Immunocytochemical expression of p16INK4A and Ki-67 in cytologically negative and equivocal pap smears positive for oncogenic human papillomavirus.
This study was designed to analyze the cross-sectional comparison of the p16 and Ki-67 immunocytochemical expression in negative and equivocal (atypical squamous cells of undetermined significance (ASC-US)) liquid-based cytology (LBC) samples testing positive for high-risk human papillomavirus (HPV) types with HC2 assay or polymerase-chain reaction (PCR). A series of 199 consecutive LBC specimens derived from the same number of women participating in the ongoing Latin American Screening Study at Leonor Mendes de Barros Hospital, Sao Paulo, were analyzed using immunocytochemistry for expression of p16 and Ki-67 in negative and equivocal LBC samples testing positive for high-risk HPV types with hybrid capture II test (HC2) or PCR. All patients with at least one test positive (cytology, PCR, and/or HC2) were followed each 6 months for 3 years. The follow-up procedure consisted of visual examination, colposcopic inspection, cytology, and HC2 assay. Among the negative cytologic samples, 101 were HPV-positive and 55 HPV-negative. Of the HPV-positive group, 59 of 101 cases (58.4%) were positive for both p16 and Ki67 immunostaining, and 17 of 101 (16.8%) were negative for both. The proportion of Ki-67-positivity increased almost in parallel with the increasing grade of p16-positivity (p = 0.0001 for linear trend). In the HPV-negative group, both markers were negative in 41 of 55 cases (74.5%), and no statistical relationship was observed between the two markers (Pearson, p = 0.595). HPV-positive ASC-US samples demonstrated a simultaneous positive immunoreaction for p16 and Ki67 in 11 of 16 cases (68.7%), whereas 3 (18.7%) were concurrently negative. The relationship between the two markers was of borderline significance (Pearson, p = 0.053), but no linear relationship was found between the graded p16 and Ki-67 expression (p = 0.065 for linear trend). In the HPV-negative ASC-US group, there was no statistical association between the graded p16 and Ki-67 positivity (Pearson, p = 0.281). After 36 months of follow-up of the ASC-US patients, 6 women still displayed ASC-US smear, of which 4 of 6 were HPV-positive and expressed both p16 and Ki-67 markers. Two of 43 ASC-US smears had high-grade squamous intraepithelial lesions diagnosed (4.6%), and 1 had low-grade squamous intraepithelial lesion (2.3%). All of those were positive for HPV, p16 and Ki-67. Patients with ASC-US diagnosis and positive high-risk HPV status and positive for p16 Ki67 should be carefully observed to exclude occurrence of a squamous intraepithelial lesion. The combination of these two markers can be a useful implement for management of women with equivocal cytology.
Longatto Filho
Adhemar
A
Pathology Division, Adolfo Lutz Institute, São Paulo, Brazil.
Utagawa
Maria Lúcia
ML
Shirata
Neuza Kasumi
NK
Pereira
Sônia Maria Miranda
SM
Namiyama
Gislene M
GM
Kanamura
Cristina Takami
CT
Santos
Gilda da Cunha
Gda C
de Oliveira
Marilene Almeida
MA
Wakamatsu
Alda
A
Nonogaki
Suely
S
Roteli-Martins
Cecília
C
di Loreto
Celso
C
Mattosinho de Castro Ferraz
Maria da Gloria
Mda G
Maeda
Marina Yoshiê Sakamoto
MY
Alves
Venâncio A F
VA
Syrjänen
Kari
K
D014408:Biomarkers, Tumor / Q000032:analysis*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis*; D065006:Papanicolaou Test; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications*; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000175:diagnosis* / Q000378:metabolism / Q000821:virology; D014412:Tumor Virus Infections / Q000150:complications; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000821:virology; D014626:Vaginal Smears; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis / Q000378:metabolism / Q000821:virology
D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen