Precancerous lesions of the cervix. Biomarkers in cytological diagnosis
ABSTRACT Despite the success of the German screening program for cervical cancer a new discussion has started with the aim to improve its quality. The main reason for this new discussion has been the finding of many international studies that the quality of screening programs could be improved by introducing human papillomavirus (HPV) testing. It is well known that the sensitivity of the HPV test is much better than that of a single Papanicolaou (PAP) smear. On the other hand, it is generally accepted that the specificity of the established HPV tests is significantly lower than that of cytology, i.e. the HPV test produces more false positive diagnoses. The introduction of new biomarkers could solve this problem and one of these biomarkers is p16(INK4a) which is a surrogate marker for the oncogenic transformation of cervical cells. Using this biomarker it is now possible to identify cases which should be sent for colposcopy and possibly biopsy directly, among those cases which have been classified cytologically as unclear (ASC-US) or mild and moderately dysplastic cervical intraepithelial neoplasia (CIN 1/2). Moreover, it is now feasible to identify the vast majority of underlying high-grade CIN disease in women tested Pap negative/HPV positive, while reducing the number of colposcopies to a level of approximately 25%. In addition, the combination of p16 and L1 probably allows a better estimate of the prognosis of cases with mild or moderate dysplasia.
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ABSTRACT: We performed p16(INK4a) immunocytochemical analysis and Hybrid Capture 2 (HC2; Digene, Gaithersburg, MD) high-risk HPV testing on 210 abnormal SurePath (TriPath Imaging, Burlington, NC) Papanicolaou specimens diagnosed as low-grade squamous intraepithelial lesion (LSIL) or high grade squamous intraepithelial lesion (HSIL). The results were compared with 121 follow-up biopsy specimens. p16(INK4a) was positive in 57.9% of women with LSIL compared with 97.1% of women with HSIL. In contrast, HC2 testing was positive in 85.0% of women with LSIL and 86.4% of women with HSIL. The differences in the positive rates for16(INK4a) between LSIL and HSIL was significant (P < .001), whereas, for HC2, it was not (P = .264). In patients who had cervical biopsies following a cytologic diagnosis of LSIL, the positive predictive value (PPV) of p16(INK4a) for a biopsy of cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3; 33.3%) was significantly higher than the PPV of HC2 results (21.2%) (P < .001). Using liquid-based cytology specimens, p16(INK4a) immunocytochemical analysis has a higher PPV than reflex HC2 HPV testing for identifying CIN2/3 among patients with LSIL and might be useful for selecting patients with LSIL for colposcopy.American Journal of Clinical Pathology 12/2004; 122(6):894-901. DOI:10.1309/0DGG-QBDQ-AMJC-JBXB · 3.01 Impact Factor
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ABSTRACT: Cervical cytopathology has limited specificity for the detection of underlying clinically significant lesions in cases with low-grade cytologic abnormalities. The current study evaluated the performance of a novel immunocytochemical test (ProEx C) for topoisomerase II alpha (TOP2A) and minichromosome maintenance protein 2 (MCM2) in normal versus high-grade squamous intraepithelial lesion (HSIL) and positive control (SiHa) pooled cytology preparations and in a pilot series of prospectively collected patient specimens. TOP2a and MCM2 were detected as markers of aberrant S-phase induction in SurePath cervical cytology specimens by an indirect polymer-based immunoperoxidase method (ProEx C, TriPath Oncology, Burlington, NC). Slides were scored based on specimen adequacy, the presence of nuclear stain in epithelial cells, and the association of nuclear staining with cytologic atypia (>/=atypical squamous cell of undetermined significance [ASC-US] or atypical glandular cells [AGC]). Intense nuclear staining was detected in cytologically abnormal cells but not in most normal squamous and glandular cells. Slides were scored positive in pooled samples in 1 of 40 (2.5%) cases that were negative for intraepithelial neoplasia or malignancy (NIL), in 40 of 40 (100%) SiHa-spiked NIL, and in 40 of 40 (100%) HSILs. There was 100% concordance in test classification of 20 slides between 2 pathologists. Subsequent evaluation of prospectively collected patient specimens was positive for ProEx C in none of 10 NIL (0%), 2 of 10 ASC-US (20%), 5 of 10 low-grade SIL (LSIL) (50%), and in 10 of 10 (100%) HSILs. The ProEx C test showed almost no variability with regard to scoring and staining reproducibility and was consistently positive in HSIL. Further studies are indicated to evaluate the potential role of ProEx C as a diagnostic adjunct for the triage of ASC-US/LSIL.Cancer 10/2006; 108(5):324-30. DOI:10.1002/cncr.22171 · 4.90 Impact Factor
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ABSTRACT: HPV L1 capsid protein is expressed together with the production of infectious viral particles, but its expression and relation to p16 expression, which has been a surrogate marker for human papilloma virus (HPV) infection in cervix, are little studied in cytology samples. The authors aimed to elucidate the relation between L1 capsid protein and p16 protein expressions in liquid-based samples from uterine cervical lesions. Immunochemical analyses using antibodies against L1 capsid protein and p16 protein were carried out on cytological materials obtained from uterine cervical lesions of low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs), and squamous cell carcinomas (SCCs). L1 capsid protein was positive in 30% of LSILs and 12% of HSILs, but in 0% of SCCs. In contrast, p16 protein was positive in 55% of LSILs, 100% of HSILs, and 100% of SCCs. L1-positive cells were only observed in the superficial layer, whereas p16-positive cells were seen throughout the full thickness of the epithelium. The relation between L1 capsid protein and p16 protein, p16(-)/L1(+) cases represented 44% of LSILs, but 0% of HSILs, and 0% of SCCs, whereas p16(+)/L1(-) cases represented 82% of LSILs, 88% of HSILs, and 100% of SCCs. Expression of L1 capsid protein decreased with lesion progression from LSILs to HSILs and SCCs, whereas p16 protein was positive in all HSILs and SCCs. The correlation between L1 and p16 expressions suggests that L1(-)/p16(+) cases have the potential for progression, whereas L1(+)/p16(-) and L1(-)/p16(-) cases may be nonprogressive lesions or potentially in remission.Cancer 04/2008; 114(2):83-8. DOI:10.1002/cncr.23366 · 4.90 Impact Factor