HPV may not play a role in all lacrimal transitional cell papilloma.

BACKGROUND: Tumours of the lacrimal duct apparatus (LDA) are rare and heterogenous but knowledge of their aetiology is important for the rhinologist. A link between transitional cell papilloma/carcinoma (TCP/TCC) and human papilloma virus (HPV) has been suggested in previous studies. We aimed to add to this body of evidence by submitting 16 LDA tumour samples from our tertiary referral centre for HPV analysis. METHODOLOGY: All LDA tumour samples stored in the University College London tissue bank were submitted for HPV analysis by centralised nucleic acid extraction and HPV genotyping via a sensitive polymerase chain reaction (PCR). RESULTS: Only one of six transitional cell papillomas tested positive for HPV. Two of three transitional cell carcinomas returned HPV 16 positive results. Two inverted papillomas submitted were also HPV positive. CONCLUSIONS: Previously published literature has suggested a strong link between HPV and neoplasia of the lacrimal system. HPV has previously been demonstrated in all TCP and TCC. This is in contrast to our data, particularly for transitional cell papilloma where, in the largest sample of transitional cell papilloma in the literature thus far, we did not find a strong association with HPV. This casts doubt on the role of HPV in the papillomatous process in the lacrimal apparatus.

Evaluation of a Novel Single-Tube Method for Extended Genotyping of Human Papillomavirus.

The use of high-risk human papillomavirus (HPV) testing for surveillance and clinical applications is increasing globally, and it is important that tests are evaluated to ensure they are fit for this purpose. In this study, the performance of a new HPV genotyping test, the Papilloplex high-risk HPV (HR-HPV) test, was compared to two well-established genotyping tests. Preliminary clinical performance was also ascertained for the detection of CIN2+ in a disease-enriched retrospective cohort. A panel of 500 cervical liquid-based cytology samples with known clinical outcomes were tested by the Papilloplex HR-HPV test. Analytical concordance was compared to two assays: a Linear Array (LA) HPV genotyping test and an Optiplex HPV genotyping test. The initial clinical performance for the detection for CIN2+ samples was performed and compared to that of two clinically validated HPV tests: a RealTime High-Risk HPV test (RealTime) and a Hybrid Capture 2 HPV test (HC2). High agreement for HR-HPV was observed between the Papilloplex and LA and Optiplex HPV tests (97 and 95%, respectively), with kappa values for HPV16 and HPV18 being 0.90 and 0.81 compared to the LA and 0.70 and 0.82 compared to the Optiplex test. The sensitivity, specificity, positive predictive value, and negative predictive value of the Papilloplex test for the detection of CIN2+ were 92, 54, 33, and 96%, respectively, and very similar to the values observed with RealTime and HC2. The Papilloplex HR-HPV test demonstrated a analytical performance similar to those of the two HPV genotyping tests at the HR-HPV level and the type-specific level. The preliminary data on clinical performance look encouraging, although further longitudinal studies within screening populations are required to confirm these findings.

RNA-Seq Analysis of Differentiated Keratinocytes Reveals a Massive Response to Late Events during Human Papillomavirus 16 Infection, Including Loss of Epithelial Barrier Function.

The human papillomavirus (HPV) replication cycle is tightly linked to epithelial cell differentiation. To examine HPV-associated changes in the keratinocyte transcriptome, RNAs isolated from undifferentiated and differentiated cell populations of normal, spontaneously immortalized keratinocytes (NIKS) and NIKS stably transfected with HPV16 episomal genomes (NIKS16) were compared using next-generation sequencing (RNA-Seq). HPV16 infection altered expression of 2,862 cellular genes. Next, to elucidate the role of keratinocyte gene expression in late events during the viral life cycle, RNA-Seq was carried out on triplicate differentiated populations of NIKS (uninfected) and NIKS16 (infected). Of the top 966 genes altered (>log2 = 1.8, 3.5-fold change), 670 genes were downregulated and 296 genes were upregulated. HPV downregulated many genes involved in epithelial barrier function, which involves structural resistance to the environment and immunity to infectious agents. For example, HPV infection repressed expression of the differentiated keratinocyte-specific pattern recognition receptor TLR7, the Langerhans cell chemoattractant CCL20, and proinflammatory cytokines interleukin 1α (IL-1α) and IL-1ß. However, the type I interferon regulator IRF1, kappa interferon (IFN-κ), and viral restriction factors (IFIT1, -2, -3, and -5, OASL, CD74, and RTP4) were upregulated. HPV infection abrogated gene expression associated with the physical epithelial barrier, including keratinocyte cytoskeleton, intercellular junctions, and cell adhesion. Quantitative PCR (qRT-PCR) and Western blotting confirmed changes in expression of seven of the most significantly altered mRNAs. Expression of three genes showed statistically significant changes during cervical disease progression in clinical samples. Taken together, the data indicate that HPV infection manipulates the differentiating keratinocyte transcriptome to create an environment conducive to productive viral replication and egress.IMPORTANCE HPV genome amplification and capsid formation take place in differentiated keratinocytes. The viral life cycle is intimately associated with host cell differentiation. Deep sequencing (RNA-Seq) of RNA from undifferentiated and differentiated uninfected and HPV16-positive keratinocytes showed that almost 3,000 genes were differentially expressed in keratinocytes due to HPV16 infection. Strikingly, the epithelial barrier function of differentiated keratinocytes, comprising keratinocyte immune function and cellular structure, was found to be disrupted. These data provide new insights into the virus-host interaction that is crucial for the production of infectious virus and reveal that HPV infection remodels keratinocytes for completion of the virus replication cycle.

Reduction in colposcopy workload and associated clinical activity following human papillomavirus (HPV) catch-up vaccination programme in Scotland: an ecological study.

OBJECTIVE: To measure patterns of clinical activity at colposcopy before and after vaccinated women entered the Scottish Cervical Screening Programme (SCSP). DESIGN: Population-based observational study using nationally collected data. SETTING: Scottish colposcopy clinics. SAMPLE: All women with a date of birth on or after 1 January 1985 who attended colposcopy in Scotland between 2008 and 2014. METHODS: Routinely collected data from the Scottish National Colposcopy Clinical Information Audit System (NCCIAS) were extracted, including: referral criteria, referral cervical cytology, colposcopic findings, clinical procedures, and histology results. Analysis was restricted to those referred to colposcopy at age 20 or 21 years. MAIN OUTCOME MEASURES: Referral criteria, positive predictive value of colposcopy, default rates, and rates of cervical biopsies and treatments. RESULTS: A total of 7372 women referred for colposcopy at age 20 or 21 years were identified. There was a downward trend in the proportion of those referred with abnormal cytology (2008/9, 91.0%; 2013/14, 90.3%; linear trend P = 0.03). Women were less likely to have diagnostic or therapeutic interventions. The proportion with no biopsy (2008/9, 19.5%; 2013/14, 26.9%; linear trend P < 0.0001) and no treatment (2008/9, 74.9%; 2013/14, 91.8%; linear trend P < 0.0001) increased over the period of observation. CONCLUSIONS: A reduction in clinical activity related to abnormal screening referrals is likely to be associated with the human papillomavirus (HPV) catch-up immunisation programme. Referral criteria and the service provision of colposcopy needs to be planned carefully, taking account of the increasing number of women who have been immunised against HPV that will be entering cervical screening programmes worldwide. TWEETABLE ABSTRACT: Colposcopy referral criteria and service planning need attention following HPV immunisation programme.

The impact of human papillomavirus type on colposcopy performance in women offered HPV immunisation in a catch-up vaccine programme: a two-centre observational study.

OBJECTIVE: To determine whether human papillomavirus (HPV) immunisation has affected the prevalence of HPV genotypes and colposcopic features of cervical intraepithelial neoplasia (CIN) in young women referred for colposcopy. DESIGN: A two-centre observational study including vaccinated and unvaccinated women. SETTING: Colposcopy clinics serving two health regions in Scotland, UK. POPULATION: A total of 361 women aged 20-25 years attending colposcopy following an abnormal cervical cytology result at routine cervical screening. METHODS: Cervical samples were obtained from women for HPV DNA genotyping and mRNA E6/E7 expression of HPV 16, 18, 31, 33, and 45. Demographic data, cytology, and histology results and colposcopic features were recorded. Chi-square analysis was conducted to identify associations between vaccine status, HPV genotypes, and colposcopic features. MAIN OUTCOME MEASURES: Colposcopic features, HPV genotypes, mRNA expression, and cervical histology. RESULTS: The prevalence of HPV 16 was significantly lower in the vaccinated group (8.6%) compared with the unvaccinated group (46.7%) (P = 0.001). The number of cases of CIN2+ was significantly lower in women who had been vaccinated (P = 0.006). The HPV vaccine did not have a statistically significant effect on commonly recognised colposcopic features, but there was a slight reduction in the positive predictive value (PPV) of colposcopy for CIN2+, from 74% (unvaccinated) to 66.7% (vaccinated). CONCLUSIONS: In this group of young women with abnormal cytology referred to colposcopy, HPV vaccination via a catch-up programme reduced the prevalence of CIN2+ and HPV 16 infection. The reduced PPV of colposcopy for the detection of CIN2+ in women who have been vaccinated is at the lower acceptable level of the UK national cervical screening programme guidelines. TWEETABLE ABSTRACT: Reduction of hrHPV positivity and CIN in immunised women consistent with lower PPV of colposcopy for CIN2+.

Impact of partial bivalent HPV vaccination on vaccine-type infection: a population-based analysis.

BACKGROUND: Data on the effectiveness of one dose of HPV vaccine are lacking, particularly in population-based settings. Data from a national HPV immunisation catch-up programme of 14-18-year-old girls were used to assess the effectiveness of<3 doses of the bivalent vaccine on vaccine-type and cross-reactive-type HPV infection. METHODS: Cervical samples from women attending for their first cervical smear, which had been genotyped for HPV as part of a longitudinal HPV surveillance programme were linked to immunisation records to establish the number of vaccine doses (0, 1, 2 and 3) administered. Vaccine effectiveness (VE) adjusted for deprivation and age at first dose, was assessed for prevalent HPV 16/18 and HPV 31/33/45 infection. RESULTS: VE for prevalent HPV 16/18 infection associated with 1, 2 and 3 doses was 48.2% (95% CI 16.8, 68.9), 54.8% (95% CI 30.7, 70.8) and 72.8% (95% CI 62.8, 80.3). Equivalent VE for prevalent HPV 31/33/45 infection was -1.62% (95% CI -85.1, 45.3), 48.3% (95% CI 7.6, 71.8) and 55.2% (95% CI 32.6, 70.2). CONCLUSIONS: Consistent with recent aggregated trial data, we demonstrate the potential effectiveness of even one dose of HPV vaccine on vaccine-type infection. Given that these women were immunised as part of a catch-up campaign, the VE observed in this study is likely to be an underestimate of what will occur in girls vaccinated at younger ages. Further population-based studies which look at the clinical efficacy of one-dose schedules are warranted.

HPV immunisation and increased uptake of cervical screening in Scottish women; observational study of routinely collected national data.

BACKGROUND: To measure the uptake of first invitation to cervical screening by vaccine status in a population-based cohort offered HPV immunisation in a national catch-up campaign. METHODS: A retrospective observational study of routinely collected data from the Scottish Cervical Screening Programme. Data were extracted and linked from the Scottish Cervical Call Recall System, the Scottish Population Register and the Scottish Index of Multiple Deprivation. Records from 201 023 women born between 1 January 1988 and 30 September 1993 were assessed. Women born in or after 1990 were eligible for the national catch-up programme of HPV immunisation. Attendance for screening was within 12 months of the first invitation at age 20 years. RESULTS: There was a significant decline in overall attendance from the 1988 cohort to the 1993 cohort with the adjusted attendance ratio of the 1988 cohort being 1.49 times (95% CI 1.46-1.52) that of the 1993 cohort. Immunisation compensated for this decrease in uptake with unvaccinated individuals having a reduced ratio of attendance compared with those fully vaccinated (RR=0.65, 95% CI 0.64-0.65). Not taking up the opportunity for HPV immunisation was associated with an attendance for screening below the trend line for all women before the availability of HPV immunisation. CONCLUSIONS: HPV immunisation is not associated with the reduced attendance for screening that had been feared. Immunised women in the catch-up cohorts appear to be more motivated to attend than unimmunised women, but this may be a result of a greater awareness of health issues. These results, while reassuring, may not be reproduced in routinely immunised women. Continued monitoring of attendance for the first smear and subsequent routine smears is needed.

HPV immunisation and cervical screening--confirmation of changed performance of cytology as a screening test in immunised women: a retrospective population-based cohort study.

BACKGROUND: To document the effect of bivalent HPV immunisation on cervical cytology as a screening test and assess the implications of any change, using a retrospective analysis of routinely collected data from the Scottish Cervical Screening Programme (SCSP). METHODS: Data were extracted from the Scottish Cervical Call Recall System (SCCRS), the Scottish Population Register and the Scottish Index of Multiple Deprivation. A total of 95 876 cytology records with 2226 linked histology records from women born between 1 January 1988 and 30 September 1993 were assessed. Women born in or after 1990 were eligible for the national catch-up programme of HPV immunisation. The performance of cervical cytology as a screening test was evaluated using the key performance indicators used routinely in the English and Scottish Cervical Screening Programmes (NHSCSP and SCSP), and related to vaccination status. RESULTS: Significant reductions in positive predictive value (16%) and abnormal predictive value (63%) for CIN2+ and the mean colposcopy score (18%) were observed. A significant increase (38%) in the number of women who had to be referred to colposcopy to detect one case of CIN2+ was shown. The negative predictive value of negative- or low-grade cytology for CIN2+ increased significantly (12%). Sensitivity and specificity, as used by the UK cervical screening programmes, were maintained. CONCLUSIONS: The lower incidence of disease in vaccinated women alters the key performance indicators of cervical cytology used to monitor the quality of the screening programme. These findings have implications for screening, colposcopy referral criteria, colposcopy practice and histology reporting.

Clinical and Analytical Performance of the Onclarity HPV Assay Using the VALGENT Framework.

As the demand for human papillomavirus (HPV)-related cervical screening increases, emerging HPV tests must be evaluated robustly using well-annotated samples, such as those generated in the Validation of HPV Genotyping Tests (VALGENT) framework. Through VALGENT, we assessed the performance of the BD Onclarity HPV assay, which detects 14 high-risk (HR) types and resolves six individual types and three groups of types. Consecutive samples from a screening population (n = 1,000), enriched with cytologically abnormal samples (n = 300), that had been tested previously with the GP5+/6+ PCR enzyme immunoassay (EIA) and the GP5+/6+ PCR LMNX assay (Diassay) were tested with the Onclarity assay. Type-specific HPV prevalences were analyzed according to age and cytological result. The accuracy of the Onclarity assay for the detection of cervical intraepithelial neoplasia grade 2+ (CIN2+) and CIN3+ was assessed relative to the GP5+/6+ EIA results by using noninferiority criteria. Overall agreement and type-specific agreement between the Onclarity assay and the GP5+/6+ LMNX assay were assessed. The prevalence of HPV types 16, 18, 31, and 45 increased with the severity of cytological results (P for trend, <0.05). For the detection of CIN2+, the Onclarity assay had a relative sensitivity of 1.02 (95% confidence interval [CI], 0.99 to 1.05; P < 0.001 for noninferiority) and a relative specificity of 0.99 (95% CI, 0.97 to 1.00; P = 0.186 for noninferiority). The kappa for agreement between the Onclarity assay and the GP5+/6+ LMNX assay for HR-HPV was 0.92 (95% CI, 0.89 to 0.94), and values for the six individual types ranged from 0.78 (95% CI, 0.68 to 0.87) for HPV-52 to 0.96 (95% CI, 0.93 to 0.99) for HPV-16. These data suggest that the Onclarity assay offers applications for clinical workstreams while providing genotyping information that may be useful for risk stratification beyond types 16 and 18.

Influence of HPV type on prognosis in patients diagnosed with invasive cervical cancer.

