p16<sup>INK4a</sup>immunostaining as an alternative to histology review for reliable grading of cervical intraepithelial lesions

Dijkstra, Maaike G.; Heideman, Daniëlle A.M.; Roy, Sabine C de; Rozendaal, Lawrence; Berkhof, Johannes; Krimpen, Kees van; Groningen, K. van; Snijders, Peter J.F.; Meijer, Chris J.L.M.; Kemenade, Folkert J. van

doi:10.1136/jcp.2010.078634

Cited by 69 publications

(63 citation statements)

References 31 publications

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“…Nevertheless, due to the variation in immunohistochemistry assays and microscopic interpretation criteria, many studies have demonstrated a relationship between p16 overexpression and CIN3 (Tsoumpou et al, 2009). In the present study, p16 overexpression was significantly associated with the diffuse group rather than the focal group (P < 0.001), demonstrating a high sensitivity and specificity to diagnosis cervical premalignant lesions (Dijkstra et al, 2010). The HPV genotype (16 and 52 versus others) did not show a statistically significant correlation with p16 expression (P = 0.320), and independent of genotype, p16 expression was highlighted in the diffuse group.…”

Section: Discussionsupporting

confidence: 53%

“…After that, the blades were set up with Entellan resin (Sigma-Aldrich ® , St. Louis, MO, USA). Distribution of p16 staining was scored as described by Dijkstra et al (2010), and representative focal, basal, diffuse, and diffuse full thickness staining are shown in Figure 1. We adapted and regrouped this rating for better evaluation where the negative, focal, and basal staining were considered focal and diffuse and diffuse full thickness staining were considered diffuse.…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

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HPV genotyping and p16 expression in Xingu Indigenous Park, Brazil

et al. 2016

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ABSTRACT. The association between high-risk human papillomavirus (HPV) genotypes and p16 expression in indigenous women from the Xingu Indigenous Park, Brazil, was unknown. This study evaluated p16 expression in women with a histological diagnosis of cervical intraepithelial neoplasia (CIN) 3 or higher and correlated this expression with HPV genotypes to determine possible discrepancies in the expression of this marker. We evaluated 37 previously collected samples with different HPV genotypes and high-grade lesions diagnosed based on cytology, histology, and colposcopy. Immunohistochemical analysis was performed using paraffin-embedded tissue sections and the CINtec ® Histology Kit. p16 protein expression was investigated by immunostaining with an anti-p16 antibody. HPV genotyping was performed by reverse hybridization. The age of the study population ranged from 22-75 years (43.81 ± 15.89 years) and parity ranged from 1-11 (5.92 ± 2.58). Thirteen different HPV genotypes were found using the INNO-LiPA kit. Single and multiple infections by HPV were found with prevalence of single infections (P = 0.029). Comparison between HPV genotype and simple or multiple infections was highly significant; it was observed more HPV 52 followed by HPV 16 in single infections (P < 0.001). p16 expression was predominantly diffuse, which was observed in 91.7% of lesions, whereas 8.3% were focal (P < 0.001). HPV 52, HPV 16 and 31 were the most prevalent HPV types in high-grade CIN in these indigenous women. Diffuse p16 expression in high-grade CIN was not influenced by the viral genotype; however, more studies are necessary to further our understanding of this restricted group.

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Section: Discussionsupporting

confidence: 53%

Section: Immunohistochemical Analysismentioning

confidence: 99%

HPV genotyping and p16 expression in Xingu Indigenous Park, Brazil

et al. 2016

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“…A large number of biomarkers have been identified that are overexpressed in cervical cancer cells with potential for cervical cancer screening, such as p16 INK4A , Ki-67, Cyclin E, p53, and survivin, among others [5][6][7]. P16 INK 4A is a tumor suppressor protein which is induced in cells upon expression of high-risk HPV E7 protein [8] and several reports indicate that overexpression of p16 is associated with the process of carcinogenesis in the cervical epithelium [9].…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Expression of Long Noncoding Mitochondrial RNAs (lncmtRNAs) During Cervical Cancer Progression and Cervical Carcinoma

