Relationships of p16 Immunohistochemistry and Other Biomarkers With Diagnoses of Cervical Abnormalities: Implications for LAST Terminology

Abstract

Context.— Lower Anogenital Squamous Terminology (LAST) standardization recommended p16INK4a immunohistochemistry (p16 IHC) for biopsies diagnosed morphologically as cervical intraepithelial neoplasia (CIN) grade 2 (CIN2) to classify them as low-grade or high-grade squamous intraepithelial lesions (HSILs). Objective.— To describe the relationships of p16 IHC and other biomarkers associated with cervical cancer risk with biopsy diagnoses. Design.— A statewide, stratified sample of cervical biopsies diagnosed by community pathologists (CPs), including 1512 CIN2, underwent a consensus, expert pathologist panel (EP) review (without p16 IHC results), p16 IHC interpretation by a third pathology group, and human papillomavirus (HPV) genotyping, results of which were grouped hierarchically according to cancer risk. Antecedent cytologic interpretations were also available. Results.— Biopsies were more likely to test p16 IHC positive with increasing severity of CP diagnoses, overall ( Ptrend ≤ .001) and within each HPV risk group ( Ptrend ≤ .001 except for low-risk HPV [ Ptrend < .010]). All abnormal grades of CP-diagnosed biopsies were more likely to test p16 IHC positive with a higher HPV risk group ( Ptrend < .001), and testing p16 IHC positive was associated with higher HPV risk group than testing p16 IHC negative for each grade of CP-diagnosed biopsies ( P < .001). p16 IHC–positive, CP-diagnosed CIN2 biopsies were less likely than CP-diagnosed CIN3 biopsies to test HPV16 positive, have an antecedent HSIL+ cytology, or to be diagnosed as CIN3+ by the EP ( P < .001 for all). p16 IHC–positive, CP-diagnosed CIN1 biopsies had lower HPV risk groups than p16 IHC–negative, CP-diagnosed CIN2 biopsies ( P < .001). Conclusions.— p16 IHC–positive, CP-diagnosed CIN2 appears to be lower cancer risk than CP-diagnosed CIN3. LAST classification of “HSIL” diagnosis, which includes p16 IHC–positive CIN2, should annotate the morphologic diagnosis (CIN2 or CIN3) to inform all management decisions, which is especially important for young (<30 years) women diagnosed with CIN2 for whom surveillance rather than treatment is recommended.

Accuracy of HPV E6/E7 RNA examination using in situ hybridization in diagnosing cervical intraepithelial lesions

“…P16 expression status cannot accurately predict the potential risk of CINs. Furthermore, the negative expression of p16 does not exclude HPV infection, and p16 positive does not mean HPV infection or HSIL results [25,26]. This is consistent with the present data.…”

Efficacy and safety of an adsorbent and anti-oxidative vaginal gel on CIN1 and 2, on high-risk HPV, and on p16/Ki-67: a randomized controlled trial

“…A systematic review of hr-HPV screening alone or with cytology showed higher colposcopy consultations and a tendency for more destructive treatments, which may increase preterm deliveries [1,17]. As a consequence, a number of onco-markers have gained relevance, among them especially IHC p16 for diagnosis and p16/Ki-67 dual staining for screening, which have been progressively recognized as prognostic factors and are currently recommended [18]. In hr-HPV positive women it was recently proposed that the cytological examination should be substituted by the p16/ Ki-67 test, due to both a better sensitivity and a better specificity of the dual staining test compared to cytology [19,20].…”

Moving forward—the 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors and beyond: implications and suggestions for laboratories

“…It is important for pathologists to remember that p16 IHC is not a highly specific test 34 and thus to use p16 only as suggested by the LAST recommendations to avoid overusage. As with other immunostains, correct interpretation of p16 IHC is also needed to avoid over interpretation of positivity.…”