While much is known about the influence of HPV type on the progression of pre-invasive cervical lesions, the impact of HPV type on cervical cancer prognosis is less evidenced. Thus, we assessed the impact of HPV type on the survival of women diagnosed with cervical cancer. A total of 370 cases of cervical cancer were assessed. Univariate analysis is presented using Kaplan-Meier survival curves and log-rank statistics and multivariable Cox proportional hazard models were generated using age group, socio-economic deprivation, FIGO stage, differentiation and HPV type. HPV grouping was considered in a number of ways with particular reference to the presence or absence of HPV 16 and/or 18. In the univariate analysis, FIGO, age at diagnosis and treatment were associated with poorer survival (p < 0.0001) as was absence of HPV 16 and/or 18 (p = 0.0460). The 25% mortality time in the non-HPV 16/18 vs. HPV16/18 positive group was 615 days and 1,307 days respectively. An unadjusted Cox PH model based HPV16/18 vs. no HPV 16/18 resulted in a hazard ratio of 0.669 (0.450, 0.995). Adjusting for deprivation, FIGO and age group resulted in a hazard ratio of 0.609 (0.395, 0.941) p = 0.025. These data indicate that cancers associated with HPV 16 and/or 18 do not confer worse survival compared to cancers associated with other types, and may indicate improved survival. Consequently, although HPV vaccine is likely to reduce the incidence of cervical cancer it may not indirectly improve cervical cancer survival by reducing the burden of those cancers caused by HPV16/18.

Reduction of low- and high-grade cervical abnormalities associated with high uptake of the HPV bivalent vaccine in Scotland.

BACKGROUND: In Scotland, a national HPV immunisation programme began in 2008 for 12- to 13-year olds, with a catch-up campaign from 2008 to 2011 for those under the age of 18. To monitor the impact of HPV immunisation on cervical disease at the population level, a programme of national surveillance was established. METHODS: We analysed colposcopy data from a cohort of women born between 1988 and 1992 who entered the Scottish Cervical Screening Programme (SCSP) and were aged 20-21 in 2008-2012. RESULTS: By linking datasets from the SCSP and colposcopy services, we observed a significant reduction in diagnoses of cervical intraepithelial neoplasia 1 (CIN 1; RR 0.71, 95% CI 0.58 to 0.87; P=0.0008), CIN 2 (RR 0.5, 95% CI 0.4 to 0.63; P<0.0001) and CIN 3 (RR 0.45, 95% CI 0.35 to 0.58; P<0.0001) for women who received three doses of vaccine compared with unvaccinated women. CONCLUSIONS: To our knowledge, this is one of the first studies to show a reduction of low- and high-grade CIN associated with high uptake of the HPV bivalent vaccine at the population level. These data are very encouraging for countries that have achieved high HPV vaccine uptake.

Introduction and sustained high coverage of the HPV bivalent vaccine leads to a reduction in prevalence of HPV 16/18 and closely related HPV types.

BACKGROUND: In 2008, a national human papillomavirus (HPV) immunisation programme began in Scotland for 12-13 year old females with a three-year catch-up campaign for those under the age of 18. Since 2008, three-dose uptake of bivalent vaccine in the routine cohort aged 12-13 has exceeded 90% annually, while in the catch-up cohort overall uptake is 66%. METHODS: To monitor the impact of HPV immunisation, a programme of national surveillance was established (pre and post introduction) which included yearly sampling and HPV genotyping of women attending for cervical screening at age 20. By linking individual vaccination, screening and HPV testing records, we aim to determine the impact of the immunisation programme on circulating type-specific HPV infection particularly for four outcomes: (i) the vaccine types HPV 16 or 18 (ii) types considered to be associated with cross-protection: HPV 31, 33 or 45; (iii) all other high-risk types and (iv) any HPV. RESULTS: From a total of 4679 samples tested, we demonstrate that three doses (n=1100) of bivalent vaccine are associated with a significant reduction in prevalence of HPV 16 and 18 from 29.8% (95% confidence interval 28.3, 31.3%) to 13.6% (95% confidence interval 11.7, 15.8%). The data also suggest cross-protection against HPV 31, 33 and 45. HPV 51 and 56 emerged as the most prevalent (10.5% and 9.6%, respectively) non-vaccine high-risk types in those vaccinated, but at lower rates than HPV 16 (25.9%) in those unvaccinated. CONCLUSIONS: This data demonstrate the positive impact of bivalent vaccination on the prevalence of HPV 16, 18, 31, 33 and 45 in the target population and is encouraging for countries which have achieved high-vaccine uptake.

Clinical evaluation of a GP5+/6+-based luminex assay having full high-risk human papillomavirus genotyping capability and an internal control.

The LMNX genotyping kit HPV GP (LMNX) is based on the clinically validated GP5+/6+ PCR, with a genotyping readout as an alternative for the more established enzyme immunoassay (EIA) detection of 14 targeted high-risk human papillomavirus (HPV) types. LMNX is additionally provided with an internal control probe. Here, we present an analysis of the clinical performance of the LMNX using a sample panel and infrastructure provided by the international VALGENT (Validation of Genotyping Tests) project. This panel consisted of cervical specimens from approximately 1,000 women attending routine screening, "enriched" with 300 women with abnormal cytology. Cases were defined as women classified with cervical intraepithelial neoplasia (CIN) grade 2+ (CIN2+) (n = 102) or CIN3+ (n = 55) within the previous 18 months. Controls were women who had normal cytology results over two subsequent screening rounds at a 3-year interval (n = 746). The GP5+/6+-PCR EIA (EIA) was used as a comparator assay and showed sensitivities of 94.1% and 98.2% for CIN2+ and CIN3+, respectively, with a clinical specificity of 92.4% among women aged ≥ 30 years. The LMNX demonstrated clinical sensitivities of 96.1% for CIN2+ and of 98.2% for CIN3+ and a clinical specificity of 92.6% for women aged ≥ 30 years. The LMNX and EIA were in high agreement (Cohen's kappa = 0.969) for the detection of 14 hrHPVs in aggregate, and no significant difference was observed (McNemar's P = 0.629). The LMNX internal control detected 0.6% inadequate specimens. Based on our study results, we consider the LMNX, similarly to the EIA, useful for HPV-based cervical cancer screening.

Understanding HPV tests and their appropriate applications.

Greater understanding of the role played by human papillomavirus (HPV) in the causation of disease has led to the development of an increasing number of HPV tests with different characteristics. The bewildering choice facing healthcare professionals and providers is daunting. Clearly, HPV testing is no longer simply of research interest, but can provide information that can be used for individual patient management and at the population level for cervical screening and vaccine surveillance. This review aims to provide the background to the development of HPV tests, to explain the different technologies and to discuss the challenges of the application of these optimally in the varied contexts of disease management. Few HPV tests are approved for clinical use and it is important that clinicians understand which test can be utilized, in what circumstances, with what specimens and the meaning of the report issued. HPV testing is no longer applicable only to cervical disease, and we have suggested additional areas, such as the oropharynx, in which HPV testing services might be implemented in the near future. New tests will continue to emerge and we have identified some of the indirect measures of HPV activity, or biomarkers, that could help in the risk stratification of HPV infection and associated disease. The challenges relating to the optimal application of the various HPV technologies are compounded by the lack of evidence regarding their performance in vaccinated populations. Currently published work, including modelling studies, has been undertaken in non-immunized populations. We therefore end by addressing the issues regarding appropriate strategies and tests for immunized populations.

Effect of glacial acetic acid pre-treatment of cervical liquid-based cytology specimens on the molecular detection of human papillomavirus.

