Morphologic Characteristics of p16&lt;sup&gt;INK4a&lt;/sup&gt;-Positive Cells in Cervical Cytology Samples

Trunk, Marcus J.; Dallenbach-Hellweg, Gisela; Ridder, Ruediger; Petry, Karl Ulrich; Ikenberg, Hans; Schneider, Volker; Doeberitz, Magnus von Knebel

doi:10.1159/000326445

Cited by 70 publications

(58 citation statements)

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“…ASCUS indicates atypical squamous cells of undetermined significance; LSIL, low-grade squamous intraepithelial lesion; CIN2þ, cervical intraepithelial neoplasia of grade 2 or higher. 2 In recent studies, it has been shown that p16 immunocytochemical analyses may provide similar sensitivities for underlying CIN2þ as testing for presence of high-risk HPV at significantly higher specificity levels. 7,8 Thus, although those studies demonstrated that the cells of interest in most of the cases are on the slides and, when being immunostained for p16, can be used to efficiently triage equivocal or mildly abnormal Pap cytology results, the interpretation still comprised a morphology interpretation component that is known to contribute to reader-dependent variability that may negatively affect sensitivity or specificity for predicting outcome.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8] In the majority of the studies, p16 cytology was found to provide sensitivity rates for the detection of underlying high-grade cervical intraepithelial neoplasia (CIN of grade 2 or higher, CIN2þ), which were similar or slightly lower compared with the sensitivity of testing for the presence of human papillomavirus (HPV) infections. 7,9,10,11 At the same time, specificity of p16 cytology-based testing was found to be substantially higher than the specificity of HPV testing in all studies.…”

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confidence: 99%

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p16/ki‐67 dual‐stain cytology in the triage of ASCUS and LSIL Papanicolaou cytology

Schmidt¹,

Bergeron²,

Denton³

et al. 2011

Cancer Cytopathology

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BACKGROUND:The objective of this study was to analyze the diagnostic performance of a newly established immunocytochemical dual‐stain protocol, which simultaneously detects p16INK4a and Ki‐67 expression in cervical cytology samples, for identifying high‐grade cervical intraepithelial neoplasia (CIN2+) in women with Papanicolaou (Pap) cytology results categorized as atypical squamous cells of undetermined significance (ASCUS) or low‐grade squamous intraepithelial lesions (LSIL).METHODS:Residual liquid‐based cytology material from 776 retrospectively collected ASCUS/LSIL cases that were available from a recent study evaluating p16 cytology and HPV testing were subjected to p16/Ki‐67 dual staining. The presence of 1 or more double‐immunoreactive cell(s) was regarded as a positive test outcome, irrespective of morphology. Test results were correlated to histology follow‐up.RESULTS:Sensitivity of p16/Ki‐67 dual‐stain cytology for biopsy‐confirmed CIN2+ was 92.2% (ASCUS) and 94.2% (LSIL), while specificity rates were 80.6% (ASCUS) and 68.0% (LSIL), respectively. Similar sensitivity/specificity profiles were found for both age groups of women aged <30 years versus women aged ≥30 years. Dual‐stain cytology showed comparable sensitivity, but significantly higher specificity, when compared with human papillomavirus (HPV) testing.CONCLUSIONS:The results of this study show that p16/Ki‐67 dual‐stain cytology provided a high sensitivity for the detection of underlying CIN2+ in women with ASCUS or LSIL Pap cytology results, comparable to the rates previously reported for HPV testing and p16 single‐stain cytology. However, the specificity of this morphology‐independent interpretation of p16/Ki‐67 dual‐stain cytology testing was further improved compared with the earlier p16 single‐stain cytology approach, which required morphology interpretation, and it is significantly higher when compared with HPV testing. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.

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Section: Discussionmentioning

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confidence: 99%

p16/ki‐67 dual‐stain cytology in the triage of ASCUS and LSIL Papanicolaou cytology

Schmidt¹,

Bergeron²,

Denton³

et al. 2011

Cancer Cytopathology

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207

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“…Previous reports have shown good sensitivity and specificity of immunocytochemical staining of cervical samples, both histology and cytology. 2,3 Some authors have proposed that p16 INK4a staining could be used to triage women with low-grade cytology results and predict who is more likely to have CIN3 or worse. 4,5 HPV transformed cells with high levels of p16 INK4a can be identified with a protein-based assay.…”

