Cases Of CIN Research Articles

The role of EP-2 receptor expression in cervical intraepithelial neoplasia

Prostaglandin induced signalling is involved in different cancers. As previously described, the EP3 receptor expression decreases with increasing stage of cervical intraepithelial lesions (CIN). In addition, in cervical cancer EP3 is an independent prognosticator for overall survival and correlates with FIGO stages. Currently the role of Prostaglandin 2 receptor 2 (EP2) in CIN is unknown. The aim of this study was to analyse the expression of EP2 for potential prognostic value for patients with cervical dysplasia. EP2 expression was analysed by immunohistochemistry in 33 patient samples (CIN1–3) using the immune-reactivity scoring system (IRS). Expression levels were correlated with clinical outcome to analyse prognostic relevance in patients with CIN2. Data analysis was performed using non parametric Kruskal–Wallis and Spearman rank sum test. Cytoplasmic expression levels of EP2 correlated significantly (p < 0.001) with different grades of cervical dysplasia. Median EP2-IRS in CIN1 was 2 (n = 8), 3 in CIN2 (n = 9) and 6 in CIN3 (n = 16). Comparing regressive (n = 3, median IRS = 2) to progressive (n = 6, median IRS = 4) CIN2 cases the median IRS differed significantly (p = 0.017). Staining intensity (p = 0.009) and IRS (p = 0.005) of EP2 and EP3 correlate inversely. EP2 expression level significantly increases with higher grade of CIN and could qualify as a potential prognostic marker for the regressive or progressive course in CIN2 lesions. These findings emphasize the significant role of PGE2 signalling in CIN and could help to identify targets for future therapies.

The value of p16(INK4a) cytology for early diagnosis of cervical cancer

Objective: To investigate the use of p16(INK4a) immuno-stained cytology as the primary screening for cervical cancer prevention. Methods: From March to August 2018, 902 women from Shenzhen and surrounding area were recruited for cervical cancer screening with ThinPrep Cytologic Test (TCT), cobas4800 HPV test, and p16(INK4a) co-test. Colpo/biopsies were performed using the point of interest biopsy protocol of directed and random cervical biopsies plus endocervical curettage for all women, any of whose tests was positive. Two senior cytopathologists interpreted TCT and p16(INK4a) test. The performance of p16(INK4a) for early detection of CIN2+ and inter-observer reproducibility of the interpretation of p16(INK4a) were evaluated. Results: The positive rates of HPV test, p16(INK4a) co-test and TCT diagnosed as LSIL/AGC or higher grade were 8.1% (73/902), 6.8% (61/902) and 4.7% (42/902), respectively. Colposcopy referring rate was 79.6% (109/137), among which 10 cases were diagnosed as CIN2+ (5 cases of CIN2 and 5 cases of CIN3). The sensitivity and specificity for CIN2+ of p16(INK4a) test, TCT (LSIL/AGC or higher grade) and HPV test were 90.0%, 80.0%, 100.0% and 90.9%, 91.9%, 82.5%, respectively. Compared to TCT and HPV test, there was no significant difference in sensitivity and specificity between p16(INK4a) and TCT/HPV test (P>0.05). The Kappa value of the 2 cytopathologists in interpreting p16(INK4a) and TCT was 0.944 and 0.425, respectively (P<0.05). Conclusions: p16(INK4a) for cervical cancer screening is equally sensitive to HPV test and specific to TCT while subjective difference of cytopathologists' interpretation of p16(INK4a) is small. Therefore, p16(INK4a) can be used as a new cervical cancer screen method for its better diagnostic performance.

Reflex cytology for triage of high-risk human papillomavirus positive self-sampled material in cervical cancer screening: a prospective cohort study.

ObjectiveHigh‐risk human papillomavirus (HrHPV)‐positive women detected by self‐sampling require an extra visit at the general practitioner for additional cytology testing, but the loss to follow up within this triage is substantial. The aim of this study was to evaluate the clinical utility of reflex cytology on hrHPV‐positive self‐samples for immediate stratification of women who need referral for colposcopy.DesignA prospective cohort study.SettingTwo Dutch cervical cancer‐screening laboratories.Population1014 screenees who tested hrHPV‐positive on self‐samples between 1 December 2018 and 1 August 2019.MethodsSelf‐samples were directly used for cytological analysis. Cytological and histological outcomes during follow up were obtained from the Dutch Pathology Registry (PALGA).Main outcome measuresTest performance of reflex cytology on self‐samples was determined for different thresholds and compared with physician‐taken cytology and histological outcomes.ResultsReflex cytology on self‐samples for detecting abnormal cytology showed a sensitivity of 26.4% (95% CI 21.8–31.3) and specificity of 90.5% (95% CI 87.7–92.8). Of all ≥CIN2 cases, 29.4% (95% CI 22.5–37.1) were detected with reflex cytology on self‐samples. The positive predictive value for detection of ≥CIN2 was higher with cytology on self‐collected samples than on physician‐collected samples. Of women who were lost to follow up, 12.9% were found to have abnormal cytology on their self‐sampled material.ConclusionCytology testing is achievable on hrHPV‐positive self‐samples, could decrease the loss to follow up in screening and is easily implementable in the current clinical practice. Of all hrHPV‐positive women with abnormal cytology on additional physician‐collected samples, 26.4% could have been directly referred for colposcopy if triage with reflex cytology on self‐sampled material had been performed.Tweetable abstractReflex cytology for triage of hrHPV+ self‐samples is of added value for direct referral of women for colposcopy.

Value of endocervical curettage in follow-up for patients with cervical intraepithelial neoplasia stage 2+ after loop electrosurgical excision

ObjectiveTo assess the value of endocervical curettage (ECC) during follow-up for patients with cervical intraepithelial neoplasia (CIN2+) after loop electrosurgical excision procedures (LEEP) and to explore risk factors for positive ECC during this evaluation. MethodsThere were 383 CIN2+ patients in the one-step method group who underwent LEEP and were prospectively followed up using ECC as a routine strategy, with colposcopy and liquid-based cytology (LCT) + human papilloma virus (HPV) co-testing performed. The finding were then compared with those from 1041 patients in the retrospective database who underwent colposcopy unless LCT and/or HPV screening was abnormal, and ECC was performed depending on colposcopy images (two-step method group). The two groups were matched using propensity score matching analysis for further statistical comparisons. ResultsIn total, 383 pairs of patients from both groups were matched. The persistent/recurrent CIN2+ cases were 20 and 21, respectively (P > .05). However, 47 persistent/recurrent CIN1 cases were detected in the one-step method group; this number was significantly higher than that detected in the two-step method group (P < .05). High-risk factors for positive ECC during follow-up included positive ECC before treatment (odds ratio [OR]: 1.670), involved margins (OR: 1.239), and HPV infection and abnormal LCT during follow-up (ORs: 3.130 and 2.637). ConclusionsECC can detect early recurrent lesions after LEEP in patients with CIN2+ and can offset the limitation of colposcopy and co-testing resulting from LEEP. For patients with positive ECC before LEEP, involved margins, HPV infection, and abnormal LCT after treatment, ECC should be included in the follow-up strategy.

Better triage tests needed for HPV-positive women.

Tidy et al showed that 1/3 of all referrals for colposcopy, in settings where primary high-risk HPV (HR-HPV) test is used for screening, are due to persistently positive tests with a negative triage cytology (BJOG 2020 xxxx). These represent a significant burden for colposcopists but yielding a relatively low number of cases of CIN2+ (7%), thus translating to a low positive predictive value (PPV) for this approach.

Assessing the epidemiological impact on cervical cancer of switching from 4-valent to 9-valent HPV vaccine within a gender-neutral vaccination programme in Switzerland

BackgroundAn infection with high-risk human papillomavirus (HPV) is the obligatory aetiological factor for the development of cervical cancer. In Switzerland, the prevention strategy for cervical cancer is based on primary prevention via HPV vaccination and secondary prevention with an opportunistic screening programme for precancerous lesions. Vaccination is recommended to 11–26 years old male and female persons. The objective of the study was to assess the epidemiological impact on cervical cancer of switching from the currently implemented programme with the 4-valent vaccine to the 9-valent vaccine, in an 11–26 years old gender-neutral vaccination programme in Switzerland.MethodsA previously validated dynamic transmission model of HPV infections was adapted and calibrated to the Swiss setting assuming an 80% coverage rate in HPV-vaccination and lifelong vaccine type-specific protection. A gender-neutral vaccination programme (males and females) for 11–26 years old with a 9-valent HPV vaccine was compared with the current 11–26 years old gender-neutral 4-valent vaccination programme. Sensitivity analyses were conducted in order to test the impact of lower vaccination coverage rates and a shorter duration of protection on the model outcomes.ResultsIn Switzerland, a 9-valent gender-neutral vaccination programme would result in an additional prevention of 2979 cervical cancer cases, 13,862 CIN3 and 15,000 CIN2 cases, compared with the 4-valent gender-neutral vaccination programme over 100 years. These additional disease cases avoided would correspond to a 24, 36 and 48% cumulative incidence decrease in cervical cancer, CIN3 and CIN2 cases, respectively. It would also prevent additional 741 cervical cancer-related deaths over 100 years. A substantial additional reduction in cervical cancer and precancerous lesions burden is still observed when varying the vaccination coverage rate from 30 to 60% or reducing the duration of protection from lifelong to 20 years.ConclusionsThe switch to the 9-valent vaccine in Switzerland to prevent cervical diseases showed an important contribution in terms of public health impact compared with the 4-valent vaccine in an 11–26 years old gender-neutral population, even with very conservative assumptions such as low coverage rates or low duration of protection and limiting analysis to only cervical disease.

