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Prevalence of human papillomavirus16 DNA and p16INK4a protein in oral squamous cell carcinoma: A systematic review and meta-analysis

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      Abstract

      Background and Aim:Indian patients with oral squamous cell carcinoma (OSCC) are etiologically associated with the use of tobacco and alcohol; yet, a proportion of tumors that may harbor human papillomavirus (HPV) infections cannot be neglected. The following meta-analysis was conducted to address the association of p16INK4a and HPV DNA with OSCC. In addition, the study also provides the updated prevalence of HPV-induced OSCC.Materials and Methods:Literature survey was performed using databases such as PubMed with the help of the following keywords – “HPV infection,” “oral squamous cell carcinoma,” “p16INK4a,” “HPV DNA,” “E6,” “E7,” “L1,” “L2” and “LCR.” Proportion method was performed to derive the forest plot using MedCalc statistical software version 16.4.3.Results:Among 145 research articles, 33 articles were selected for further analysis, in which 13 articles were related to HPV DNA detection in tissues, 11 articles detected the overexpression of p16INK4a and nine articles reported the detection of both HPV DNA and p16INK4a expression. Meta-analysis revealed significant heterogeneity (P < 0.0001) among the articles. Overall, the study consisted of 3339 patients with OSCC, among which 559 patients were diagnosed with the presence of HPV16 DNA with a random proportion of 20.1% at 95% confidence interval (CI) (13.9–27.1, P < 0.0001). Overexpression of p16INK4a protein was observed in 709 patients with a random proportion of 25.4% at 95% CI (14.3–38.3, P < 0.0001).Conclusion:HPV DNA and expression of p16INK4a was suggested as gold standard for the detection of HPV infection in many cases of cancers. Frequency of HPV infection is significantly higher in patients with OSCC as identified through the detection of HPV DNA and p16INK4a expression. Even though the association of HPV infection has been established in head and neck cancer, this review could further the establishment of molecular level interaction of HPV in patients with oral cancer.

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      Current Aspects on Oral Squamous Cell Carcinoma

      Oral squamous cell carcinoma is the most common malignant epithelial neoplasm affecting the oral cavity. This article overviews the essential points of oral squamous cell carcinoma, highlighting its risk and genomic factors, the potential malignant disorders and the therapeutic approaches. It also emphasizes the importance of the early diagnosis.
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        p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia.

        It has been repeatedly shown that there is a substantial lack of interobserver reproducibility in the histologic diagnosis of cervical intraepithelial neoplasia (CIN), which might be improved by a more specific diagnostic biomarker. Cervical cancer and CIN, but not other cervical epithelia, express high levels of the cyclin-dependent kinase inhibitor p16, suggesting that staining for this marker could help to more precisely identify CIN in tissue sections and therefore reduce variation in interpretation of cervical lesions. To test this hypothesis, 194 cervical cone biopsy samples were selected from a routine histopathology laboratory. Two consecutive sections from each biopsy were stained with hematoxylin and eosin and with a p16 -specific monoclonal antibody, respectively. Five experienced cervical pathologists examined the slides. The agreement in the diagnosis between pairs or groups of observers was calculated by kappa statistics. Significant discrepancies were observed in the diagnostic interpretation of hematoxylin and eosin-stained slides, particularly for low-grade lesions (kappa value 0.60 [95% confidence interval 0.58-0.63]). There was significantly better agreement in the interpretation of p16 expression (kappa value 0.91 [95% confidence interval 0.84-0.99]). Expression of p16 was restricted to CIN 2/CIN 3, CIN 1 associated with high-risk human papillomavirus, or cervical cancer. p16 immunostaining allowed precise identification of even small CIN or cervical cancer lesions in biopsy sections and helped to reduce interobserver variation in the histopathologic interpretation of cervical biopsy specimens. Thus, p16 immunohistochemistry can reduce false-negative and false-positive biopsy interpretation and thereby significantly improve cervical (pre)-cancer diagnosis.
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          High-risk human papillomavirus E6/E7 mRNA detection by a novel in situ hybridization assay strongly correlates with p16 expression and patient outcomes in oropharyngeal squamous cell carcinoma.

          Human papillomavirus (HPV) is established as causative in oropharyngeal squamous cell carcinomas (OSCCs), being detected in 50% to 80% of tumors by DNA in situ hybridization (ISH) and/or polymerase chain reaction. However, these tests do not assess viral transcription. Many consider E6/E7 messenger ribonucleic acid (mRNA) the best indicator of HPV status, but it has not been detected in situ in OSCC. We constructed tissue microarrays (TMAs) from a cohort of OSCC for which p16 immunohistochemistry and HPV DNA ISH were previously performed on whole sections. We utilized a novel, chromogenic RNA ISH assay called RNAscope to detect E6/E7 mRNA of HPV-16 and other high-risk types on these TMAs. RNA ISH results were obtained for 196 of 211 TMA cases, of which 153 (78.1%) were positive. p16 immunohistochemistry and HPV DNA ISH were positive in 79.0% and 62.4% of cases, respectively. Concordance between RNA and p16, DNA and p16, and RNA and DNA were 96.4%, 78.7%, and 83.5%, respectively. Only 7 cases (3.6%) were discrepant between RNA ISH and p16. In univariate analysis, all 3 tests correlated with better overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) (all P<0.001). In multivariate analysis, OS correlated significantly with RNA (hazard ratio=0.39, P=0.001), DNA (0.53, P=0.03), and p16 (0.30, P<0.001), but DSS and DFS correlated significantly only with p16 (DSS: 0.36, P=0.006; DFS: 0.42, P=0.016). RNA ISH is more sensitive than DNA ISH in detecting HPV in OSCC, and it correlates strongly with p16. Although both tests were comparable, p16 more strongly stratified patient outcomes.
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            Author and article information

            Affiliations
            Department of Oral Pathology, VS Dental College and Hospital, Bengaluru, Karnataka, India
            [1 ]Dental Care and Research Centre, Bengaluru, Karnataka, India
            [2 ]Department of Oral Pathology, Sri Rajiv Gandhi College of Dental Science, Bengaluru, Karnataka, India
            Author notes
            Address for correspondence: Dr. T Smitha, Department of Oral Pathology, VS Dental College and Hospital, Bengaluru - 560 004, Karnataka, India. E-mail: dr.smitha.t@ 123456gmail.com
            Journal
            J Oral Maxillofac Pathol
            J Oral Maxillofac Pathol
            JOMFP
            Journal of Oral and Maxillofacial Pathology : JOMFP
            Medknow Publications & Media Pvt Ltd (India )
            0973-029X
            1998-393X
            Jan-Apr 2017
            : 21
            : 1
            : 76-81
            5406823
            JOMFP-21-76
            10.4103/jomfp.JOMFP_248_16
            Copyright: © 2017 Journal of Oral and Maxillofacial Pathology

            This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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