diagnostic process is important, because it is detected in almost all HSIL/CIN2-3, whereas reactive mimickers, such as immature metaplasia or atrophy, are negative or show focal staining. 5,13,15 Thus, p16 staining has achieved a major role in indisputably classifying a lesion as HSIL/CIN2-3 or as reactive.…”

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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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“…There is extensive evidence showing that CDKN2A/p16 staining in histological sections increases the detection of HSIL 13,16 and can identify LSIL at higher risk of progression. 10,17 Recently, the combination of p16 and Ki67 detected by immunohistochemistry has been used in cytological samples to identify patients with high-grade cervical lesions.…”

Section: Discussionmentioning

confidence: 99%

“…For CDK2A/p16, the positivity was scored as focal for cases with either focal staining of basal cells or any type of staining in suprabasal layers, and diffuse when all basal and suprabasal cells in an area stained positive. 13 The histoscore method was also used to further evaluate the immunohistochemistry expression of the biomarkers. 14 This semiquantitative immunohistochemical method consists of a sum of the percentages of positively stained cells multiplied by a weighted intensity of staining: Histoscore 1/4 SPi(i þ 1), in which Pi is the percentage of stained cells in each intensity category (0-100%), and i is the intensity indicating weak (i 1/ 4 1), moderate (i 1/4 2), or strong staining.…”

Section: Immunohistochemistrymentioning

confidence: 99%

mRNA biomarker detection in liquid-based cytology: a new approach in the prevention of cervical cancer

Pino

Svanholm-Barrie²,

Torné

et al. 2015

Modern Pathology

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Several high-risk human papillomavirus (HPV)-induced cell biomarkers have been proposed as possible candidates to identify patients harboring high-grade squamous intraepithelial lesions (HSILs) of the uterine cervix. We aimed to determine the feasibility of the detection of the mRNA of six biomarkers in cervical smear specimens obtained by liquid-based cytology and to evaluate whether this approach might be useful in the identification of patients with HSIL. One-hundred and twenty three women referred to colposcopy in the Hospital Clinic of Barcelona were included in the study. After a thorough study, including Pap test, high-risk HPV testing (Hybrid Capture 2 test), and colposcopy with directed biopsy and/or endocervical curettage, 48 patients were diagnosed with HSIL, whereas 75 were classified as negative (n ¼ 28), or harboring low-grade SIL (n ¼ 47). CDKN2A/p16, BIRC5, MMP9, TOP2A, MCM5, and MKI67 mRNA expression was analyzed by reverse transcription quantitative polymerase chain reaction in liquid-based cytology after the Pap test and Hybrid Capture 2 performance. The tissue expression of these biomarkers was analyzed by immunohistochemistry in the biopsy material. One-hundred and thirteen out of 123 (92%) liquid-based cytology yielded adequate material for mRNA analysis. TOP2A was the most sensitive (97%) biomarker for the detection of HSIL and CDKN2A/p16 the most specific (78%). The combination of TOP2A and CDKN2A/p16 showed a sensitivity of 96% (95% confidence interval (CI): 88-99) and a specificity of 71% (95% CI: 55-82). In the immunohistochemistry analysis, all biomarkers showed a high sensitivity but low specificity for HSIL, except CDKN2A/p16 which had a sensitivity of 100% and a specificity of 63%. The combination of TOP2A and CDKN2A/p16 showed a sensitivity of 100% (95% CI: 91-100) and a specificity of 43% (95% CI: 32-55). The detection of mRNA of cell biomarkers in liquid-based cytology material is feasible. The combination TOP2A and CDKN2A/p16 has a good balance between sensitivity and specificity for the detection of women with HSIL. Modern Pathology (2015) 28, 312-320; doi:10.1038/modpathol.2014.106; published online 5 September 2014Screening programs based on cervical cytology (Pap test) have led to a decrease in the incidence and the mortality by cervical cancer. However, the efficacy of cytological screening is hampered by the suboptimal sensitivity and interobserver variability of the conventional Pap test. 1,2 Although the introduction of liquid-based cytology has not led to improvements in terms of relative sensitivity for the detection of cervical cancer precursors, 3 this technique has enabled the use of adjunctive tests that may help to reduce the rate of false-negative cytological results and add objectivity to the classical morphological evaluation.High-risk human papillomaviruses (HPV) are the causative agents of cervical cancer, and high-risk HPV testing has shown to improve the sensitivity of the Pap test to over 95%. 4,5 However, high-risk HPV tests have a lower specificity than...

