J Gynecol Oncol.  2018 May;29(3):e38. 10.3802/jgo.2018.29.e38.

E2/E6 ratio and L1 immunoreactivity as biomarkers to determine HPV16-positive high-grade squamous intraepithelial lesions (CIN2 and 3) and cervical squamous cell carcinoma

• Choi YJ
• Lee A
• Kim TJ
• Jin HT
• Seo YB
• Park JS
• Lee SJ

• KMID: 2409939
• DOI: http://doi.org/10.3802/jgo.2018.29.e38

Abstract

OBJECTIVE
Human papillomavirus (HPV) 16 is the most carcinogenic HPV genotype. We investigated if HPV16 L1 capsid protein and E2/E6 ratio, evaluated by cervical cytology, may be used as biomarkers of ≥cervical intraepithelial neoplasia (CIN) 2 lesions.
METHODS
Cervical specimens were obtained from 226 patients with HPV16 single infection. Using cytology specimen, L1 capsid protein and E2/E6 ratio were detected and the results were compared with those of the conventional histologic analysis of cervical tissues (CIN1-3 and squamous cell carcinoma [SCC]) to evaluate the association.
RESULTS
The L1 positivity of CIN2/3 was significantly lower than that of normal cervical tissue (p < 0.001) and SCC demonstrated significantly lower L1 positivity than CIN1 (p < 0.001). The mean E2/E6 ratios of specimens graded as SCC (0.356) and CIN2/3 (0.483) were significantly lower than those of specimens graded as CIN1 (0.786) and normal (0.793) (p < 0.05). We observed that area under the receiver operating characteristic curve (AUC) for E2/E6 ratio (0.844; 95% confidence interval [CI]=0.793-0.895) was higher than that for L1 immunochemistry (0.636; 95% CI=0.562-0.711). A combination of E2/E6 ratio and L1 immunocytochemistry analyses showed the highest AUC (0.871; 95% CI=0.826-0.917) for the prediction of ≥CIN2 lesions.
CONCLUSION
To our knowledge, this is the first study to validate HPV L1 capsid protein expression and decreased HPV E2/E6 ratio as valuable predictive markers of ≥CIN2 cervical lesions. Cervical cytology may be analyzed longitudinally on an outpatient basis with noninvasive procedures as against invasive conventional histologic analysis.

Keyword

Cervical Intraepithelial Neoplasia; Uterine Cervical Neoplasms; Human Papillomavirus Type 16 L1 Protein; Immunocytochemistry; Viral Integration

MeSH Terms

Area Under Curve
Biomarkers*
Capsid Proteins
Carcinoma, Squamous Cell*
Cervical Intraepithelial Neoplasia
Epithelial Cells*
Genotype
Humans
Immunochemistry
Immunohistochemistry
Outpatients
ROC Curve
Squamous Intraepithelial Lesions of the Cervix*
Uterine Cervical Neoplasms
Virus Integration
Biomarkers
Capsid Proteins