The impact of age and high-risk human papillomavirus (hrHPV) status on the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women with persistent hrHPV-positive, cytology-negative screening samples: a prospective cohort study.

To establish the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women referred to colposcopy with persistent high-risk human papillomavirus (hrHPV) cytology-negative screening sample according to hrHPV genotype, age at referral and colposcopic performance. Prospective cohort study. Single colposcopy clinic linked to a population-based screening programme. Women referred with persistent hrHPV cytology-negative routine screening samples. Prospective study with descriptive statistics from a single colposcopy unit between June 2014 and July 2019. Prevalence of hrHPV genotypes and CIN2+, positive predictive value for colposcopic impression, and inadequate colposcopic examinations. A total of 3107 women were referred. Prevalence of CIN2+ was highest for persistent HPV16 infections (10.7%) compared with HPV18 (3.6%) or HPVO (4.7%). Prevalence of CIN2+ declined with age (25-34years 14.2% to 55-64years 1.1%) whereas the percentage of women with an inadequate colposcopic examination increased (25-34years 0.9% to 55-64years 29.5%). High-grade colposcopic impression fell over time during the study from 16.1 to 5.1%. The positive predictive value for colposcopic impression of CIN2+ was affected by hrHPV genotype (57.3% for HPV16 versus 32.1% for nonHPV16). The adjunctive use of electrical impedance spectroscopy detected an extra 42 cases of CIN2+, which was irrespective of hrHPV genotype. Primary hrHPV cervical screening increases detection of CIN2+; however, low specificity results in more women being referred to colposcopy with a low prevalence of CIN2+. Colposcopy performs poorly in some groups, particularly with HPVO infections and women over 50years of age. An appropriate threshold for referral to colposcopy in primary hrHPV screening has not been established. Low prevalence of CIN2+ in HPV-positive negative cytology samples. HPV genotype, age and prevalence of CIN2+ affect colposcopic performance.

A broad-based approach to differentiate CIN from its mimics: The utility of in situ hybridization and immunohistochemistry

The hematoxylin and eosin slides of 100 consecutive cases diagnosed as CIN 1–2 were combined with 25 CIN 1 and 25 negative for CIN as documented by in situ HPV testing. The 150 cases were then reviewed blinded and scored as “CIN” or “negative for CIN”. Each of the 50 controls was correctly scored. Of the 100 cases, 62 were diagnosed as CIN and the other 38 were scored as negative for CIN on re-review. Each of the CIN cases was positive for HPV as proven by the in situ detection of either HPV DNA or the L1 capsid protein. The 38 cases diagnosed as negative for CIN and 38 of the CIN cases were tested for HPV DNA by in situ hybridization and for a panel of biomarkers that included p16, Ki67, importin-β, exportin-5, and Mcl1 plus the L1 HPV capsid protein. Each of the 38 CIN cases was positive for HPV as well as each biomarker that localized towards the basal aspect of the lesion. Two of the 38 negative for CIN cases were positive for HPV DNA/L1 capsid protein and each of the biomarkers. The other 36 cases were negative for HPV DNA/L1 protein and each of the biomarkers showed baseline expression. Thus, 36% of the diagnoses of CIN 1–2 were incorrect and this could have been prevented with either in situ detection of the viral DNA/capsid protein or the immunohistochemistry detection of a panel of biomarkers that included p16, Ki67, importin-β, exportin-5, and Mcl1.

Clinical Performance of Human Papillomavirus (HPV) Testing versus Cytology for Cervical Cancer Screening: Results of a Large Danish Implementation Study.