Dadlani¹,

López²,

Fern³

et al. 2016

J Cancer Sci Ther

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Objective: Cervical cancer is the second most common cancer in women with high rates of mortality worldwide. Cervical cancer is slowly progressive and is preceded by pre-invasive intraepithelial lesions. Therefore, detection of premalignant lesions is key to preventing disease progression to advanced stages. The objective of the present study was examination and quantification of the differentially expressed non-coding mitochondrial RNAs during progression of disease. Material and methods:The differential expression of S-ncmtRNA and AS-ncmtRNA was analyzed by in situ hybridization (ISH) using tissue macroarrays (TMA) from normal, CIN1, CIN2, CIN3 and invasive squamous carcinoma (SCC). PCNA and p16INK-4a were detected in consecutive biopsies by immunohistochemistry. Quantification of ISH signal was carried out with Image ProPlus 6.1 software and the results were expressed as percentage of Integrated Optical Density (IOD). Results:We found a marked down-regulation of AS-ncmtRNA in 95% of tissues analyzed (CIN 1/2, CIN 3, and invasive squamous cancer). Moreover, differential expression of ASncmtRNA v/s S-ncmtRNA showed significant difference. Normal proliferating tissues did not display down-regulation of AS-ncmtRNA. Down regulation of ASncmtRNA correlated with the expression of the tumor suppressor protein p16INK-4a Conclusions:We found down-regulation of AS-ncmtRNA in pre-malignant and tumor samples which could distinguish normal tissues from early lesions and tumor samples. These results suggest that the down-regulation of AS-ncmtRNA is a novel marker of early lesions and cervix neoplasia. Previously, we reported that human cells express a unique family of mitochondrial long ncmtRNAs (ncmtRNAs) [12,13]. One of these transcripts, named sense ncmtRNA (SncmtRNA) is expressed in normal proliferating cells and tumor cells but not in resting cells, suggesting a functional role in cell cycle progression [12]. Normal proliferating cells express, in addition to the S-ncmtRNA, two antisense mitochondrial ncmtRNAs (AS-ncmtRNA-1 and AS-ncmtRNA-2) where both AS-ncmtRNAs are down-regulated in human cancer cells regardless of tissue of origin. In order to analyze the expression pattern of these ncmtRNAs in cervical cancer, we performed a qualitative pilot study in cervical biopsies encompassing the progression of the disease. We found that AS-ncmtRNAs are down-regulated in mild, moderate and severe neoplasia and in invasive cervical carcinoma [14]. In the present study a quantitative analysis of the differential expression of the S-ncmtRNA and the ASncmtRNAs was performed in biopsies of CIN1 to CIN3 and invasive cervical carcinoma, correlating it with the expression of the tumor suppressor p16 Assessment of the Expression of LongINK 4A and proliferating cell nuclear antigen (PCNA). Methods Tissue specimensAll the tissues were purchased from Pantomics Inc. (Richmond, CA, USA), corresponding to Tissue Macroarrays (TMA) containing normal cervix, CIN1, CIN2, CIN3 and invasive squamous carcinoma (SCC). For normal specimens,...

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“…Its use in conjunction with hematoxylin and eosin (H&E)-stained sections has substantially improved the interobserver agreement and diagnostic accuracy in the histopathologic evaluation of cervical biopsies. [8][9][10] Furthermore, there is evidence that detection of p16…”

mentioning

confidence: 99%

“…9,10 We hypothesized that it is likely that markers associated with proliferation can differentiate p16…”

mentioning

confidence: 99%

Evaluation of cervical cone biopsies for coexpression of p16^INK4a and Ki‐67 in epithelial cells

Reuschenbach

Seiz

Doeberitz

et al. 2011

Intl Journal of Cancer

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Diffuse overexpression of p16INK4a in basal and parabasal cells of cervical epithelium is a hallmark of human papillomavirus‐mediated transformation. Focal p16INK4a expression is occasionally observed in nondysplastic epithelium. In normal cells, expression of p16INK4a triggers cell cycle arrest. However, cells undergoing transformation in intraepithelial lesions actively proliferate. To prove that the different expression patterns of p16INK4a, i.e., focal versus diffuse, reflect biologically different entities, we hypothesized that p16INK4a‐positive cells in epithelia displaying focal p16INK4a expression pattern do not coexpress proliferation‐associated Ki‐67 protein, while p16INK4a‐positive cells in lesions with diffuse p16INK4a expression may do. A total of 138 cervical cone biopsies were stained for the expression of p16INK4a and Ki‐67 using a primary antibody cocktail. All metaplastic lesions (n = 21) displayed focal staining for p16INK4a, and in all of these lesions p16INK4a‐positive cells were found to be negative for Ki‐67 expression. Diffuse expression of p16INK4a was observed in 12/21 (57.1%) cervical intraepithelial neoplasia (CIN) 1 lesions, all of them simultaneously showed Ki‐67 immunoreactivity in a large proportion of p16INK4a‐positive cells. Seventeen of 23 (73.9%) CIN2 lesions and all 27 (100%) CIN3/carcinoma in situ (CIS) as well as all 46 (100%) carcinoma cases displayed diffuse and combined expression of p16INK4a and Ki‐67. Coexpression of Ki‐67 and p16INK4a in the same cell is entirely restricted to cervical lesions displaying diffuse p16INK4a expression, whereas in lesions with focal p16INK4a expression, p16INK4a‐expressing cells are negative for Ki‐67. Thus, diffuse expression of p16INK4a reflects lesions with proliferation‐competent cells, while p16INK4a‐expressing cells associated with focal expression patterns are cell cycle arrested.

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p16^INK4aimmunostaining as an alternative to histology review for reliable grading of cervical intraepithelial lesions

Cited by 69 publications

References 31 publications

HPV genotyping and p16 expression in Xingu Indigenous Park, Brazil

HPV genotyping and p16 expression in Xingu Indigenous Park, Brazil

Assessment of the Expression of Long Noncoding Mitochondrial RNAs (lncmtRNAs) During Cervical Cancer Progression and Cervical Carcinoma

Evaluation of cervical cone biopsies for coexpression of p16^INK4a and Ki‐67 in epithelial cells

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p16INK4aimmunostaining as an alternative to histology review for reliable grading of cervical intraepithelial lesions

Cited by 69 publications

References 31 publications

HPV genotyping and p16 expression in Xingu Indigenous Park, Brazil

HPV genotyping and p16 expression in Xingu Indigenous Park, Brazil

Assessment of the Expression of Long Noncoding Mitochondrial RNAs (lncmtRNAs) During Cervical Cancer Progression and Cervical Carcinoma

Evaluation of cervical cone biopsies for coexpression of p16INK4a and Ki‐67 in epithelial cells

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p16^INK4aimmunostaining as an alternative to histology review for reliable grading of cervical intraepithelial lesions

Evaluation of cervical cone biopsies for coexpression of p16^INK4a and Ki‐67 in epithelial cells