Section: Discussionmentioning

confidence: 99%

“…Staining of histology and cytology specimens for p16 INK4a has shown that detection of antibodies to the protein is a sensitive and specific marker of high-grade cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. [2][3][4][5] In a number of studies, p16 INK4a staining of biopsy tissue was seen in over 90% of cases with high-grade CIN and invasive cervical cancer, being generally absent from the normal tissue and staining only zonal or patchy areas of the low-grade CIN cases. 2,6,7 Findings from these immunostaining studies suggest that compared to high-risk HPV DNA, which is detected in the majority of both high-and low-grade lesions, 8 p16 INK4a might be a better marker for identifying those lesions most likely to progress.…”

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Evaluation of a new p16^INK4A ELISA test and a high‐risk HPV DNA test for cervical cancer screening: Results from proof‐of‐concept study

Mao

Balasubramanian

et al. 2007

Intl Journal of Cancer

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p16 INK4a , a cell cycle regulation protein, accumulates in abnormal epithelial cells infected with high-risk human papilloma virus (HPV). In immunostaining studies, p16 INK4a has shown potential as a marker of high grade cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. To evaluate its potential use in cervical cancer screening, we conducted a feasibility study to compare the performance of a new enzyme linked immunosorbant assay (ELISA) for p16 INK4a (mtm laboratories, Heidelberg, Germany) to that of the Hybrid capture 2 TM (hc2) test for high-risk HPV DNA for the detection of CIN3. Three hundred and nineteen women were referred from Western Washington Planned Parenthood clinics for colposcopy examination and cervical biopsy because of abnormal Pap test results. Cervical samples were obtained from study participants for p16 INK4a ELISA, liquidbased cytology and hc2. The order (first and second) for obtaining samples for cervical cytology and p16 INK4a ELISA changed with every other subject. Concentrations of p16 INK4a protein were higher when the sample was taken before the cytology. The sensitivity of p16 INK4a ELISA (concentration 8 units/ml) taken as first sample was 90.0% for CIN3, and the sensitivity of HC2 taken as a second sample was 85%. In the same group, the specificity of p16 INK4a ELISA (46.9%) was slightly better than hc2 (35.4%) Results from this proof-of-concept study suggest that p16 INK4a ELISA has a similar sensitivity and slightly better specificity for CIN3 compared to hc2. These findings support proceeding with a larger study with samples from a population of women presenting for routine cytology screening. ' 2007 Wiley-Liss, Inc.Key words: p16 INK4a ; ELISA; CIN; screening; HPV The Pap smear has been an effective screening tool for cervical cancer, but it is limited with respect to its sensitivity, cost and requirement of significant infrastructure and technology to be effective. Human papillomavirus (HPV) testing has been proposed as a possible screening tool in resource poor settings where Pap screening is not feasible; however testing for high-risk HPV deoxyribonucleic acid (DNA) is limited by its poor specificity. 1 The search for specific biomarkers of HPV infected precancerous cells has yielded a number of possible markers of disease, including p16 INK4a .p16 INK4a is a protein involved in cell cycle regulation and accumulates in abnormal epithelial cells infected with high-risk HPV. p16 INK4a is a cyclin dependent kinase (CDK) inhibitor that regulates the activity of CDK4 and CDK6. It is inactivated in many cancers by genetic deletion or hypermethylation. 2 In non-HPV associated tumors, this inactivation leads to increased CDK activity and inactivation of the retinoblastoma protein (pRb), resulting in disruption of the cell cycle and increased cell proliferation. However, in HPV-associated tumors, inactivation of pRb by highrisk HPV oncoprotein E7 leads to cell proliferation and markedly increased levels of p16 INK4a . Staining of histology and cytology ...

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“…p16INK4a overexpression indicates inactivation of cellular cycle control mediated by the E7 oncoprotein of high-risk human papillomaviruses (HR-HPVs) (12)(13)(14)(15)(16)(17)(18). In normal Pap smears, the p16INK4a protein is not evident by immunocytochemistry, with the exception of some normal cells where it is physiologically expressed (16). The age of the women ranged from 18 to 54 years (average 38) in the ASC-US group, and from 18 to 50 years (average 34) in the LSIL group.…”

Section: Introductionmentioning

confidence: 99%

Prediction of clinical outcome using p16INK4a immunocytochemical expression in low-grade squamous intraepithelial lesions and high-risk HPV-positive atypical squamous cells of undetermined significance in patients with and without colposcopic evident cervical disease

