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1.
Schmidt D Bergeron C Denton KJ Ridder R;European CINtec Cytology Study Group 《Cancer cytopathology》2011,119(3):158-166
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. 相似文献2.
Marianne Waldstrøm MD Rikke Kølby Christensen MD Dorthe Ørnskov PhD 《Cancer cytopathology》2013,121(3):136-145
BACKGROUND:
The objective of the current study was to investigate the clinical performance of detecting high‐grade lesions with the CINtec PLUS p16INK4a/Ki‐67 dual stain and the APTIMA human papillomavirus (HPV) Assay in a cohort of women with low‐grade squamous intraepithelial lesion (LSIL) cytology. The authors also assessed the reproducibility of the evaluation of immunocytochemical staining.METHODS:
The 2 tests were performed on liquid‐based residual material from 469 women with LSILs. The samples had at least 5 years of follow‐up and the gold standard used was high‐grade cervical intraepithelial neoplasia (CIN2+/CIN3+) proven on histology.RESULTS:
Approximately 69% of all the women included in the study had a positive test for HPV mRNA and 56% was positive for the dual stain. The 2 tests demonstrated high sensitivities. When examining the specificities, the APTIMA HPV Assay performed with significantly lower values than the CINtec PLUS test. For patients with CIN2+, the APTIMA HPV Assay had a specificity of 36.1% versus 51.3% for the CINtec PLUS test, and for women with CIN3+, the specificity was 33.8% versus 48.2%, respectively. The difference was even more pronounced when analyzing women aged < 30 years separately. The kappa values between the 3 observers in scoring the dual stain ranged from 0.43 to 0.49 and improved in a second evaluation round to values ranging from 0.50 to 0.66.CONCLUSIONS:
The CINtec PLUS p16INK4a/Ki‐67 dual‐staining test in LSIL cytology samples demonstrated high sensitivity that was similar to that of the APTIMA HPV Assay in the detection of underlying high‐grade disease but with enhanced specificity, especially among women aged < 30 years. The kappa value for the evaluation of the CINtec PLUS dual‐staining test was moderate but could be improved through training. Cancer (Cancer Cytopathol) 2013. © 2012 American Cancer Society. 相似文献3.
Panduka Samarawardana MD Donna L. Dehn PhD Meenakshi Singh MD Douglas Franquemont MD Chesney Thompson MD Loretta Gaido MD Kathleen C. Torkko PhD Petra Homer MS Stephanie Burke BS Matthew A. Titmus BS Vipul Nayi BS Kenneth R. Shroyer MD PhD 《Cancer cytopathology》2010,118(3):146-156
BACKGROUND
The primary goal of this study was to compare the clinical performance of an optimized and rigorously controlled immunocytochemical (ICC) assay for p16INK4a to high‐risk (HR) human papillomavirus (HPV) detection by polymerase chain reaction (PCR) as diagnostic adjuncts for cytology specimens from colposcopy patients.METHODS:
The study included 403 cervical cytology specimens collected within 3 months of colposcopy. The colposcopic impression and cervical biopsy diagnosis served as the standards for correlation with cytological, p16INK4a, and HPV data. p16INK4a was evaluated using an immunoperoxidase‐based assay that was linear over 4 logs for the detection of HeLa‐spiked positive control cytology specimens, using a threshold for positive test results that was based on receiver operating characteristic curve analysis. HR‐HPV was detected by multiplex PCR using genotype‐specific primers.RESULTS:
In all combined diagnostic categories (negative for intraepithelial lesion and malignancy, atypical glandular cells, atypical squamous cells of undetermined significance, atypical squamous cells cannot exclude high‐grade squamous intraepithelial lesion, low‐grade squamous intraepithelial lesion, and high‐grade squamous intraepithelial lesion), the p16INK4a ICC and HR‐HPV assays, respectively, had sensitivity of 81.7% and 83.3% (P = .81) and specificity of 78.1% and 50.9% (P < .001) for the detection of underlying ≥grade 2 cervical intraepithelial neoplasia (CIN) lesions on biopsy. Furthermore, the positive predictive value of p16INK4a ICC was greater than that of HR‐HPV for patients with biopsies ≥CIN‐2 (41.2% and 24.2%, respectively, P = .001).CONCLUSIONS:
This p16INK4a immunocytochemical assay has superior specificity but similar sensitivity to HR‐HPV testing to predict underlying high‐grade dysplastic lesions in patients who are referred for colposcopy. The determination of the overall performance characteristics of p16INK4a immunocytochemistry, as an independent test or in combination with HPV testing in low‐risk screening populations, however, will require subsequent large‐scale prospective clinical trials. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society. 相似文献4.
Jane L. Meyer CT David W. Hanlon PhD Birthe T. Andersen CT Ole F. Rasmussen PhD Kirsten Bisgaard BSc 《Cancer cytopathology》2007,111(2):83-92
BACKGROUND.
The aim of this study was to examine p16INK4a protein expression in ThinPrep (Cytyc Corporation, Marlborough, Mass) cervical specimens by using the CINtec p16INK4a Cytology Kit (Dako, Glostrup, Denmark). The ability of this assay to accurately identify underlying high‐grade lesions was assessed by using follow‐up biopsies and comparing these results with Hybrid Capture 2 (Digene, Gaithersburg, Md) high‐risk HPV (hc2) results.METHODS.
Three hundred ninety‐eight residual ThinPrep samples were collected, and histological follow‐up data were retrieved for abnormal cytology specimens. After preparation of a Papanicolaou‐stained slide, a second slide was processed in preparation for p16INK4a immunostaining. High‐risk human papillomavirus testing (hc2) was also performed.RESULTS.
Of the 163 cytologically abnormal samples, 6‐month biopsy follow‐up data were available for 45% of the specimens. At initial blinded evaluation, 21 of the 26 cases with cervical intraepithelial neoplasia (CIN) II/III follow‐up were positive for p16INK4a, yielding an overall diagnostic sensitivity of 81%; 29 of the 47 cases diagnosed as CIN I or less were p16INK4a negative, yielding a diagnostic specificity of 62%. In comparison, the hc2 test results indicated a diagnostic sensitivity of 100% with a diagnostic specificity of 15%. After review of selected cases with CIN II/III follow‐up, 25 of 26 slides were deemed to be positive for p16INK4a, increasing the diagnostic sensitivity to 96%.CONCLUSIONS.
The CINtec p16INK4a Cytology Kit, in combination with ThinPrep cervical samples, allowed clear evaluation of p16INK4a protein overexpression. Diagnostic specificity of the CINtec p16INK4a assay was significantly improved relative to hc2. To increase p16INK4a immunostaining in abnormal cells, a modified kit version with improved staining performance has been developed and is currently being evaluated. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society. 相似文献5.
Li Yu MD Liantang Wang MD PhD Juemin Zhong MD Shangwu Chen MD PhD 《Cancer cytopathology》2010,118(1):47-55
BACKGROUND:
This study was conducted to evaluate the reliability and role of cell block preparations in the diagnosis of neoplastic and preneoplastic lesions of the cervix and to improve the value of cell block preparations in diagnosing and predicting the prognosis of cervical lesions through immunostaining of p16INK4A (p16), Ki‐67, and human papillomavirus (HPV) L1 capsid protein (HPV L1).METHODS:
In total, 138 specimens were diagnosed on liquid‐based cytology (LBC) and cell block preparations, and 63 specimens were subjected subsequently to tissue follow‐up and immunostaining for p16, Ki‐67, and HPV L1 on cell block sections.RESULTS:
In 42 specimens that were diagnosed as low‐grade squamous intraepithelial lesion, high‐grade squamous intraepithelial lesion (HSIL), and squamous cell carcinoma (SCC) on cell blocks, 38 specimens (90.5%) were confirmed by histopathologic reports, and there was slightly better than 81.6% agreement between LBC and tissue follow‐up. Immunointensity and cells that were positive for p16 were enhanced according to increased pathologic grade and differed statistically between cervical intraepithelial neoplasia 1 (CIN‐1) and CIN‐2/CIN‐3 as well as SCC. The positive rates of HPV L1 decreased gradually according to the severity of cervical neoplasia, and HPV L1/p16 expression patterns were related to the severity of cervical lesions.CONCLUSIONS:
The cell block preparation technique was complementary to LBC, and the authors concluded that the application of LBC combined with cell block preparations may improve the diagnostic accuracy of cytology. Immunostaining for p16 and Ki‐67 on cell block preparations can help to improve the diagnostic accuracy of HSIL and SCC. A combined expression pattern of p16 and HPV L1 may serve as a valuable index for predicting prognosis and follow‐up of cervical dysplastic lesions. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society. 相似文献6.
Nicolas Wentzensen MD Christine Bergeron MD PhD Frederic Cas CT Svetlana Vinokurova PhD Magnus von Knebel Doeberitz MD PhD 《Cancer cytopathology》2007,111(1):58-66
BACKGROUND.