BackgroundHuman papillomavirus (HPV) testing is increasingly used as the primary cervical cancer screening test. In a large pilot implementation, we compared participation, referrals and detection of high-grade cervical intraepithelial neoplasia (CIN) in HPV- versus cytology-based cervical cancer screening.MethodsThe implementation was embedded into the routine screening program at Lillebaelt Hospital, Department of Pathology, Vejle, Denmark. Based on the area of residence, women aged 30–59 years were screened by either HPV testing (with HPV16/18 genotyping and cytology triage) or cytology (with HPV triage for minor abnormalities). Our analysis includes women invited or screened during May 2017–May 2018 (invited: n=35,081; screened: n=28,352) with 6 months of follow-up. Information on screening results and sociodemographic characteristics were obtained from registers. Using logistic regression, we estimated odds ratios (ORs) with 95% confidence intervals (CIs) of participation, referral and CIN3+-detection in HPV- versus cytology-based screening, adjusting for sociodemographic characteristics.ResultsParticipation was virtually identical in the HPV- and cytology group (58.4% vs 58.8%; ORadjusted=0.97, 95% CI, 0.93–1.01). Referral to colposcopy was more common in the HPV- than cytology group (3.8% vs 2.1%; ORadjusted=1.88, 95% CI, 1.63–2.17). More cases of CIN3+ were detected in the HPV- than cytology group (1.0% vs 0.7%, ORadjusted=1.47; 95% CI, 1.13–1.91).ConclusionParticipation did not differ between HPV- and cytology-based screening. HPV-based screening detected more cases of CIN3+, but in this initial screening round also led to more colposcopies than cytology-based screening.

The risk of cervical cancer after cervical intraepithelial neoplasia grade 3: A population-based cohort study with 80,442 women

ObjectiveTo estimate the risk of cervical cancer in women with a history of cervical intraepithelial neoplasia (CIN) grade 3 and to review the compliance with post-treatment follow-up. MethodsA population-based retrospective cohort study including 80,442 women with a median follow-up of 15.8 years, and 1,278,297 person years. Women with CIN3 between 1990 and 2010 were identified from the Dutch Pathology Registry (PALGA) and linked to the general female population from the Netherlands Cancer Registry. Cases of recurrent CIN3 and cervical cancer, defined as occurrence minimally two years post-treatment, were identified until 2016. Standardized incidence ratios (SIRs) were calculated for the risk of cervical cancer. Results1554 women (1.9%) developed recurrent CIN3 and 397 women (0.5%) cervical cancer. Women with CIN3 were associated with a twofold increased risk of cervical cancer (SIR 2.29; 95%CI 2.07–2.52) compared with the general female population. Women aged ≥50 years during CIN3 diagnosis had a sevenfold and women with recurrent CIN3 a ninefold increased risk of developing cervical cancer. The increased risk up to 20 years of follow-up seems to be mostly attributable to ageing. 37.0% of women who developed cervical cancer after CIN3 did not complete the advised post-treatment follow-up. ConclusionsWomen with CIN3 have a long-lasting twofold increased risk of developing cervical cancer, even when they complete the post-treatment follow-up and adhere to the regular screening program. This risk increases with CIN3 diagnosis at older age, further ageing during follow-up and in women with recurrent CIN3. Studies on optimizing follow-up strategies are warranted.

Expression of Fhit, hWAPL and Survivin in Cervical Squamous Cell Carcinoma and Significance Thereof

Objective To preliminarily discuss the role of fragile histidine triad (FHIT) gene, human wings apart-like (hWAPL) gene, survivin gene in lymphatic metastasis of cervical squamous cell carcinoma. Method Expression of FHIT, hWAPL and survivin in 30 cases of normal squamous epithelium, 30 cases of CIN III and 60 cases of cervical squamous cell carcinoma was detected using the immunohistochemical technique. A statistical analysis was conducted for the relationship between the expression levels of FHIT, hWAPL and survivin and clinical pathologic parameters through expression count LVD of FHIT. Results FHIT value is 1.93±0.57 in the group of normal squamous epithelium, 2.87±0.63 in the group of CIN III and 4.12±0.72 in the group of cervical squamous cell carcinoma. The difference has statistical significance (P<0.05). The positive expression of hWAPL in normal cervical tissues is 0.00% (0/30), the positive expression rate is 36.67% (11/30) in the group of CIN III, and the positive expression rate is 63.33% (38/60) in the group of cervical squamous cell carcinoma. The difference has statistical significance (P<0.01). The positive expression rate of survivin in normal cervical tissues is 0.00% (0/30), the positive expression rate is 30.00% (9/30) in the group of CIN III, the expression rate is 61.67% (37/60) in the group of cervical squamous cell carcinoma. The difference has statistical significance (P<0.01). Conclusion FHIT, hWAPL and survivin promote lymphangiogenesis during occurrence and progression of cervical squamous cell carcinoma and lymphangiogenesis plays a vital role in lymphatic metastasis of cervical squamous cell carcinoma.

Relationship Between CHA2DS2-VASC Score With CIN For AMI Patients After PCI

The CHA2DS2-VASC score has been reported recently to predict adverse clinical outcomes so is CIN in patients with AMI regardless of having AF. We investigated relationship between CHA2DS2-VASC score with CIN in patients who underwent PCI strategies. This is a study of 40 patients with and underwent PCI. The CHA2DS2-VASC score was calculated for each patient. From this study 16 cases(18.82%) of CIN were diagnosed. CIN was defined as rise in serum creatinine&gt;0,5mg/dL or&gt;25% increase in baseline within 24h after PCI. In the ROC curve analysis,the cut-off value of CHA2DS2-VASC score in the prediction of CIN was&gt;4(sensitivity:56.25%,Specificity:87.5%)(AUC0.698,95%:CI1.460-6.163,p=0.003) and has a significant association with CIN(R20.485). We also identified Hb level&lt;12mg/dL as an independent predictor of CIN with (RR3.44,95%:CI1.816-6.532,p&lt;0.001). The CHA2DS2-VASC score was positively associated with CIN. Therefore,it can be used as a simple and reliable tools to predict CIN in AMI patients who underwent PCI.

Combining HPV DNA load with p16/Ki-67 staining to detect cervical precancerous lesions and predict the progression of CIN1\u20132 lesions

BackgroundHuman Papilloma Virus (HPV) DNA tests are highly sensitive and can triage women with mild lesions, improving the prognosis and diagnosis of cervical lesions. However, additional efficient strategies should be developed to improve the specificity of these tests.MethodsThis study aimed to evaluate the clinical value of HPV DNA load in improving the diagnosis and prognosis of cervical lesions by p16/Ki-67 testing. Histological samples were collected from 350 women with HR-HPV genotyping and analyzed by qRT-PCR. Immunohistochemical staining was used to assess p16 and Ki-67 expression and clinical performance characteristics were calculated.ResultsOf the cases, 271 had detectable HR-HPV infection, in which HPV-16 was most prevalent (52.0%), followed by HPV-58 (22.5%). P16/Ki-67-positivity increased with histological severity but not for HR-HPV infection. Amongst the 13 HR-HPV genotypes, only HPV-16 (P = 0.016) and HPV-58 (P = 0.004) viral loads significantly correlated with lesion severity. The P16/Ki-67/HPV DNA load co-test indicated an increased sensitivity for the detection of cervical intraepithelial neoplasia (CIN) lesions compared to p16/Ki-67 staining in HPV-16 and/or 58 positive cases. Viral load did not improve the sensitivity of p16/Ki-67 co-test in non-HPV-16 or 58 positive cases. The clinical performance of the p16/Ki-67/HPV DNA load co-test was limited for the prediction of the outcome of CIN1 lesions. However, amongst the 12 HPV-16 and/or 58 positive CIN2 cases in which return visit results were obtained, the behavior of the lesions could be predicted, with a sensitivity, specificity, positive prediction rate (PPV), and negative prediction rate (NPV) of 0.667, 1, 1 and 0.5, respectively.ConclusionCombination of the assessment of HPV DNA load with the intensity of p16 and Ki-67 staining could increase the sensitivity of CIN lesion diagnosis and predict the outcome of CIN2 in patients with a HPV-16 and/or 58 infection.

