Factors associated with failed 'test of cure' in the NHS Cervical Screening Programme: A retrospective cohort study.

OBJECTIVE: To determine predictive factors associated with failed 'test of cure' (TOC) in the NHS Cervical Screening Programme (NHSCSP). METHODS: Retrospective cohort study of all patients treated by large loop excision of transformation zone (LLETZ) between 1st April 2014 and 1st April 2019. Those with no documented HPV genotype on referral, no TOC outcome, those having a hysterectomy, chemotherapy and/or radiotherapy were excluded from final analysis. RESULTS: Patients referred with a singular HPV genotype of HPV 16, HPV 18, or HPV Other types (HPV O) were significantly more likely to pass TOC than those referred with multiple HPV genotypes (p < 0.0001). Those with HPV genotypes including HPV O were significantly more likely to fail TOC as compared to those with genotypes of solely HPV 16 and/or 18 (p < 0.0001). Patients aged ≥51 years were significantly more likely to fail TOC when compared to all other age groups (p < 0.0001). CONCLUSION: Age >51 yrs. and infection with multiple hr-HPV types were predictors of post treatment hr-HPV persistence. Knowledge of HPV genotype both at referral, and following treatment, could allow a more individualised, and patient-centred, approach to both the management and follow up of CIN. HPV genotype should be reported as standard on all cervical screening sample results. The term HPV O should not be utilised and instead actual HPV genotype should be reported. This would enable us to optimise not only future research but would also allow future monitoring of the efficacy of vaccination programmes.

Invasive cervical cancer audit: What lessons can we learn locally and where would we stand with regard to duty of candour?

OBJECTIVE: To identify lessons learned locally from the invasive cervical cancer audit. To estimate the impact that the application of 'Duty of Candour' may have upon our future service provision. METHODS: Retrospective cohort study with interval analysis of all women diagnosed with cervical cancer at Sheffield Teaching Hospitals NHS Foundation Trust between 1 April 2007 to 31 December 2019. Data were collected prospectively with retrospective categorisation by screening history and invasive cervical cancer audit outcomes as satisfactory, satisfactory with learning points, and unsatisfactory. Statistical analysis was performed using the chi-squared test and paired t-test. RESULTS: Cervical cancer was diagnosed in 344 women. Seventy-eight (23%) had no record of prior cervical cytology, 108 (31%) had delayed attendance to the screening programme, 102 (30%) were detected by routine screening, and 56 (16%) were screening programme compliant. Satisfactory management was undertaken in 301 (87.5%) cases, 26 cases (7.5%) were satisfactory with learning points, and 17 cases (5%) were considered as unsatisfactory. CONCLUSIONS: Seventeen cases were applicable to the Duty of Candour process equating to 1.3 cases per year, incurring minimal impact upon future service provision. Invasive audit categorisation is subject to bias, however, with the potential for considerable intra- and inter-observer variation; the authors accordingly recommend that a further study be conducted to investigate both the consistency and reproducibility of the invasive cervical cancer audit categorisation.

Clinical indications referrals - what is the risk of premalignant and malignant female genital tract disease in women referred to a dedicated nurse-led colposcopy service? A retrospective cohort study.

Post-coital bleeding (PCB) is a poor predictive factor for cancer and should not be managed as urgent referral. Urgent referral to colposcopy is justified however, in the presence of a visible suspicion of cervical cancer. This retrospective cohort study of women attending a clinical indications referral service aims to identify the risk of pre-malignant and malignant disease in women with clinical indication referrals to colposcopy. Thirty-seven of 3521 women (1%) were diagnosed with pre-malignant cervical or endometrial disease; 14 women (0.4%) were diagnosed with cancer (11 cervix, three endometrial). To detect one cancer in women referred with an abnormal cervix, one would need to see 70 women; to detect one cancer in women referred with PCB one would need to see 790 women. Improved education in primary care and obstetrics and gynaecology training is key to improving clinical indications referral services, which is otherwise an effective and efficient service.Impact StatementWhat is already known on this subject? Post-coital bleeding is a poor predictive factor for cancer and should not be considered an urgent referral.What do the results of this study add? The presence of a visible suspicion of cervical cancer however does warrant urgent referral as approximately one in 70 women will have a malignancy detected.What are the implications of these findings for clinical practice and/or further research? Improved education in primary care and obstetrics and gynaecology training is the key to improving clinical indications referral services.

Are we managing our patients correctly following treatment for cervical glandular intraepithelial neoplasia? A review of practice at the Jessop Wing Colposcopy Unit.

OBJECTIVE: Women diagnosed with cervical glandular intraepithelial neoplasia (CGIN) remain at risk of further pre-malignant and malignant disease and require rigorous post-treatment follow-up. We assess the effectiveness and safety of community cervical sampling follow-up in women treated for CGIN. METHODS: A retrospective study was conducted of women diagnosed with CGIN between April 1, 2013, and March 31, 2019, at Jessop Wing Colposcopy Unit, Sheffield, UK. RESULTS: Of 140 women diagnosed with CGIN, 76 had co-existing cervical intraepithelial neoplasia (CIN). Cytologists were significantly more likely to report glandular neoplasia in the absence of co-existing CIN, and high-grade dyskaryosis in its presence (Ps < 0.0001). Co-existing CIN was significantly more likely to be present with high or low-grade compared to normal colposcopy findings (P < 0.0001). The 6-month test of cure (TOC) was attended by 67% of women (84% within 12 months), and the 18-month post-treatment sampling by 52.5% of women (70% within 24 months). Colposcopy recalled 96% of women correctly for the 18-month sampling, but 20% of women undertaking primary care samples were incorrectly recalled at 3 years instead. CONCLUSIONS: When CGIN is diagnosed, two dates for recall should be provided at 6 and 18 months post-treatment to the Cervical Screening Administration Service and the centralised screening laboratory ensuring the 18-month post-treatment sample is correctly appointed, preventing women with HPV-negative TOC samples being returned to 3-year recall. Follow-up of CGIN should be closely audited by the centralised laboratories ensuring women with CGIN are not put at additional risk.

The outcome for women with microinvasive cervical cancer with stromal invasion 1 mm or less: should we always re-excise?

To assess the management and outcome for women with microinvasive cervical cancer with stromal invasion 1 mm or less, examining the impact of re-excision. A retrospective cohort study with interval analysis performed between December 2000 and December 2010. Sheffield Gynaecological Cancer Centre and Jessop Wing Colposcopy Unit, Sheffield, UK. Women diagnosed with microinvasive cervical cancer with stromal invasion 1 mm or less during the allocated study period. Methods used is a retrospective cohort study. Risk of recurrence and mortality from disease; incidence of residual disease in repeat excision specimens. A total of 140 women were identified as having microinvasive cervical cancer with stromal invasion 1 mm or less. Sixty-three (45%) had a completely excised lesion; 77 (55%) had an incompletely excised lesion at first treatment. Fifty-five women underwent repeat excision. No residual disease was found in the majority (n=40; 73%). No women suffered disease recurrence or died from disease during the allocated study period. Outcome for women with microinvasive cervical cancer with stromal invasion 1 mm or less is excellent. Repeat excision is associated with very low rates of residual disease. A more conservative approach to follow-up incorporating HPV testing should be explored.

Rapid pre-screening is more sensitive in liquid-based cytology than in conventional smears.

Rapid pre-screening (RPS) is a useful tool to measure and improve performance in the cytology laboratory. Whether RPS is more or less effective in liquid-based cytology than in conventional smears is unknown. We compared the estimated sensitivity in a laboratory of 11 cytotechnologists which converted from conventional smears to SurePath™ (Becton Dickinson, Franklin Lakes, N.J., USA) liquid based cytology. In the 9 months prior to conversion, 23,286 smears were screened compared with 30,610 smears in the 12 months immediately after conversion. The estimated sensitivity of rapid pre-screening for 90 s improved significantly with liquid based cytology for all abnormalities (58.7 vs. 68.7%, p<0.001), atypical squamous cells of undetermined significance+low-grade squamous intra-epithelial lesion (52.6 vs. 63.1%, p<0.001), and high-grade squamous intra-epithelial alone (76.2 vs. 85%, p<0.001). Histologic follow up for 156 cases identified by rapid pre-screening of SurePath slides showed 32 (21%) cases of CIN1 or greater and 18 cases (12%) with CIN3 or worse. We conclude that rapid pre-screening is significantly more sensitive in liquid-based cytology compared with conventional smears, and detects significant lesions that are missed by routine screening.

Impact of different sectioning of excision biopsies of the cervical transformation zone for detection of invasive cervical cancer in 2 European centers related to national cervical screening programs.

BACKGROUND: The impact of the number of sections used in cervical excision biopsies of transformation zone on sensitivity of histological detection of cervical cancer is poorly documented. AIM: To assess whether different techniques of sectioning cervical excision biopsies in 2 European laboratories influence the finding of cervical cancer by histopathological examination. MATERIALS AND METHODS: The routine assessment at the Department of Histopathology and Cytology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK (Sheffield), encompassed sectioning a cone in 3-mm tissue blocks and cutting 3 levels per block. At the Institute of Pathology, Faculty of Medicine, University of Ljubljana, Slovenia (Ljubljana), cones were cut in a 3- to 4-mm-thick tissue block, and 10 levels were cut per block, spaced every 100 microm. The number of blocks and levels per block were assessed for each cone. Histopathological detection of cervical carcinoma between the laboratories was compared. RESULTS: Among 820 cones in the Sheffield laboratory, we detected 35 invasive carcinomas, whereas 6 invasive carcinomas were detected among 94 cones in the Ljubljana laboratory. Although the Slovenian laboratory examined a significantly larger number of levels per cone biopsy (64 vs 24 in Sheffield), this was not associated with a larger proportion of invasive cervical carcinoma, especially foci of stage IA1 or high-grade cervical intraepithelial neoplasia diagnosed on excision biopsies: 6.4% of invasive cervical carcinomas (5 [83.3%] of stage IA1) in Ljubljana and 4.3% (30 [85.7%] of stage IA1) in Sheffield laboratory (P > 0.05); 71.2% of high-grade cervical intraepithelial neoplasia in Ljubljana and 75.5% in Sheffield (P > 0.05). CONCLUSIONS: Our assessment showed that a method with a large number of levels per cervical cone or large loop excision of the transformation zone biopsy did not increase sensitivity for the detection of cervical cancer. However, extensive sectioning substantially affects the pathologist's workload, and this may need to be reconsidered.

Primary cervical screening with high risk human papillomavirus testing: observational study.

OBJECTIVE: To provide the first report on the main outcomes from the prevalence and incidence rounds of a large pilot of routine primary high risk human papillomavirus (hrHPV) testing in England, compared with contemporaneous primary liquid based cytology screening. DESIGN: Observational study. SETTING: The English Cervical Screening Programme. PARTICIPANTS: 578 547 women undergoing cervical screening in primary care between May 2013 and December 2014, with follow-up until May 2017; 183 970 (32%) were screened with hrHPV testing. INTERVENTIONS: Routine cervical screening with hrHPV testing with liquid based cytology triage and two early recalls for women who were hrHPV positive and cytology negative, following the national screening age and interval recommendations. MAIN OUTCOME MEASURES: Frequency of referral for a colposcopy; adherence to early recall; and relative detection of cervical intraepithelial neoplasia grade 2 or worse from hrHPV testing compared with liquid based cytology in two consecutive screening rounds. RESULTS: Baseline hrHPV testing and early recall required approximately 80% more colposcopies, (adjusted odds ratio 1.77, 95% confidence interval 1.73 to 1.82), but detected substantially more cervical intraepithelial neoplasia than liquid based cytology (1.49 for cervical intraepithelial neoplasia grade 2 or worse, 1.43 to 1.55; 1.44 for cervical intraepithelial neoplasia grade 3 or worse, 1.36 to 1.51) and for cervical cancer (1.27, 0.99 to 1.63). Attendance at early recall and colposcopy referral were 80% and 95%, respectively. At the incidence screen, the 33 506 women screened with hrHPV testing had substantially less cervical intraepithelial neoplasia grade 3 or worse than the 77 017 women screened with liquid based cytology (0.14, 0.09 to 0.23). CONCLUSIONS: In England, routine primary hrHPV screening increased the detection of cervical intraepithelial neoplasia grade 3 or worse and cervical cancer by approximately 40% and 30%, respectively, compared with liquid based cytology. The very low incidence of cervical intraepithelial neoplasia grade 3 or worse after three years supports extending the screening interval.

Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats.