The identification of a small percentage of high‐grade cervical intraepithelial neoplasias (HGCIN) among patients with minor cytological abnormalities (atypical squamous cells of undetermined significance [ASCUS] and/or low‐grade squamous intraepithelial lesions [LSIL] group) is a major problem in cytology‐based cervical cancer screening. The authors investigated the efficacy of p16INK4a as a biomarker to identify samples of patients with HGCIN among those with an ASCUS or LSIL result in Papanicolaou cytology.METHODS.
Consecutive liquid‐based cytology specimens of 137 ASCUS and 88 LSIL results were selected from gynecologists who adopted a triage regimen with biopsy under colposcopy 2 months later, independent of the p16INK4a result. p16INK4a stained slides were prepared and independently read by 2 observers, who used a recently described score to categorize p16INK4a stained squamous cells. The endpoint of the study was detection of a biopsy‐confirmed HGCIN.RESULTS.
The overall sensitivity and specificity of p16INK4a positive cells with a nuclear score >2 for diagnosis of HGCIN in ASCUS and LSIL cases combined was 96% and 83%, respectively. The sensitivity and specificity in the ASCUS group was 95% and 84%, and 100% and 81% in the LSIL group, respectively. Two observers had a high concordance in assessing p16INK4a stained cells (κ value of 0.841).CONCLUSIONS.
These data suggested that the use of p16INK4a as a biomarker combined with nuclear scoring of p16INK4a positive cells in cervical cytology to triage ASCUS and/or LSIL cases allows identification of HGCIN with good sensitivity and specificity. Cancer (Cancer Cytopathol) 2007. © 2006 American Cancer Society. 相似文献7.
p16INK4a/Ki‐67 co‐expression specifically identifies transformed cells in the head and neck region
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Csaba Toth Gerhard Dyckhoff Steffen Wagner Franziska Müller Claus Wittekindt Kolja Freier Peter Plinkert Jürgen Hoffmann Svetlana Vinokurova Jens Peter Klussmann Magnus von Knebel Doeberitz Miriam Reuschenbach 《International journal of cancer. Journal international du cancer》2015,136(7):1589-1599
p16INK4a immunohistochemical overexpression is an overall reliable surrogate marker of human papillomavirus (HPV)‐associated head and neck squamous cell carcinomas (HNSCC). However, cases of ambiguous p16INK4a overexpression are regularly detected in the head and neck: p16INK4a expression can be observed in non‐malignant tissue, such as tonsillar crypt epithelium and a proportion of branchial cleft cysts. Additionally, diverse patterns of p16INK4 expression can complicate interpretation of “p16INK4a‐positivity”. These aspects impede the unrestricted application of p16INK4a as a diagnostic marker in the head and neck. We hypothesized that combined detection of p16INK4a and the proliferation marker Ki‐67 could support clarification of ambiguous p16INK4a expression in the head and neck by specifically indicating p16INK4a‐expressing cells with proliferative activity. p16INK4a/Ki‐67 co‐expression in a combined staining procedure was correlated to distinct p16INK4a expression patterns and HPV status (HPV DNA followed by E6*I oncogene mRNA detection) in 147 HNSCC and 50 non‐malignant head and neck samples. p16INK4a/Ki‐67 co‐expression only occurred in transformed cells of the head and neck. Co‐expression was never detected in non‐transformed cells. Combined p16INK4a/Ki‐67 expression was stringently associated with a diffuse p16INK4a expression pattern. All HPV oncogene‐expressing HNSCC showed p16INK4a/Ki‐67 co‐expression. We demonstrate that p16INK4a/Ki‐67 co‐expression occurs exclusively in transformed cells of the head and neck. Our findings indicate a substantial impact of combined p16INK4a/Ki‐67 expression in the assessment of ambiguous p16INK4a expression in the head and neck by specifically identifying p16INK4a‐expressing cells with proliferative activity. This property will be of considerable significance for head and neck histo‐ and cytopathology. 相似文献
8.
Eun Ji Nam Jae Wook Kim Jong Wook Hong Hyoung Sun Jang Sang Yub Lee Si Young Jang Dae Woo Lee Sang Wun Kim Jae Hoon Kim Young Tae Kim Sunghoon Kim Jong Wook Kim 《Journal Of Gynecologic Oncology》2008,19(3):162-168
Objective
The purposes of this study were to evaluate the expression of p16INK4a (referred as to p16) and Ki-67 in cervical intraepithelial neoplasia (CIN), and the correlation between high-risk human papillomavirus (HPV) infection and the above biomarkers.Methods
We analyzed 31 patients who were diagnosed with CIN at Kwandong University Myongji Hospital from October 2006 to September 2007. CIN specimens (CIN1, 12; CIN2, 6; CIN3, 13) were obtained by colposcopy-directed biopsy (CDB) or loop electrical excision procedure (LEEP). The expressions of p16 and Ki-67 were evaluated by immunohistochemical methods with antibodies to p16 and Ki67. The immunohistochemical staining results were classified into four grades: 0, 1, 2 and 3. HPV genotyping or Hybrid Capture-II test was used to detect high-risk HPV.Results
The expression of p16 (p<0.001) and Ki-67 (p=0.003) were positively associated with CIN grade. p16 expressions increased significantly with high-risk HPV infection (p=0.014), especially HPV type 16 and 58. Ki-67 expression was not related with high-risk HPV. There was positive correlation between the expression of the p16 and Ki-67 (p=0.007).Conclusion
CIN grade were positively related to the expression of p16 and Ki-67. p16 expressions of high-risk HPV specimens significantly increased more than Ki-67. Therefore, in the diagnosis of CIN and high-risk HPV infection, p16 can be a useful biomarker. 相似文献9.
Jolien Roelens MSc Miriam Reuschenbach MD Magnus von Knebel Doeberitz MD PhD Nicolas Wentzensen MD Christine Bergeron MD PhD Marc Arbyn MD MSc DrTMH 《Cancer cytopathology》2012,120(5):294-307
The best method for identifying women who have minor cervical lesions that require diagnostic workup remains unclear. The authors of this report performed a meta‐analysis to assess the accuracy of cyclin‐dependent kinase inhibitor 2A (p16INK4a) immunocytochemistry compared with high‐risk human papillomavirus DNA testing with Hybrid Capture 2 (HC2) to detect grade 2 or greater cervical intraepithelial neoplasia (CIN2+) and CIN3+ among women who had cervical cytology indicating atypical squamous cells of undetermined significance (ASC‐US) or low‐grade cervical lesions (LSIL). A literature search was performed in 3 electronic databases to identify studies that were eligible for this meta‐analysis. Seventeen studies were included in the meta‐analysis. The pooled sensitivity of p16INK4a to detect CIN2+ was 83.2% (95% confidence interval [CI], 76.8%‐88.2%) and 83.8% (95% CI, 73.5%‐90.6%) in ASC‐US and LSIL cervical cytology, respectively, and the pooled specificities were 71% (95% CI, 65%‐76.4%) and 65.7% (95% CI, 54.2%‐75.6%), respectively. Eight studies provided both HC2 and p16INK4a triage data. p16INK4a and HC2 had similar sensitivity, and p16INK4a has significantly higher specificity in the triage of women with ASC‐US (relative sensitivity, 0.95 [95% CI, 0.89‐1.01]; relative specificity, 1.82 [95% CI, 1.57‐2.12]). In the triage of LSIL, p16INK4a had significantly lower sensitivity but higher specificity compared with HC2 (relative sensitivity, 0.87 [95% CI, 0.81‐0.94]; relative specificity, 2.74 [95% CI, 1.99‐3.76]). The published literature indicated the improved accuracy of p16INK4a compared with HC2 testing in the triage of women with ASC‐US. In LSIL triage, p16INK4a was more specific but less sensitive. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society. 相似文献
10.
Triaging HPV‐positive women with normal cytology by p16/Ki‐67 dual‐stained cytology testing: Baseline and longitudinal data
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Nicole J. Polman Birgit I. Witte Folkert J. van Kemenade Dorien Rijkaart Johannes Berkhof G.A.M.A. Balfoort‐van der Meij Ruediger Ridder Peter J.F. Snijders Chris J.L.M. Meijer 《International journal of cancer. Journal international du cancer》2015,136(10):2361-2368
Primary human papillomavirus (HPV)‐based screening results in a 2–5% lower specificity for cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) compared to Pap cytology. To identify HPV‐positive women with CIN2+, we retrospectively evaluated the cross‐sectional and longitudinal performance of p16/Ki‐67 dual‐stained cytology in HPV‐positive women with normal cytology participating in population‐based cervical screening. Conventional Pap cytology specimens of 847 of these women derived from the VUSA‐Screen study were dual‐stained for p16/Ki‐67. Cross‐sectional clinical performance in detecting CIN3 or worse (CIN3+), and CIN2+ was compared to that of baseline HPV genotyping. Moreover, 5‐year cumulative incidence risks (CIR) for CIN3+ (CIN2+) were determined. The sensitivity of p16/Ki‐67 dual‐stained cytology for CIN3+ (CIN2+) was 73.3% (68.8%) with a specificity of 70.0% (72.8%). HPV16/18 genotyping showed a sensitivity for CIN3+ (CIN2+) of 46.7% (43.8%), with a specificity of 78.3% (79.4%). The 5‐year CIR for CIN3+ in HPV‐positive women with normal cytology was 6.9%. Testing these women with p16/Ki‐67 dual‐stained cytology resulted in a significantly lower CIN3+ 5‐year CIR of 3.3% (p = 0.017) in case of a negative test result. A negative HPV16/18 genotyping test result also led to a lower 5‐year CIN3+ CIR of 3.6%. p16/Ki‐67 dual‐stained cytology detects more than 70% of underlying CIN3+ lesions in HPV‐positive women with normal cytology at baseline and is therefore suitable for triaging these women to colposcopy. Furthermore, the CIN3+ 5‐year CIR of 3.3% after a negative dual‐stain result is significantly lower compared to the 5‐year CIR of 6.9% in women without p16/Ki‐67 dual‐stained cytology triage. 相似文献
11.