Methylation estimates the risk of precancer in HPV-infected women with discrepant results between cytology and HPV16/18 genotyping

BackgroundVigilant management of women with high-risk human papillomavirus (hrHPV) is necessary in cancer screening programs. To this end, we evaluated the performance of S5 (targeting DNA methylation in HPV16, HPV18, HPV31, HPV33, and human gene EPB41L3) to predict cervical intraepithelial neoplasia grade 2 or higher (CIN2+) in a sample of hrHPV-infected women referred to colposcopy in the FRIDA Study, a large screening trial in Mexico. A nested case-control sample with women referred to colposcopy either by atypical squamous cells of undetermined significance or higher (ASCUS+) in cytology and/or positive for HPV types 16 or 18 was tested by S5. Seventy-nine cases of CIN2+ were age-matched to 237 controls without a diagnosis of CIN2+ (<CIN2). DNA from exfoliated cervical cells was bisulfite converted and PCR amplified for S5 targets, and methylation was quantified at specific cytosines by pyrosequencing.ResultsThe S5 classifier separated women with CIN2+ from <CIN2 with a highly significant area under the curve (AUC) of 0.75 (95% CI 0.69–0.82), while AUC for CIN3+ was 0.81 (95% CI 0.74–0.89). To optimize sensitivity and specificity for Mexico, an alternative S5 cutoff of 3.7 was implemented to account for overall higher methylation seen in our already triaged women. All three invasive cancers were detected by methylation or HPV16/18 but none by cytology. Sensitivity of S5 for CIN2+ was 62% (95% CI 50.4–72.7%), specificity was 73% (95% CI 66.9–78.5%), and adjusted PPV was 15.1% (95% CI 12.0–18.3%). In contrast, the crude sensitivity of HPV16/18 detection and cytology were 63.3% (95% CI 51.7–73.9%) and 57.0% (95% CI 45.3–68.1%) respectively; specificity was 29.1% (95% CI 23.4–35.3%) and 62.4% (95% CI 55.9–68.6%) respectively, while adjusted PPV was 6.4% (95% CI 4.9–8.1%) and 10.5% (95% CI 8.0–13.1%), respectively. Methylation testing could reduce colposcopy referrals by 30 to 50% with virtually no loss of sensitivity for CIN2+ and CIN3+.ConclusionsS5 testing on hrHPV-positive women significantly increased diagnostic information compared to triage by HPV16/18 plus cytology and appears to have clinical utility as an additional test to substantially lessen burdens on colposcopy.Trial registrationThe FRIDA Study is registered in ClinicalTrials.gov, number NCT02510027.

Approaches to triage optimization in HPV primary screening: Extended genotyping and p16/Ki‐67 dual‐stained cytology—Retrospective insights from ATHENA

The objective of our study was to assess the performance of different triage strategies for high‐risk human papillomavirus (hrHPV)‐positive results utilizing either extended genotyping or a p16/Ki‐67 dual‐stained cytology (DS) approach, with or without partial genotyping. A subset of women with hrHPV infections participating in the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study were analyzed to determine the number of cervical intraepithelial neoplasia grade 3 or worse (≥CIN3) cases detected, and the absolute risk for ≥CIN3 of each genotype. A clinical utility table was constructed to compare the impact of different triage strategies. In all, 2,339 women with single‐genotype hrHPV infections were identified. Among these were 171 ≥CIN3 cases. The U.S. Food and Drug Administration (FDA)‐approved algorithm (HPV16/18 positive, or 12‐other hrHPV positive and Pap positive, i.e., ≥ atypical squamous cells of undetermined significance) for primary HPV screening detected 132/171 (77.2%) ≥CIN3 cases and required 964 colposcopies (colposcopies per ≥CIN3 ratio: 7.3). An approach that uses DS instead of cytology in the FDA‐approved algorithm detected 147/171 (86.0%) ≥CIN3 cases, requiring 1,012 colposcopies (ratio: 6.9). Utilizing DS for triage of all hrHPV‐positive women identified 126/171 (73.7%) ≥CIN3 cases, requiring 640 colposcopies (ratio: 5.1). A strategy that detected HPV16/18/31/33/35+ captured 130/171 (76.0%) ≥CIN3 cases, requiring 1,025 colposcopies (ratio: 7.9). Inclusion of additional genotypes resulted in greater disease detection at the expense of higher colposcopy ratios. Substituting cytology with a DS triage approach improved disease detection and the colposcopy detection rate. Further reduction of colposcopy rates can be achieved by using DS without partial genotyping. Extended genotyping strategies can identify a comparable number of cases but requires an increased number of colposcopies.

Key Determinants of the Value of Random Cervical Biopsy at Colposcopy.

