Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population.
OBJECTIVE
Cytology-based screening has limited sensitivity to detect prevalent cervical precancers. Human papilloma virus (HPV) DNA testing is highly sensitive and provides a high, long-term reassurance of low risk of cervical cancer. However, the specificity of HPV DNA testing is limited, requiring additional, more disease-specific markers for efficient screening approaches.


METHODS
Liquid-based cytology samples were collected from 625 women referred to colposcopy. A slide was stained using the CINtec plus cytology assay. Pap cytology and HPV genotyping were conducted from the same vial. Clinical performance characteristics were calculated for all women, stratified by age, and for women referred with a low-grade squamous intraepithelial lesion (LSIL) Pap.


RESULTS
p16/Ki-67 positivity increased with histologic severity, from 26.8% in normal histology, 46.5% in CIN1, 82.8% in CIN2 to 92.8% in CIN3. Among women with CIN3, p16/Ki-67 positivity increased from 77.8% for women younger than 30 years without HPV16 to 100% for women 30 years and older with HPV16. The sensitivity and specificity to detect CIN3+ were 93.2% and 46.1%, respectively, and increased to 97.2% and 60.0% among women 30 years and older. In women with high-risk (HR)-HPV-positive atypical squamous cells of undetermined significance (ASC-US) and LSIL, sensitivity and specificity for detection of CIN3 were 90.6% and 48.6%, respectively.


CONCLUSIONS
p16/Ki-67 testing could reduce referral to colposcopy by almost half while detecting the most severe cases of CIN3. The high sensitivity of p16/Ki-67 with significantly improved specificity compared with HPV testing makes p16/Ki-67 a viable option for LSIL triage. Further studies are required to evaluate p16/Ki-67 as triage marker in HPV-based screening strategies.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20852, USA. wentzenn@mail.nih.gov
Nicolas
N
Wentzensen
Lauren
L
Schwartz
Rosemary E
RE
Zuna
Katie
K
Smith
Cara
C
Mathews
Michael A
MA
Gold
R Andy
RA
Allen
Roy
R
Zhang
S Terence
ST
Dunn
Joan L
JL
Walker
Mark
M
Schiffman
D000293:Adolescent; D000328:Adult; D000368:Aged; D003127:Colposcopy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D005260:Female; D005838:Genotype; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis*; D008403:Mass Screening / Q000379:methods; D008875:Middle Aged; D060787:Neoplasm Grading; D018307:Neoplasms, Squamous Cell / Q000175:diagnosis / Q000378:metabolism* / Q000821:virology; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000378:metabolism / Q000821:virology; D012017:Referral and Consultation; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000821:virology; D014626:Vaginal Smears; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis / Q000378:metabolism* / Q000821:virology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen