Is p16(INK4A) expression more useful than human papillomavirus test to determine the outcome of atypical squamous cells of undetermined significance-categorized Pap smear? A comparative analysis using abnormal cervical smears with follow-up biopsies.

Abstract

OBJECTIVE:

To correlate high-risk human papillomavirus (HR-HPV) viral load to p16(INK4A) expression in atypical squamous cells of undetermined significance (ASCUS)-categorized Pap smears with follow-up biopsies in order to elucidate their relationships in gynecological pathology.

METHODS:

We studied 66 ASCUS-categorized Pap smears with subsequent follow-up biopsies. HR-HPV viral load was determined by Hybrid Capture II assay from the cervical swab in each ASCUS-diagnosed Pap smear. Both smears and biopsies were immunostained with a primary anti-p16 antibody, clone E6H4, and we analyzed the correlations between HR-HPV viral load in each ASCUS-diagnosed Pap smear and p16 expression of smears with follow-up biopsies.

RESULTS:

Correlation analyses of the corresponding histological diagnoses from 66 ASCUS-diagnosed Pap smears revealed that 21 (32%) cases had only reactive changes and 45 cases showed cervical intraepithelial neoplasia including LSIL (24 cases, 36%) and HSIL or higher (21 cases, 32%). Tests for HR-HPV viral load revealed 17 (26%) negative cases and 49 (74%) positive cases. Immunostaining showed that 26 cases (39%) were negative and 40 (61%) were positive for p16 expression. Comparative analysis of these two tests indicated consistencies as well as discrepancies. They showed significant differences (P < 0.001) between negative p16 expressions of Pap smears with the presence of reactive lesions in follow-up biopsies and HR-HPV viral load. However, no significant difference (P = 0.739 and 0.606) between p16 expression of Pap smears with the presence of LSIL, HSIL or higher in follow-up biopsies and high HR-HPV viral load was found. In addition, there were significant differences (P < 0.001) in specificity and positive predictive value, but no significant differences were found in sensitivity (P = 0.606) and negative predictive value (P = 0.062) between p16 immunostaining and HR-HPV viral load.

CONCLUSION:

The results indicate that there is a close association between weak or strong p16 expressions in ASCUS-categorized smears with the presence of SILs in follow-up biopsies and positive HR-HPV viral loads. Conversely, there is also a clear association between the lack of p16 expression and the absence of significant lesions in follow-up biopsies, but this is not consistent with a negative HR-HPV viral load. It is concluded that p16 expression is an indicator of pathogenic activity of HR-HPV, which is an objective biomarker for clarification of ASCUS-categorized Pap smears in gynecological cytopathology. Furthermore, through comparative analysis, directly visualized p16 immunostaining on smears appears to be a more effective method than HR-HPV viral load for the detection of reactive changes and LSILs from ASCUS-categorized Pap smears.

• Authors: Shin Nieh, Su-Feng Chen, Tang-Yuan Chu, Hung-Cheng Lai, Yaoh-Shiang Lin, Earl Fu, Ching-Hwa Gau
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 97 Issue 1 Pg. 35-40 (Apr 2005) ISSN: 0090-8258 [Print] United States
• PMID: 15790434 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Cyclin-Dependent Kinase Inhibitor p16

Topics

• Biomarkers, Tumor (biosynthesis)
• Biopsy
• Cervix Uteri (metabolism, pathology, virology)
• Cyclin-Dependent Kinase Inhibitor p16 (biosynthesis)
• Epithelial Cells (metabolism, pathology, virology)
• Female
• Follow-Up Studies
• Humans
• Papillomaviridae
• Papillomavirus Infections (metabolism, virology)
• Tumor Virus Infections (metabolism, virology)
• Uterine Cervical Neoplasms (metabolism, pathology, virology)
• Viral Load
• Uterine Cervical Dysplasia (metabolism, pathology, virology)