The aim of the study was to assess whether lower proportions of cervical intraepithelial neoplasia 2+ diagnosed by random biopsy are from lower cut points defining an abnormal colposcopic impression or obtaining only one random biopsy when colposcopic impression is normal. We compared colposcopy experiences within Shanxi Province Cervical Cancer Screening Study (SPOCCS) (n = 1,383) and Shenzhen Cervical Cancer Screening Trial (SHENCCAST) (n = 631), which had instructive differences in the cut point defining an abnormal colposcopic impression. The proportion of CIN 2+ diagnosed by random biopsy in SPOCCS (35.0%, 141/403) was higher than SHENCCAST (18.4%, 35/190, p < .001). Quadrant-specific receiver operating characteristic curves for diagnosis of CIN 2+ by colposcopic impression in SPOCCS and SHENCCAST were similar; a lower cut point for an abnormal colposcopic impression in SHENCCAST resulted in lower proportion of CIN 2+ diagnosed by random biopsy. Normal colposcopic impression was found in 85.1% (120/141) of cases of CIN 2+ diagnosed by random biopsy in SPOCCS and in 57.1% (20/35) of such cases in SHENCCAST. Of CIN 2+ diagnosed by random cervical biopsy with normal colposcopic impression, one cervical quadrant was involved with CIN 2+ in 66.7% (80/120) of colposcopies in SPOCCS and 80% (16/20) of colposcopies in SHENCCAST. Colposcopy series with higher proportions of CIN 2+ diagnosed by random biopsy likely have more stringent cut points defining an abnormal colposcopic impression and have more random biopsies when the colposcopic impression is normal. At colposcopy, we advise multiple biopsies of all acetowhite epithelium or multiple random biopsies to increase the sensitivity of colposcopy.

Clinical Utility of Biomarkers in Diagnosis and Management of High Grade Cervical Intraepithelial Neoplasia (HSIL)

Objective of the study: The increasing inter- and intra-observer variability in the diagnosis of CIN by histopathology has led to the advent of different biomarkers. The aim of this study is to evaluate Ki-67 and p16 INK4a marker in differentiating CIN lesions and the clinical utility of it in the management of high grade squamous intraepithelial lesions (HSIL).&#x0D; Materials and methods: This cross-sectional study has been carried out among the biopsy proved cases of CIN2 and CIN3 in which P16 and Ki-67 immunostain was performed in the Colposcopy clinic, Bangabandhu Sheikh Mujib Medical University (BSMMU) and Department of Pathology, BSMMU respectively from 14-3-17 to 30-05-18. Thirty-two cases were incorporated in the study by purposive sampling. Data was analyzed using SPSS version 17.&#x0D; Results: Among 32 cases of HSIL, 25 were diagnosed as CIN 2 (78.13 %) and 7 cases as CIN 3 (21.87 %) by histopathology. All the cases were subjected to immunohistochemistry with P16 and Ki 67. Regarding the status of P16, it was found positive only in 32% cases of CIN 2 but in 100% cases of CIN 3. Similarly, Ki67 was found positive in 36 % of CIN2 cases but in all cases of CIN 3 lesions. Thus immunostain confirmed one third histopathologically diagnosed CIN 2 cases. On the other hand, all cases of CIN 3 were confirmed as HSIL with the immunostain. All the cases of CIN 2 were reviewed for consensus opinion. Only 8 (32%) cases of CIN 2 were both immunostain positive , the review diagnosis by consensus opinion was also CIN 2 in those cases. One case (4%) of CIN 2 was P16 negative but Ki 67 positive, which ultimately revealed as immature squamous metaplasia. Sixteen cases of CIN 2 were negative for both P16 and Ki 67. Among these, majority cases (52%) , consensus opinion revealed as CIN 1 and 12% cases as immature squamous metaplasia. Therefore, an HSIL diagnosed by histopathology could be false positive in a significant number of cases and overtreatment of a false positive CIN 2 lesion can affect future reproductive status, also have some psychological consequences and economic burden in the health sector.&#x0D; Conclusion: By using the biomarkers, overtreatment and undertreatment of CIN can be avoided. All cases of CIN 2 should be carefully dealt with either review of the slides by consensus opinion or by doing immunohistochemistry if facility is available.&#x0D; Bangladesh J Obstet Gynaecol, 2019; Vol. 34(2): 79-86

An on-going study of three different cervical cancer screening strategies based on primary healthcare facilities in Beijing China

