Triaging HPV-Positive Cervical Samples with p16 and Ki-67 Dual Stained Cytology within an Organized Screening Program-A Prospective Observational Study from Western Norway.

The implementation of high-risk human papillomavirus testing (hrHPV testing) as a screening method in substitute for cytology has evoked the need for more sensitive and less objective tests for the triage of HPV-positive women. In a cohort of 1763 HPV-positive women, the potential of immunocytochemical p16 and Ki-67 dual staining as compared to cytology, alone or in combination with HPV partial genotyping, was tested for triage of women attending a cervical cancer screening program. Performance was measured using sensitivity, specificity, and positive and negative predictive values. Comparisons were assessed using logistic regression models and the McNemar test. Dual staining was evaluated in a prospectively collected study cohort of 1763 HPV-screened women. For triage of CIN2+ and CIN3+, NPV and sensitivity, 91.8% and 94.2% versus 87.9% and 89.7%, respectively, were significantly higher using dual staining together with HPV 16/18 positive, as compared to cytology (p < 0.001). The specificities, however, were lower for dual staining as compared to cytology. Conclusions: Dual staining is safer for decision-making regarding HPV-positive women's need for follow-up with colposcopy and biopsy, as compared to cytology.

Randomized Implementation of a Primary Human Papillomavirus Testing-based Cervical Cancer Screening Protocol for Women 34 to 69 Years in Norway.

BACKGROUND: Cervical cancer screening programs are facing a programmatic shift where screening protocol based on human papillomavirus testing (HPV-Screening protocol) is replacing the liquid-based cytology (LBC-Screening protocol). For safe technology transfer within the nationwide screening programme in Norway, HPV-Screening protocol was implemented randomized to compare the real-world effectiveness of HPV-Screening protocol and LBC-Screening protocol at the first screening round. METHODS: Among 302,295 women ages 34 to 69 years scheduled to attend screening from February 2015 to June 2017, 157,447 attended. A total of 77,207 were randomly allocated to the HPV-Screening protocol and 80,240 were allocated to the LBC-Screening protocol. All women were followed up for 18 months. RESULTS: The HPV-Screening protocol resulted in a relative increase of 60% in the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse [risk ratio (RR) = 1.6, 95% confidence interval (CI) = 1.5-1.7], 40% in CIN grade 3 or worse (RR = 1.4, 95% CI = 1.3-1.6), 40% in cancer (RR = 1.4, 95% CI = 1.0-2.1), and 60% in colposcopy referrals (RR = 1.6, 95% CI = 1.5-1.6) compared with LBC-Screening. The performance of both protocols was age dependent, being more effective in women ages under 50 years. CONCLUSIONS: The HPV-Screening protocol was well accepted by women in Norway and detected more CIN2, CIN3, and cancers compared with the LBC-Screening protocol. IMPACT: A randomized implementation of the HPV-Screening protocol with real-world assessment enabled a gradual, quality assured, and safe technology transition. HPV-based screening protocol may further be improved by using HPV genotyping and age-specific referral algorithms.

Accuracy of cervical cytology: comparison of diagnoses of 100 Pap smears read by four pathologists at three hospitals in Norway.

BACKGROUND: Cervical cancer can be prevented by early detection and treatment for precancerous lesions. Since 1995, there has been a national cervical cancer screening program in Norway, where women aged 25-69 years are recommended to take Pap smears every three years. There are 17 cytology laboratories covering a population of 5 million people. The detection rate of cervical abnormalities varies from laboratory to laboratory. We wanted to investigate the accuracy of cytology diagnoses by four different pathologists at three different hospitals in Norway. METHODS: One hundred Pap smears (20 Normal, 20 ASC-US, 20 LSIL, 20 ASC-H and 20 HSIL) screened at UNN in 2015 were evaluated by four pathologists at three hospitals in Norway. All patients were followed up through December 2016. Histologically confirmed high-grade dysplasia (CIN2+) was considered as study endpoint. RESULTS: The number of Pap smears evaluated as abnormal (ASC-US+) by the four pathologists varied from 61 to 85. The number of high-grade cytology (ASC-H+) varied from 26 to 50. There was moderate agreement (weighted kappa 0.45-0.58) between the observers. There were 32 women with high-grade histology (CIN2+) in the follow-up, including 19 CIN2, 12 CIN3 and one squamous cell carcinoma (SCC). Using high-grade cytology (ASC-H+) as cut-off, the sensitivity for CIN2+ varied from 68.8% to 93.8% (mean 77.4%) and specificity from 70.6% to 95.6% (mean 81.3%). The pathologist with the highest sensitivity for CIN2+ had the highest false positive rate and the lowest specificity (p<0.05). The accuracy for CIN2+ varied from 74.1% to 83.8% (mean 79.4%). The Pap smear from the woman with cervical cancer was diagnosed as high-grade (ASC-H+) by one of the four pathologists. CONCLUSIONS: Cervical cancer screening based on cytology has limited accuracy. The study revealed a moderate agreement between the observers, along with a trade-off between sensitivity and specificity. This might indicate that hospitals with high detection rates of cervical cytology have higher sensitivity for CIN2+ but lower specificity.

Clinical value of fully automated p16/Ki-67 dual staining in the triage of HPV-positive women in the Norwegian Cervical Cancer Screening Program.

BACKGROUND: More accurate biomarkers in cervical cytology screening could reduce the number of women unnecessarily referred for biopsy. This study investigated the ability of p16/Ki-67 dual staining to predict high-grade cervical intraepithelial neoplasia (CIN) in human papillomavirus (HPV)-positive women from the Norwegian Cervical Cancer Screening Program. METHODS: Automated p16/Ki-67 dual staining was performed on liquid-based cytology samples from 266 women who were HPV-positive at their secondary screening. At a mean of 184 days after p16/Ki-67 staining, 201 women had a valid staining result and a conclusive follow-up diagnosis (histological diagnosis or HPV-negative diagnosis with normal cytology findings). The sensitivity and specificity for predicting the follow-up diagnosis were compared for cytology, p16/Ki-67 dual staining, and their combination. RESULTS: Sixty-seven percent of the study sample was p16/Ki-67-positive. The sensitivity of p16/Ki-67 staining for predicting CIN-2/3 was statistically significantly higher than the sensitivity of cytology (0.88 vs 0.79; P = .008), but this was not true for the prediction of CIN-3 (0.94 vs 0.88; P = .23). The specificity of cytology for predicting CIN-3 was significantly higher than the specificity of p16/Ki-67 staining (0.35 vs 0.28; P = .002), but this was not true for CIN-2/3 (0.35 vs 0.31; P = .063). For predicting CIN-2/3 and CIN-3, combination testing gave potentially better sensitivity (0.95 and 0.96, respectively) and better specificity (0.49 and 0.50, respectively). CONCLUSIONS: In a population of HPV-positive women, p16/Ki-67 dual staining was more sensitive but less specific than cytology for predicting high-grade CIN. The advantage of using both tests in different combinations is the potential for increasing the specificity or sensitivity in comparison with both methods performed individually. Cancer Cytopathol 2017;125:283-291. © 2016 American Cancer Society.

Arteriovenous malformation as a consequence of a scar pregnancy.

A scar pregnancy is an ectopic pregnancy implanted in a previous lower segment cesarean scar, and the incidence of this complication may be expected to rise along with increasing cesarean section rates. Arteriovenous malformation of the uterus may be congenital, associated with early pregnancy loss, trophoblastic disease, or surgical procedures. We describe a case of uterine arteriovenous malformation as a consequence of a scar pregnancy, complicated by recurrent, serious bleeding. The condition was diagnosed using three-dimensional ultrasound with color Doppler and magnetic resonance imaging and appears not to have been described before. Selective embolization was performed, but eventually surgical intervention with resection of the affected uterine segment was necessary, and the patient recovered. The diagnosis was confirmed by pathologic-anatomical diagnosis showing trophoblastic cells in the resected area. Because of collateral formation, non-surgical options may be limited and not successful.

Quality of fetal, perinatal and infant autopsy reports. An audit of all reports of postmortem examinations following fetal, perinatal and infant death in Rogaland County, Western Norway, 1997-1999.

The aim of the present study was to investigate the quality of fetal, perinatal and infant (< 12 months of age) autopsy reports. One hundred and thirty-six reports were scored for seven major categories (History, External description, Internal examination, Histology report, Other investigations, Placenta, Conclusions/Commentary) derived from "Guidelines for post mortem reports" published by the Royal College of Pathologists. The time taken for the final reports to be issued was also investigated. Of the 136 reports, 31 failed to reach a minimum standard of a 50% score. The one major category clearly falling below the recommended standard was Conclusions/Commentary. Other major categories such as History, External description and Histology report were also in need of improvement. Only three final reports were issued within the Department of Pathology's goal of 4 weeks. Although 77% of the reports fulfilled a minimum standard of a 50% score, the audit clearly showed that the standardised report form used was in need of revision and that many reports failed to give the clinicians an evaluation of the data presented in the autopsy reports. Based on the present findings, a number of measures have been implemented in order to improve the quality of future fetal, perinatal and infant autopsy reports.