Cases Of High-grade Cervical Intraepithelial Neoplasia Research Articles

Association between PEG3 DNA methylation and high-grade cervical intraepithelial neoplasia

BackgroundEpigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, although empirical data are limited.MethodsWomen (n = 419) were enrolled at colposcopic evaluation at Duke Medical Center in Durham, North Carolina. Human papillomavirus (HPV) was genotyped by HPV linear array and CIN grade was ascertained by biopsy pathologic review. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of the IGF2/H19, IGF2AS, MESTIT1/MEST, MEG3, PLAGL1/HYMAI, KvDMR and PEG10, PEG3 imprinted domains, using Sequenom-EpiTYPER assays. Logistic regression models were used to evaluate the associations between HPV infection, DMR methylation and CIN risk overall and by race.ResultsOf the 419 participants, 20 had CIN3+, 52 had CIN2, and 347 had ≤ CIN1 (CIN1 and negative histology). The median participant age was 28.6 (IQR:11.6) and 40% were African American. Overall, we found no statistically significant association between altered methylation in selected DMRs and CIN2+ compared to ≤CIN1. Similarly, there was no significant association between DMR methylation and CIN3+ compared to ≤CIN2. Restricting the outcome to CIN2+ cases that were HR-HPV positive and p16 staining positive, we found a significant association with PEG3 DMR methylation (OR: 1.56 95% CI: 1.03–2.36).ConclusionsWhile the small number of high-grade CIN cases limit inferences, our findings suggest an association between altered DNA methylation at regulatory regions of PEG3 and high grade CIN in high-risk HPV positive cases.

Human papillomavirus, high-grade intraepithelial neoplasia and killer immunoglogulin-like receptors: a Western Australian cohort study

BackgroundHuman papillomavirus (HPV) is the causative agent in cervical cancer and HPV genotypes 16 and 18 cause the majority of these cancers. Natural killer (NK) cells destroy virally infected and tumour cells via killer immunoglobulin-like receptors (KIR) that recognize decreased MHC class I expression. These NK cells may contribute to clearance of HPV infected and/or dysplastic cells, however since KIR controls NK cell activity, KIR gene variation may determine outcome of infection.MethodsKIR gene frequencies were compared between 147 patients with a history of high-grade cervical intraepithelial neoplasia (CIN) and a control population of 187, to determine if any KIR genes are associated with high-grade CIN. In addition a comparison was also made between cases of high grade CIN derived from 30 patients infected with HPV 16/18 and 29 patients infected with non-16/18 HPV to determine if KIR variation contributes to the disproportional carcinogenesis derived from HPV 16/18 infection.ResultsHigh-grade CIN was weakly associated with the absence of KIR2DL2 and KIR2DS2 (p = 0.046 and 0.049 respectively, OR 0.6; 95% CI 0.4 – 0.9) but this association was lost after correction for multi-gene statistical analysis. No difference in KIR gene frequencies was found between high-grade CIN caused by HPV 16/18 and non-16/18.ConclusionNo strong association between KIR genes, high-grade CIN and HPV genotype was found in the Western Australian population.

P16, Ki-67, and BD ProEx™C immunostaining: a practical approach for diagnosis of cervical intraepithelial neoplasia

p16, Ki-67, and BD ProExC (TriPath Imaging, Inc., Burlington, NC) have each been shown to be helpful adjuncts in the diagnosis and grading of human papillomavirus-associated cervical intraepithelial neoplasia. However, no clear guidelines are available regarding their use in routine practice. This study was designed to evaluate the efficacy of the 3 stains alone and in combinations to determine the most useful strategy in the diagnosis of cervical intraepithelial neoplasia and provide guidance in instances with discordant staining patterns. Serial sections of 136 formalin-fixed paraffin-embedded cervical samples with consensus diagnoses of 39 benign-reactive, 46 low-grade cervical intraepithelial neoplasia (CIN I/human papillomavirus), and 51 high-grade cervical intraepithelial neoplasia (CINII/III) were immunostained using p16, Ki-67, and BD ProExC antibodies. Results of high-risk human papillomavirus testing were available in 70 cases. Immunostaining patterns were designated as negative, intermediate, and strongly positive based on the patterns observed most commonly in benign-reactive, low-grade cervical intraepithelial neoplasia, and high-grade cervical intraepithelial neoplasia lesions, respectively. A concordant staining pattern with all 3 stains correctly identified benign-reactive, low-grade cervical intraepithelial neoplasia, and high-grade cervical intraepithelial neoplasia cases. p16 was the most sensitive and specific individual stain (sensitivity, 33%; specificity, 93%; positive predictive value [PPV], 81%; negative predictive value [NPV], 58%). Performing all 3 immunostains and using concordant results of any 2 improved diagnostic accuracy (sensitivity, 35%; specificity, 98%; PPV, 93%; NPV, 67%). However, a significant proportion of low-grade cervical intraepithelial neoplasia cases showed aberrant staining patterns with 52% staining negative and 9% staining strongly positive. Low-grade cervical intraepithelial neoplasia cases with the negative staining pattern were more likely to be negative for high-risk human papillomavirus, whereas those showing the strongly positive staining pattern were high-risk human papillomavirus positive. Performing p16 and BD ProExC initially followed by Ki-67 only when p16 and BD ProExC yielded discordant results provided similar diagnostic accuracy at reduced cost because only one third of the cases required the additional stain.

Cost-effectiveness of Human Papillomavirus Testing After Treatment for Cervical Intraepithelial Neoplasia

Women today who are treated for high-grade cervical intraepithelial neoplasia (CIN) customarily have repeat cytologic testing to detect persistent or recurrent disease. Reported recurrence rates range from 5% to 15%. It is assumed that effective treatment eradicates both CIN and preexisting infection by high-risk human papillomavirus (HPV). The investigators developed a computer-based mathematical Markov model with which 6 follow-up regimens were compared with standard cytologic follow-up at 6, 12, and 24 months. The model parameters were based on 3 Dutch follow-up studies and a Dutch population-based screening cohort. Outcome measures included the number of cases of high-grade CIN (CIN2/3) missed after 5 years of follow-up, the number of diagnostic procedures, and cost. Strategies including adjunctive HPV testing missed fewer cases of posttreatment CIN2/3 than did the current approach of cytologic testing at 6, 12, and 24 months. The effect was most evident with combined cytology and HPV testing at 6 and 24 months. Use of this strategy would spare one case of missed CIN2/3 for every 192 women treated. Combined testing reduced missed cases of CIN2/3 by 32% to 77%. This strategy also was less inconvenient; the number of repeat smears declined by 28% to 65%. With HPV testing alone at 6 months and combined HPV and cytologic testing 24 months after treatment, posttreatment CIN was detected at high rates, while rates of colposcopy did not increase. In addition, this strategy was less expensive that current cytologic follow-up. The cost reduction was greatest when combined testing was done only at 12 months. These observations endorse the use of testing for high-risk HPV in women who have been treated for CIN2 or CIN 3. Apart from its clinical value, combined testing is warranted by cost savings arising from the need for only 2 rather than 3 repeat smears (provided that only HPV testing is done at initial follow-up).

Cost-Effectiveness of Human Papillomavirus Testing After Treatment for Cervical Intraepithelial Neoplasia

Women today who are treated for high-grade cervical intraepithelial neoplasia (CIN) customarily have repeat cytologic testing to detect persistent or recurrent disease. Reported recurrence rates range from 5% to 15%. It is assumed that effective treatment eradicates both CIN and preexisting infection by high-risk human papillomavirus (HPV). The investigators developed a computer-based mathematical Markov model with which 6 follow-up regimens were compared with standard cytologic follow-up at 6, 12, and 24 months. The model parameters were based on 3 Dutch follow-up studies and a Dutch population-based screening cohort. Outcome measures included the number of cases of high-grade CIN (CIN2/3) missed after 5 years of follow-up, the number of diagnostic procedures, and cost. Strategies including adjunctive HPV testing missed fewer cases of posttreatment CIN2/3 than did the current approach of cytologic testing at 6, 12, and 24 months. The effect was most evident with combined cytology and HPV testing at 6 and 24 months. Use of this strategy would spare one case of missed CIN2/3 for every 192 women treated. Combined testing reduced missed cases of CIN2/3 by 32% to 77%. This strategy also was less inconvenient; the number of repeat smears declined by 28% to 65%. With HPV testing alone at 6 months and combined HPV and cytologic testing 24 months after treatment, posttreatment CIN was detected at high rates, while rates of colposcopy did not increase. In addition, this strategy was less expensive that current cytologic follow-up. The cost reduction was greatest when combined testing was done only at 12 months. These observations endorse the use of testing for high-risk HPV in women who have been treated for CIN2 or CIN 3. Apart from its clinical value, combined testing is warranted by cost savings arising from the need for only 2 rather than 3 repeat smears (provided that only HPV testing is done at initial follow-up).

Nm23-H1 protein immunoreactivity in intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix.

Differences in the immunohistochemical expression of the 17 kDa protein encoded by the human nm23-H1 gene were studied in premalignant lesions and invasive squamous cell carcinoma (SCC) (N = 8) of the cervix using routine streptavidin-biotin immunohistochemistry and a polyclonal antibody to the nm23-H1 protein. The premalignant lesions were koilocytic atypia due to wart virus infection (N = 5), low-grade cervical intraepithelial neoplasia (CIN) (N = 7) and high-grade CIN (N = 7). The carcinomas were either moderately (N = 3) or poorly differentiated (N = 5). The non-neoplastic controls were normal squamous epithelium from cases with uterine prolapse (N = 7) and normal squamous epithelium not affected by the infective or neoplastic areas of some of the cases with wart virus infection (N = 2) and carcinoma (N = 2). Moderate to strong cytoplasmic and, occasionally, nuclear immunostaining for the nm23-H1 protein was seen in all cells above the basal layer of the normal squamous epithelium. However, most of the cervical SCC show a relative reduction in nm23-H1 immunoreactivity (7/8 cases; 88%). This difference in nm23-H1 expression was statistically significant (P = 0.0006; Chi-squared test with continuity correction). All of the cases with wart virus infection (N = 5; 100%) displayed moderately strong nm23-H1 immunostaining throughout the squamous epithelium except for the basal layer where no staining was observed. The cases that had low-grade squamous dysplasia of the cervix (CIN I-II) (N = 7; 100%) also displayed moderate to strong nm23-H1 immunoreactivity in the epithelium except for the basal layer (CIN I) or the lower two-thirds of the epithelium (CIN II). nm23-H1 Immunoreactivity was either absent or was significantly reduced in all of the high-grade CIN (CIN III) cases (N = 7; 100%) in which only the non-dysplastic superficial third of the squamous epithelium displayed nm23-H1 immunolabeling. The difference in nm23-H1 expression between low-grade and high-grade CIN cases was statistically significant (P = 0.0013; Chi-squared test with continuity correction). Similarly, the difference between low-grade CIN and SCC cases in the expression of nm23-H1 was also significant (P = 0.0041; Chi-squared test with continuity correction). However, no statistically significant difference in nm23-H1 immunoreactivity was found between cases of high-grade CIN and SCC. In conclusion, nm23-H1 protein immunoreactivity is reduced in high-grade CIN and cervical SCC but not in low-grade CIN. These findings suggest that reduced expression of the protein may be important early in the sequential development of cervical squamous neoplasia.