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“…33 Liberal elective use of immunohistochemical staining with P16 and Ki-67 is also used by staff pathologists to increase the reliability of CIN/VAIN 2/3 diagnoses. 34 Statistical Analysis hrHPV detection rates were compared between different groups, including cervical vs. vaginal HSIL Paps, EC/ TZS present versus EC/TZS absent HSIL Paps, and according to age group, using the Pearson chi-squared or Fisher exact test. The Mantel-Haenszel chi-squared test was applied to assess the association of hrHPV positive/ negative, EC/TZS presence/absence, and age grouping with follow-up results since the histopathologic finding was an ordinal outcome.…”

Section: Histopathologic Follow-upmentioning

confidence: 99%

Histopathologic follow‐up and human papillomavirus DNA test results in 290 patients with high–grade squamous intraepithelial lesion papanicolaou test results

Gao

Austin

Zhao

2011

Cancer Cytopathology

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BACKGROUND:The study documents histopathologic outcomes and high‐risk (hr) human papillomavirus (HPV) test results in a large cohort of patients with high‐grade squamous intraepithelial lesion (HSIL) liquid‐based cytology (LBC) Pap test results.METHODS:A total of 352 patients with HSIL results (338 cervical and 14 vaginal) who had hrHPV testing and 290 patients with biopsy follow‐up were studied. hrHPV detection rates were compared at different ages, with or without an endocervical/transformation zone sample (EC/TZS), and for cervical and vaginal HSIL Pap smears. Histopathologic follow‐up findings were also compared. hrHPV‐negative HSIL slides were re‐evaluated in a blinded manner.RESULTS:A total of 325 of 338 (96.2%) cervical HSIL and 12 of 14 (87.5%) vaginal HSIL tested hrHPV‐positive. A total of 271 of 281 (96.4%) EC/TZS‐positive cervical HSIL and 54 of 57 (94.7%) EC/TZS‐negative cervical HSIL tested hrHPV‐positive. The percentage of hrHPV‐positive HSIL declined slightly with increasing age. 197 of 273 (72.3%) hrHPV‐positive cervical HSIL had histopathologic cervical intraepithelial neoplasia (CIN) 2/3+ follow‐up, including 8 squamous carcinomas, compared with 4 of 12 (33.3%) hrHPV‐negative HSIL with CIN2/3 (no carcinomas). 167 of 241 (69.2%) EC/TZS‐positive HSIL had CIN2/3+ follow‐up, compared with 34 of 44 (77.3%) EC/TZS‐negative HSIL. Equivocal HSIL morphology characterized some HPV‐negative HSIL without CIN2/3+ follow‐up.CONCLUSIONS:hrHPV was detected in LBC vials from 96.2% of 338 cervical HSIL and 85.7% of 14 vaginal HSIL. CIN2/3+ was significantly more likely with hrHPV‐positive cervical HSIL than with hrHPV‐negative cervical HSIL. Presence or absence of an EC/TZS did not significantly impact HSIL hrHPV or CIN2/3+ rates. Some hrHPV‐negative HSIL cases may represent HSIL cytologic mimics. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.

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Conjunctive p16INK4a Testing Significantly Increases Accuracy in Diagnosing High-Grade Cervical Intraepithelial Neoplasia

Cited by 202 publications

References 30 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

mRNA biomarker detection in liquid-based cytology: a new approach in the prevention of cervical cancer

Histopathologic follow‐up and human papillomavirus DNA test results in 290 patients with high–grade squamous intraepithelial lesion papanicolaou test results

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