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that is secreted during meal absorption and is essential for normal glucose homeostasis. However, the relatively low plasma levels and rapid metabolism of GLP-1 raise questions as to whether direct endocrine action on target organs, such as islet cells, account for all of its effects on glucose tolerance. Recently, an alternative neural pathway initiated by sensors in the hepatic portal region has been proposed to mediate GLP-1 activity. We hypothesized that visceral afferent neurons in the portal bed express the GLP-1 receptor (GLP-1r) and regulate glucose tolerance. Consistent with this hypothesis, GLP-1r mRNA was present in the nodose ganglia, and nerve terminals innervating the portal vein contained the GLP-1r. Rats given an intraportal infusion of the GLP-1r antagonist, [des-His(1),Glu(9)] exendin-4, in a low dose, had glucose intolerance, with a 53% higher glucose excursion compared with a vehicle-infused control group. Infusion of [des-His(1),Glu(9)] exendin-4 at an identical rate into the jugular vein had no effect on glucose tolerance, demonstrating that this dose of GLP-1r antagonist did not affect blood glucose due to spillover into the systemic circulation. These studies demonstrate that GLP-1r are present on nerve terminals in the hepatic portal bed and that GLP-1 antagonism localized to this region impairs glucose tolerance. These data are consistent with an important component of neural mediation of GLP-1 action.

Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion: diagnostic features in surepath™ cervical samples.

This study was undertaken to identify the situations in which a diagnosis of "Atypical squamous cells, cannot exclude a high-grade squamous intraepithelial lesion (ASC-H)" is offered in SurePath™ cervical samples and to identify cytological criteria helpful in predicting high-grade disease. 2,335 (3.4%) SurePath samples reported as atypical squamous cells (ASC) over a period of 2 years, including 1,112 cases with known hrHPV status were retrieved. 105/1,112 cases were categorized into ASC-H, and slides were available for review in 88/105 cases. These 88 samples were divided into two categories based on follow-up histological outcome and hrHPV status-category A: cases with CIN2+ lesions on follow-up (n = 48) and category B: cases with ≤CIN1 lesions or hrHPV negative status (n = 40). 78% (82/105) cases of ASC-H tested positive for hrHPV. Overall CIN2+ lesions were found in 50.3% (53/105) cases. Of 88 cases reviewed, HCGs were noted in 56.3% (27/48) cases in category A and 75% (30/40) cases in category B. Dispersed metaplastic cells and scattered small atypical cells were seen in 37.5% (18/48) cases in category A and 12.5%(5/40) in category B. The majority of cases with dispersed atypical cells had <20 cells/sample and cases with HCGs had <10 HCGs per sample. The majority of the cases reported as ASC-H contained HCGs. Of these groups with nuclear crowding, disorganization and those with steep edges ("blocks") are likely to predict high-grade disease. The samples with only dispersed atypical cells had <20 cells/sample in majority of cases. In these, a disproportionate and especially high nuclear: cytoplasmic ratio and irregular chromatin were the most useful features in predicting high-grade disease.

Individual estimated sensitivity and workload for manual screening of SurePath gynecologic cytology.

Data correlating individual screening sensitivity in gynecologic cytology and workload is limited. We compared the estimated sensitivity of manual screening of SurePath slides with individual workload. Estimated sensitivity determined by rapid prescreening was correlated with total workload in a laboratory performing manual screening of SurePath preparations for a 1 year period. There were 12 CTs with a total daily workload ranging from 8-35 slides. The mean estimated sensitivity for SurePath was 97.0% (range 91-100%). The mean estimated sensitivity for the lowest half workload (8-23 slides/day) was significantly higher than that for the highest half workload (23-35 slides/day) (98.3 versus 95.7%, P ≤ 0.001). The highest workload that achieved 100% estimated sensitivity was 30 slides/day. For manual screening of SurePath slides, individual estimated sensitivity is correlated with workload even at relatively low daily workloads.

Improved sensitivity over time with rapid prescreening in gynecologic cytology.

Rapid prescreening (RPS) is a powerful tool to measure and improve performance in the cytology laboratory. Long-term use of RPS has been shown to result in improved sensitivity and precision in routine screening. The effect of long-term RPS on RPS itself is not known. We compared the sensitivity of 100% RPS of Surepath™ liquid-based cytology over a 4-year period in a laboratory of 11 cytotechnologists (CTs). In comparison with the first 2 years, RPS for the laboratory showed a significant increase in sensitivity for all abnormalities (72.2% vs. 67.3%, P < 0.001) and ASCUS + LSIL (68.5% vs. 62.1%, P < 0.001). For individual CTs s, the lowest sensitivity for all abnormalities increased from 59.0 to 63.2%, whereas, for HSIL, it increased from 71.4% to 75.0%. We conclude that long-term use of RPS leads to significant increase in the sensitivity of RPS.