Assessment of Correlation Between p16INK4a Staining, Specific Subtype of Human Papillomavirus, and Progression of LSIL/CIN1 Lesions

Razmpoosh, Maryam; Sansregret, A; Oligny, Luc L.; Patey, Natalie; Dormoy-Raclet, Virginie; Ducruet, Thiérry; Soglio, Dorothée Bouron‐Dal

doi:10.1309/ajcpbx74qxcpxikk

Cited by 24 publications

(15 citation statements)

References 20 publications

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“…However, a recent study concluded that the hrHPV subtype is a poor predictor of the behavior of a LSIL/CIN1 lesion. 29 Another controversial issue is that the biopsy procedure might alter the natural evolution of lesions favoring spontaneous resolution, particularly of small lesions. However, previous studies using either cytology or biopsy have shown no effect of the biopsy on the short-term evolution of LSIL/ CIN1 lesions.…”

Section: Discussionmentioning

confidence: 99%

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%

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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“…Several prior studies have tried to assess whether p16 can stratify patient risk of CIN2/3 by scoring of the prevalent CIN1 biopsy [3][4][5][6][7][8] in studies in which case numbers ranged from 64 to 171, raising questions about the statistical power of the observed results. Furthermore, there is some variability in author interpretations of p16, although they generally agree that staining that fails to extend through the lower one third of the epithelium is negative.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Other studies have looked at CIN1 p16 and/or Ki-67 positivity as a harbinger of subsequent CIN2/3+ diagnosis with promising results but limited data sets. [3][4][5][6][7][8] Importantly, such studies are ultimately querying the prognostic rather than the diagnostic value of these markers. To accurately assess prognosis, one must work from a data set populated by cases with adjudicated diagnoses to best approximate a histologic "criterion standard," by minimizing diagnostic variability, which can be considerable.…”

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confidence: 99%

Risk Stratification By p16 Immunostaining of CIN1 Biopsies

Mills

Paquette

Castle

et al. 2015

American Journal of Surgical Pathology

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Previous studies of p16 immunohistochemistry (IHC) on CIN1 have suggested the likely utility of p16 in stratification of women at risk for subsequent CIN2/3. But those studies had limitations in statistical power, histologic diagnosis, and disease ascertainment. We conducted a retrospective study of p16 IHC on adjudicated CIN1 tissue diagnosed in young women participating in the placebo arm of the quadrivalent human papillomavirus (HPV) vaccine trials. Tissue sections were stained with p16 IHC and hematoxylin and eosin. p16 IHC was scored using LAST criteria, and hematoxylin and eosin-stained sections were reviewed for concordance with the adjudicated diagnosis. p16 IHC, antecedent high-grade cytology, review diagnosis, and HPV16 detection were assessed as independent risk factors for subsequent CIN2/3. Five hundred twenty-four patients with CIN1 biopsies and complete data were identified, 63 (12.0%) of whom developed CIN2/3 in follow-up. p16 positivity (P=0.06), review diagnosis of CIN2/3 (P=0.04), HPV16 positivity (P=0.01), and antecedent high-grade cytology (P=0.02) were (marginally) associated with CIN2/3. In a logistic regression model, the associations with CIN2/3 (vs. other), expressed as odds ratios (95% confidence intervals), were 1.6 (0.91-2.8) for p16, 2.0 (1.0-3.7) for HPV16, and 2.2 (1.1-2.4) for antecedent high-grade cytology. The mean risks for CIN2/3 estimated from the model ranged from 7.6% for negative for all markers to 36.3% for positive for all 3 markers. p16 IHC does not risk stratify CIN1 patients in a manner that would alter recommended management for CIN1. This reinforces the LAST recommendations that p16 should only be used selectively for problematic scenarios, such as CIN2 because of its inherent lack of reproducibility, cases in which one is struggling between CIN1 and CIN2, and benign mimics of CIN3.

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“…19 Additionally, in HIV-1 positive specimens there is a potential reason for caution when interpreting the immunohistochemical staining of p16 in cervical lesions. 20 Razmpoosh et al 21 conducted a study matching the immunohistochemical staining with DNA-HPV data by polymerase chain reaction, and found that p16 expression with a diffuse staining pattern was associated with high-risk HPV. They suggested that cases with a p16/HPV ratio within the high-risk range should not be considered to have clinical value, because the mere presence of high risk HPV is a poor predictor of CIN 1.…”

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confidence: 99%

The role of p16 as putative biomarker for cervical neoplasia: A controversial issue?

Gonçalves¹,

Andrade²,

Russomano³

et al. 2017

Medical Express

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Assessment of Correlation Between p16INK4a Staining, Specific Subtype of Human Papillomavirus, and Progression of LSIL/CIN1 Lesions

Abstract: There is a significant relationship between p16(INK4a) immunostaining and follow-up (P = .002). p16(INK4a)-negative specimens or positivity in the lower one-third of CIN1 lesions seldom progress to a CIN2-3 lesion.

Cited by 24 publications

References 20 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

Risk Stratification By p16 Immunostaining of CIN1 Biopsies

The role of p16 as putative biomarker for cervical neoplasia: A controversial issue?

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