Sakiko Nishio Takuma Fujii Hiroshi Nishio Kaori Kameyama Miyuki Saito Takashi Iwata Kaneyuki Kubushiro Daisuke Aoki 《Journal Of Gynecologic Oncology》2013,24(3):215-221
Objective
In cervical intraepithelial neoplasia (CIN), p16INK4a immunohistochemistry has been reported to be a useful diagnostic biomarker. However, limited information is available about the association between the p16INK4a immunohistochemistry and the outcomes of CIN. Here, we report p16INK4a immunohistochemistry as an effective biomarker to predict the outcomes of CIN.Methods
p16INK4a immunohistochemistry was performed in patients with CIN from January 2000 to August 2009. Among these patients, we have performed a retrospective analysis of the medical records to evaluate the outcome of CIN 1-2 and performed statistical analysis to determine the correlation between p16INK4a expression and the outcomes. We also performed HPV genotyping and analyzed the relation between the infecting human papillomavirus (HPV) genotype and the outcomes.Results
A total of 244 patients, including 82 with CIN 1, 60 with CIN 2, and 102 with CIN 3, were examined. The rate of p16INK4a overexpression increased with increasing CIN grade, 20.7% for CIN 1, 80.0% for CIN 2, and 89.2% for CIN 3, with significant differences between CIN 1 and CIN 2-3 group. In the 131 CIN 1-2 patients, the progression rate was significantly higher for the patients showing p16INK4a overexpression than for those not showing p16INK4a overexpression (p=0.005); the regression rate was also found to be significantly lower for the patients showing p16INK4a overexpression (p=0.003). High-risk HPV genotypes were detected in 73 patients (73.7%). Both progression and regression rates were not significantly different between the high-risk HPV-positive and HPV-negative groups (p=0.401 and p=0.381, respectively).Conclusion
p16INK4a overexpression was correlated with the outcome of CIN 1-2, and p16INK4a is considered to be a superior biomarker for predicting the outcome of CIN 1-2 compared with HPV genotyping. 相似文献12.
Remila Rezhake Feng Chen Shang-Ying Hu Xue-Lian Zhao Xun Zhang Jian Cao You-Lin Qiao Fang-Hui Zhao Marc Arbyn 《International journal of cancer. Journal international du cancer》2020,147(8):2053-2064
Improvement in managing HPV-positive women is urgently needed. Based on a population-based study which included 2112 women aged 49 to 69 from Shanxi, China, we aimed to evaluate the clinical performance of multiple triage strategies based on liquid-based cytology (LBC), p16INK4a, viral load and partial genotyping, as a single or combined strategy for detecting cervical intraepithelial neoplasia grade 2/3 or higher (CIN2+/CIN3+) in women who tested positive by Hybrid Capture 2 (HC2). Among 452 HC2-positive women, the test positivity of LBC (ASC-US+), p16INK4a, HPV16/18 and HPV16/18/31/33/45 were 39.6%, 38.5%, 18.0% and 40.0%, respectively. Compared to LBC (ASC-US+) triage, a single triage strategies using p16INK4a or extended genotyping (SureX HPV16/18/31/33/45) achieved comparable sensitivity (relative sensitivity: 1.08, 95% confidence interval [CI]: 0.93-1.26 and 0.96, 95% CI: 0.76-1.22) and specificity (relative specificity: 1.05, 95% CI: 0.96-1.14 and 1.02, 95% CI: 0.92-1.14) for CIN3+. Viral load triage using a ≥50 RLU/CO cut-point also yielded similar results with LBC (ASC-US+). Among combined triage strategies, HPV16/18 genotyping with reflex p16INK4a showed higher sensitivity and slightly lower specificity than LBC (ASC-US+) for CIN3+ detection, however, the differences were not statistically significant. Of note, after a negative result by p16INK4a or LBC among HPV16/18 negative women, the posttest probability of CIN3+ was lower than 1%. Our study suggested that p16INK4a, extended genotyping and increased viral load cut-point could be promising alternatives to cytology triage. Combined triage algorithms of HPV16/18 with reflex p16INK4a or cytology, if negative, are associated with the substantial low posttest risk sufficient to release women to next screening round. 相似文献
13.
The clinical impact of using p16INK4a immunochemistry in cervical histopathology and cytology: An update of recent developments
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Christine Bergeron Guglielmo Ronco Miriam Reuschenbach Nicolas Wentzensen Marc Arbyn Mark Stoler Magnus von Knebel Doeberitz 《International journal of cancer. Journal international du cancer》2015,136(12):2741-2751
Cervical cancer screening test performance has been hampered by either lack of sensitivity of Pap cytology or lack of specificity of Human Papillomavirus (HPV) testing. This uncertainty can lead to unnecessary referral and treatment, which is disturbing for patients and increases costs for health care providers. The identification of p16INK4a as a marker for neoplastic transformation of cervical squamous epithelial cells by HPVs allows the identification of HPV‐transformed cells in histopathology or cytopathology specimens. Diagnostic studies have demonstrated that the use of p16INK4a immunohistochemistry substantially improves the reproducibility and diagnostic accuracy of histopathologic diagnoses. p16INK4a cytology has substantially higher sensitivity for detection of cervical precancer in comparison to conventional Pap tests. Compared to HPV DNA tests, immunochemical detection of p16INK4a‐stained cells demonstrates a significantly improved specificity with remarkably good sensitivity. About 15 years after the initial observation that p16INK4a is overexpressed in HPV‐transformed cells we review the accumulated clinical evidence suggesting that p16INK4a can serve as a useful biomarker in the routine diagnostic work up of patients with HPV infections and associated lesions of the female anogenital tract. 相似文献
14.
Alameda F Juanpere N Pijuan L Lloveras B Gimeno J Baró T Salido M Serrano S Lloreta J 《Cancer cytopathology》2012,120(4):276-282
BACKGROUND:
The sensitivity of urinary cytology for the diagnosis of urothelial carcinomas is low, particularly in low‐grade carcinomas. The UroVysion test is a fluorescent in situ hybridization multiprobe assay that increases the sensitivity of urinary cytology. However, this test is not widely available. P16INK4a, a protein involved in cell cycle progression, is overexpressed in urothelial carcinoma. Immunocytochemical expression of p16INK4a has been examined in biopsy samples from urothelial carcinomas, but few studies have addressed this protein in urine cytology.METHODS:
The authors compared the results of p16INK4a immunoreactivity in cytology and biopsy samples from 83 cases, including low‐grade urothelial carcinomas, reactive epithelial lesions, and negative cases.RESULTS:
p16INK4a assessment of in urine cytology samples showed a sensitivity of 66.7% and a specificity of 82.8% in the diagnosis of low‐grade urothelial carcinomas.CONCLUSIONS:
On the basis of these results, the authors propose that immunocytochemical detection of p16INK4a is a reliable tool in urine cytology, both for the diagnosis of low‐grade urothelial carcinomas and for follow‐up purposes. More retrospective and prospective studies are required to verify these results. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society. 相似文献15.
David Mesher Anne Szarewski Louise Cadman Janet Austin Lesley Ashdown-Barr Linda Ho George Terry Martin Young Mark Stoler Christine Bergeron Julie McCarthy Corrina Wright Stuart Liddle W.P. Soutter Deirdre Lyons Jack Cuzick 《European journal of cancer (Oxford, England : 1990)》2013,49(9):2179-2186
AimTo compare triage strategies using different human papillomavirus (HPV) consensus and genotyping tests and a p16INK4a test.Methods1228 women referred with a borderline or single mildly dyskaryotic smear. Samples were taken at colposcopy using PreservCyt. Tests included Hybrid Capture 2, Abbott RealTime PCR, BD HPV, Cobas 4800, PreTect HPV-Proofer, APTIMA and p16INK4a. Results were based on the worst histology within 9 months.Results97/1228 (7.9%) women had CIN3+ (203/1228 (17%) CIN2+). HPV testing alone using Hybrid Capture 2, Abbott RealTime PCR, BD HPV, Cobas 4800 or APTIMA had a sensitivity for CIN3+ ranging from 99.0% to 100.0% and specificity for <CIN2 from 23.3% to 34.7%. p16INK4a had a sensitivity of 86.8% and specificity of 50.7%. PreTect HPV-Proofer had a sensitivity of 85.1% and specificity of 73.2%. Testing for HPV type 16 only had sensitivities ranging from 66.0% to 75.5% and specificities from 81.3% to 87.6%. Dual testing with HPV type 16 combined with p16INK4a gave a high sensitivity for CIN3+ (78.7% to 98.0%) and specificity for <CIN2 of 58.6% to 81.5%.ConclusionsTriage with sensitive HPV testing assays can substantially reduce the number of unnecessary referrals in women with low grade cytology with virtually no loss of sensitivity. Even greater gains can be made if p16 and type 16 are used, but some cases of CIN2 will be missed. In both cases short term surveillance will be needed. 相似文献
16.