BackgroundTo evaluate and compare the results of three different cervical cancer screening strategies including cytology screening, HR-HPV screening which taking HR-HPV testing as primary test and co-testing which taking both tests at the same time, then provide evidence to explore whether the cervical cancer screening can be conducted in community healthcare centers in Beijing. Methods182,119 women aged between 35 and 64, who were screened in the primary healthcare facilities of nine districts in Beijing from January 2014 to March 2015, were enrolled in this study. Cytology screening was performed in participants during January 2014 and December 2014 as a conventional arm. HR-HPV screening strategy and co-testing were randomly allocated to participants on districts level as experimental arm 1 and 2 during January 2015 and March 2015. Cervical Intraepithelial Neoplasia grade 2 or worse (CIN 2+) was defined as endpoint. The screening results and costs to detect a case of three strategies were calculated. ResultsThe positivity rate, colposcopy referral rate and biopsy referral rate of co-testing were 8.46%, 6.36% and 4.65% respectively, which were all significantly higher than the other two screening strategies. The detection rate of CIN 2+ by co-testing was 5.06‰ and was much more than the other two screening strategies, while the HR-HPV screening had the highest PPV of 14.40%. The HR-HPV screening ignores some lesion which can be found by co-testing. Co-testing refers a woman to colposcopy with a positive screening result at the least cost, but it costs the most to detect a CIN 2+ case. ConclusionsTo detect more cases of CIN 2+, co-testing performs better although with the most cost. And the primary healthcare facilities in Beijing have the capability to carry out the cervical cancer screen programs and prompts women with positive screen results to the hospital.

Cervical Cancer Screening Program in Rangpur Medical College Hospital: 11 Years Experience

Background: Prevention of cervical cancer is the easiest with regular screening tests and follow up. CIN is a pre-malignant condition, detection of which is possible by VIA and colposcopy.&#x0D; Objective: To identify the performance of Cervical Cancer Screening Program in Rangpur Medical College Hospital through 11 Years.&#x0D; Methods and materials: Apparently healthy, married or sexually active women (&gt;10 years) and women aged &gt;30 years attending Gynae OPD were included in this study. After counseling and informed consent a speculum examination was performed for direct visualization of cervix to identify the squamo-columner junction. Freshly prepared 5% acetic acid was applied to the cervix for one minute. All the VIA positive women were further evaluated by colposcopy. Women with negative VIA were advised for 3 yearly VIA test. Suspected CIN cases were evaluated by colposcopy guided punch biopsy or LEEP biopsy and histopathology.&#x0D; Results: VIA screening was provided for 11,792 women from August 2005 to August 2016 and 932 (7.9%) were positive VIA. From November 2007 to August 2016, total women underwent colposcopy were 1548. Among them 632 (40.8%) were normal, out of abnormal cases 730 (80.3%) were CIN-1, 147 (16.1%) were CIN-2, 14 (1.5%) were CIN-3, 17 (1.8%) were invasive and 8 (0.5%) were unsatisfactory. From November 2007 to August 2016 punch biopsy was taken in 384 women and total 568 women were treated by LEEP.&#x0D; Conclusion: In a low resource setting like Bangladesh VIA and colposcopy can detect 80% pre-invasive cervical lesion and may be one of the most important tool to prevent cervical cancer and its mortality.&#x0D; Bangladesh J Obstet Gynaecol, 2018; Vol. 33(1) : 11-16

HIGH-RISK HPV testing as the primary screening method in an organized regional screening program for cervical cancer: the value of HPV16 and HPV18 genotyping?

Since 2012, testing high-risk (HR)HPV has been used as the primary screening test for women ≥35years attending the organized cervical cancer screening program in the city of Tampere. We evaluated the contribution of HPV16/18 genotyping. Data from 2012 and 2013, and the follow-up samples in 2013 and 2014, respectively, were analyzed. Abbott RealTime High-Risk HPV test detecting 14 HRHPV genotypes combined with concurrent genotyping for HPV16 and HPV18 was used. HPV was positive in 794 samples out of 11346 HPV tested women (7%). HPV16/18 was represented in 22% of HPV-positive cases. Negative cervical cytology (NILM) was reported in 51% of HPV-positive samples. HPV16/18 genotype was accompanied with 50% of HSIL/ASC-H cases. The predominance of HPV16/18 in higher grade lesions was even more evident in cervical biopsies as 57% of CIN3 cases were associated with HPV16/18, and only 20% of carcinomas were associated with nonspecified high-risk (NSHR) genotypes. In agreement with previous studies HPV16/18 genotypes caused higher grade cytological and histological changes/pathologies than NSHR genotypes in primary screening. Nevertheless, the majority of HRHPV genotypes detected in the screened population were nonHPV16/18, and especially within persistent infections, precancerous lesions were found also among women with NSHR genotypes.