Lukic

Sbenaglia

Carico

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. p16INK4a as a diagnostic marker of a cervical intraepithelial neoplasia of grade 2+ (CIN2+) in atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) cytological samples has been analyzed, but has not yet been included in clinical routine practice. One hundred and ninety-one patients with an abnormal Pap test (84 ASC-US and 107 LSILs) who underwent colposcopy were selected for this study. At enrollment, 96 patients (Group 1) had a positive colposcopy and therefore underwent a cervical biopsy, while 95 (Group 2) had a negative colposcopy and were followed up for up to 1 year. Both groups were tested for p16INK4a using immunocytochemical methods, and the p16INK4a results were correlated with histology or follow-up outcome. In Group 1 ASC-US cases, 82% of lesions less than CIN2 were p16INK4a-negative and all CIN2 cases were p16INK4a-positive (p=0.00044). In Group 1 LSIL cases, 71% of lesions less than CIN2 were p16INK4a-negative and 87% of CIN2/3 were p16INK4a-positive (p= 0.00033). Seventy-seven percent of Group 2 ASC-US patients with a negative 1-year follow-up (NF-U) were p16INK4a-negative at enrollment, while all patients with positive follow-up (PF-U) were p16INK4a-positive (p=0.00113). In Group 2 LSIL cases, 83% of patients with NF-U were p16INK4a-negative, while 65% of patients with PF-U were p16INK4a-positive at enrollment (p=0.0014). In fact, 39% of the positive p16INK4a LSIL patients had CIN2+ histological lesions. The positive predictive value of p16INK4a for CIN2+ was 50% in ASC-US and 52% in LSIL cases; the negative predictive value was 100 and 94%, respectively. In conclusion, in our patients, a negative p16INK4a appears to be a marker of the absence of CIN3, while a positive p16INK4a can be correlated with the presence of histological CIN2+ found at enrollment or during the subsequent follow-up. Thus, its clinical predictive value is independent from the colposcopic aspect at enrollment. IntroductionIt has been proven that human papillomaviruses (HPVs) are strongly associated with pre-neoplastic and neoplastic lesions of the uterine cervix (1-3).According to present guidelines, patient treatment and followup vary according to the classification of the lesion (4-8). Patients with high-grade squamous intraepithelial lesions (HSILs) are referred for colposcopy and, when a cervical intraepithelial neoplasia of grade 2 or more is histologically confirmed (CIN2+), the lesion is treated with excisional procedures. However, the management of patients with low-grade squamous intraepithelial lesions (LSILs) and atypical squamous cells of undetermined significance (ASC-US) is still controversial. Therefore, the identification of patients that have CIN2+ lesions beneath a LSIL cytological superficial lesion is an important challenge in order to avoid under diagnosis and treatment.The aim to identify a specific triage test for women with ASC-US and LSILs has become increasingly crucial. The introduction of a biomarker that detects a CIN2+ cervi...

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Morphologic Characteristics of p16<sup>INK4a</sup>-Positive Cells in Cervical Cytology Samples

Cited by 70 publications

References 20 publications

p16/ki‐67 dual‐stain cytology in the triage of ASCUS and LSIL Papanicolaou cytology

p16/ki‐67 dual‐stain cytology in the triage of ASCUS and LSIL Papanicolaou cytology

Evaluation of a new p16^INK4A ELISA test and a high‐risk HPV DNA test for cervical cancer screening: Results from proof‐of‐concept study

Prediction of clinical outcome using p16INK4a immunocytochemical expression in low-grade squamous intraepithelial lesions and high-risk HPV-positive atypical squamous cells of undetermined significance in patients with and without colposcopic evident cervical disease

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Morphologic Characteristics of p16<sup>INK4a</sup>-Positive Cells in Cervical Cytology Samples

Cited by 70 publications

References 20 publications

p16/ki‐67 dual‐stain cytology in the triage of ASCUS and LSIL Papanicolaou cytology

p16/ki‐67 dual‐stain cytology in the triage of ASCUS and LSIL Papanicolaou cytology

Evaluation of a new p16INK4A ELISA test and a high‐risk HPV DNA test for cervical cancer screening: Results from proof‐of‐concept study

Prediction of clinical outcome using p16INK4a immunocytochemical expression in low-grade squamous intraepithelial lesions and high-risk HPV-positive atypical squamous cells of undetermined significance in patients with and without colposcopic evident cervical disease

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Evaluation of a new p16^INK4A ELISA test and a high‐risk HPV DNA test for cervical cancer screening: Results from proof‐of‐concept study