p16INK4A immunohistochemical staining and predictive value for progression of cervical intraepithelial neoplasia grade 1: A prospective study in China
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Guang‐Dong Liao John W. Sellors Hai‐Kui Sun Xun Zhang Yan‐Ping Bao Jose Jeronimo Wen Chen Fang‐Hui Zhao Yan Song Zhi Cao Shao‐Kai Zhang Ming‐Rong Xi You‐Lin Qiao 《International journal of cancer. Journal international du cancer》2014,134(7):1715-1724
p16INK4A is strongly expressed in tissues diagnosed as cervical intraepithelial neoplasia (CIN) and cancer in women infected with human papillomavirus (HPV), but few prospective studies have evaluated p16INK4A as a marker for the risk of low‐grade CIN (CIN1) progression. We investigated the prevalence of p16INK4A immunostaining by CIN grade and whether overexpression of p16INK4A in CIN1 predicts future risk for high‐grade CIN in Chinese women. 6,557 Chinese women aged 30–49 years were screened from 2003 to 2005 using cytology and carcinogenic HPV test. Colposcopy was performed on women with any abnormal result. p16INK4A Immunostaining was performed on biopsies from all women with CIN1, as well as randomly selected women with normal or CIN grade 2 and worse (CIN2+) biopsies. Women with CIN1 were followed up without treatment. Colposcopy was performed on all untreated women at a 2‐year interval. The prevalence of p16INK4A staining was 2.7%, 42.7%, 75.5%, 79.6% and 100% among women with normal, CIN1, 2, 3 and cancer biopsies, respectively (p < 0.001). HPV positivity was strongly associated with p16INK4A staining [odds ratios (OR) = 12.8; 95% confidence intervals (CI): 5.2–31.6]. p16INK4A staining of CIN1 biopsies at baseline was associated with an increased risk of finding high‐grade CIN over 2 years of follow‐up (OR = 1.43; 95% CI: 0.52–3.91). The two‐year cumulative incidence of CIN2+ for p16INK4A positive women was higher at 10.71% than for p16INK4A negative women at 1.30% (crude RR = 8.25, 95% CI: 1.02–66.62). p16INK4A overexpression is strongly associated with grade of CIN and risk of progression to high‐grade CIN in women with low‐grade lesions. 相似文献
17.
Hina Sarwath Devendra Bansal Nazik Elmalaika Husain Mahmoud Mohamed Ali A. Sultan Shahinaz Bedri 《Infectious agents and cancer》2017,12(1):50
Background
Cervical cancer is the fourth most common cancer in women worldwide with highest incidence reported in Eastern Africa in 2012. The primary goal of this study was to study the expression of p16INK4a in squamous cell carcinoma (SCC) of the cervix by immunohistochemistry (IHC) and determine relation with clinico-pathological parameters. This study further explored the correlation of p16INK4a immunostaining with another proliferation marker, Ki-67 and to study if human papillomavirus (HPV) IHC can be used as a marker for detection of virus in high-grade dysplasia.Methods
A total of 90 samples, diagnosed for cervical cancer, were included in the study. Fixed Paraffin Embedded (FFPE) tissue sections were stained with anti-p16INK4a, anti-Ki-67 and anti-HPV antibodies using automated immunohistochemistry platform (ASLink 48-DAKO).Results
Immunohistochemical protein expression of p16INK4a positivity was found to be highest in SCC (92.2%, n = 71) than other HPV tumors (76.9%, n = 10). The majority of cases (97.4%) were p16INK4a positive in the age group 41–60 years. In addition, a statistically significant difference between p16INK4a and HPV was observed among total cervical tumor cases and SCC cases.Conclusions
As expected staining of invasive cervical cancer with anti-HPV showed rare positivity because HPV heralds active infection in dysplastic lesions and not of frank cervical carcinoma. In contrast, anti-p16INK4a IHC results showed positive correlation in SCC and other cervical tumors.18.
M H Uijterwaal B I Witte F J Van Kemenade D Rijkaart R Ridder J Berkhof G A M A Balfoort-van der Meij M C G Bleeker P J F Snijders C J L M Meijer 《British journal of cancer》2014,110(6):1579-1586
Background:
Women with borderline/mildly dyskaryotic (BMD) cytology smears are currently followed up with repeat testing at 6 and 18 months. The objective of this study is to analyse the cross-sectional and longitudinal performance of p16/Ki-67 dual-stained cytology for the detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) and CIN2+ in women with BMD, and to compare the results with baseline human papillomavirus (HPV) testing.Methods:
Conventional Pap cytology specimens of 256 women with BMD were dual stained for p16/Ki-67 retrospectively, and compared with baseline HPV results and long-term follow-up results.Results:
p16/Ki-67 dual-stained cytology showed a sensitivity of 100%, a specificity of 64.4% and a negative predictive value (NPV) of 100.% for CIN3+. Human papillomavirus testing demonstrated similar sensitivity (96.3%), and NPV (99.1%), but a significantly lower specificity (57.6% P=0.024) for CIN3+. Sensitivity, specificity and NPV for CIN2+ of dual-stained cytology were 89.7%, 73.1% and 95.1%, respectively, which was similar when compared with HPV testing. Dual-stained cytology showed a significant lower referral rate than HPV testing (43.6% vs 49.1% P=0.043). During long-term follow-up, no CIN3+ lesions developed in HPV-positive, dual-stained negative women.Conclusions:
Comparable sensitivity and NPV of dual-stained cytology for CIN3+, combined with a significantly higher specificity, makes p16/Ki-67 dual-stained cytology a viable alternative to HPV testing for triaging BMD. 相似文献19.
Good performance of p16/ki‐67 dual‐stained cytology for surveillance of women treated for high‐grade CIN
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Nicole J. Polman Margot H. Uijterwaal Birgit I. Witte Johannes Berkhof Folkert J. van Kemenade Johan W.M. Spruijt W. Marchien van Baal Peppino G.C.M. Graziosi Dorenda K.E. van Dijken René H.M. Verheijen Theo J.M. Helmerhorst Renske D.M. Steenbergen Daniëlle A.M. Heideman Ruediger Ridder Peter J.F. Snijders Chris J.L.M. Meijer 《International journal of cancer. Journal international du cancer》2017,140(2):423-430
Women treated for high‐grade cervical intraepithelial neoplasia (CIN) are at risk of recurrent CIN Grade 2 or worse (rCIN2+). Currently, posttreatment monitoring is performed using cytology or cytology/high‐risk (hr)HPV cotesting. This study aimed to evaluate the performance of p16/Ki‐67 dual‐stained cytology (p16/Ki‐67) for posttreatment monitoring. Three hundred and twenty‐three women treated for high‐grade CIN in the SIMONATH study underwent close surveillance by cytology, hrHPV and DNA methylation marker testing up to 12 months posttreatment. Histological endpoints were ascertained by colposcopy with biopsy at 6 and/or 12 months. p16/Ki‐67 dual‐staining was performed on residual liquid‐based cytology samples obtained at, or shortly before biopsy collection. Clinical performance estimates of cytology, hrHPV, p16/Ki‐67 testing and combinations thereof for the detection of rCIN2+ were determined and compared to each other. Sensitivity of p16/Ki‐67 for rCIN2+ (69.2%) was nonsignificantly lower than that of cytology (82.1%; ratio 0.84, 95% CI: 0.71–1.01), but significantly lower than that of hrHPV testing (84.6%; ratio 0.82, 95% CI: 0.68–0.99). Specificity of p16/Ki‐67 for rCIN2+ (90.4%) was significantly higher compared to both cytology (70.8%; ratio 1.28, 95% CI: 1.19–1.37) and hrHPV testing (76.2%; ratio 1.19, 95% CI: 1.12–1.26). Overall, hrHPV testing showed very high sensitivity, along with a good specificity. When considering cotesting, combined p16/Ki‐67/hrHPV testing showed rCIN2+ sensitivity comparable to cytology/hrHPV cotesting (87.2% vs. 89.7%; ratio 0.97, 95% CI: 0.92–1.03), but with significantly increased specificity (74.2% vs. 58.1%; ratio 1.28, 95% CI: 1.19–1.38). Thus, when considered in combination with hrHPV, p16/Ki‐67 might be an attractive approach for surveillance of women treated for high‐grade CIN. 相似文献
20.
Yimin Ge MD Debora Smith CT Mary R. Schwartz MD Dina R. Mody MD 《Cancer cytopathology》2009,117(5):326-332