OBJECTIVE: Cytology laboratories routinely treat cervical liquid-based cytology (LBC) specimens that are heavily contaminated with blood with glacial acetic acid (GAA) in order to lyse red blood cells and facilitate assessment. However, the impact on downstream human papillomavirus (HPV) detection is not well understood. This study examines the effect of GAA pre-treatment of ThinPrep(®) Preservcyt(®) specimens on the molecular detection of HPV. METHODS: A panel of 150 routinely collected cervical LBC specimens was tested with two commercial HPV tests, the Abbott RealTime High Risk HPV test (rtHPV) and the Qiagen Hybrid Capture 2 High Risk HPV DNA test (HC2), as aliquots before and after GAA treatment. Statistical analysis was performed using McNemars test and Bland and Altman plots. RESULTS: Agreement between the results of the rtHPV test on GAA-untreated and GAA-treated specimens was 95.7%, with no evidence of a significant difference in the distribution of the discrepant results (P = 0.414). HC2 test agreement on GAA-untreated and GAA-treated specimens was 91% at a cut-off of 1 relative light unit index (RLUI) and 92% at a cut-off of 2 RLUI. There was no evidence of a difference in the distribution of discordant results at a cut-off of 1 (P = 0.405) and 2 RLUI (P = 0.564). CONCLUSIONS: GAA pre-treatment of cervical ThinPrep Preservcyt LBC specimens had little effect on the two commercial HPV tests used in this study. The impact of GAA treatment on HPV testing should, however, be validated for all HPV tests and all LBC collection media used in each particular diagnostic setting.

Benefit of chemotherapy as part of treatment for HPV DNA-positive but p16-negative squamous cell carcinoma of the oropharynx.

BACKGROUND: To determine (a) the cause of an improvement in survival from oropharyngeal squamous cell carcinoma (OSCC) in South East Scotland and (b) whether this improvement was human papillomavirus (HPV) and p16 subtype-dependent. METHODS: Clinicopathological characteristics and outcome data for patients referred with OSCC from 1999 to 2001 (Cohort-1) and 2003 to 2005 (Cohort-2) were obtained. Molecular HPV detection and immunohistochemistry for p16 were performed from paraffin blocks. RESULTS: Cohort-1 and Cohort-2 contained 118 and 136 patients, respectively. Kaplan-Meier analysis revealed significantly improved survival in Cohort-2 (P<0.0001). Sub-classification according to HPV and p16 status revealed no improvement in survival in Class-I (HPV-ve/p16-ve; 47 patients) or Class-III (HPV+ve/p16+ve; 77 patients). However in Class-II (HPV+ve/p16-ve; 56 patients) an increase in 5-year cause-specific survival from 36% in Cohort-1 to 73% in Cohort-2 was detected (P=0.0001).Proportional hazards analysis of 217 patients treated radically demonstrated that significant variables were p16 (P<0.0001), N stage (P=0.0006) and cohort (P=0.0024). Removing cohort from the variables offered to the model showed that, whereas p16 (P<0.0001) and N stage (P=0.0016) remain significant, chemotherapy (P=0.0163) and T stage (P=0.0139) are now significant. This suggests that much of the cohort effect is due to the higher use of chemotherapy in the second cohort. CONCLUSION: These data suggest that HPV+ve/p16-ve patients constitute a separate subclass of OSCC who may particularly benefit from chemotherapy. They imply that p16 status cannot be considered a surrogate for HPV status, and those trials to de-escalate treatment in HPV+ve OSCC should take p16 status into account.

HPV type-specific prevalence using a urine assay in unvaccinated male and female 11- to 18-year olds in Scotland.

BACKGROUND: We conducted a baseline prevalence survey of unvaccinated 11- to 18-year olds to inform effectiveness studies for the new human papillomavirus (HPV) immunisation programme in Scotland. METHODS: Participants were recruited from schools and colleges and invited to provide demographic data and an anonymous urine sample for type-specific HPV testing. RESULTS: Among females aged 11-14 years, the weighted prevalence was 1.1% overall; 0.9% for high-risk types and no infections were associated with types 16 and 18. Among 15- to 18-year old females, the weighted prevalence was 15.2% overall; 12.6% for high-risk types and 6.5% for types 16 and 18. Among females aged 16-18 years, infection was more frequently associated with attending college and rural schools, and showed a trend towards increasing prevalence with increasing social deprivation (P=0.045). Among males aged 11-14 years, the weighted prevalence was 1.4% overall; 1.0% for high-risk types and 0.7% for types 16 and 18. Among 15- to 18-year old males, the weighted prevalence was 3.9% overall; 2.4% for high-risk types and 0.7% for types 16 and 18. CONCLUSIONS: Human Papillomavirus prevalence is low among 11- to 14-year olds, which includes the age group targeted for routine vaccination. The prevalence in males and correlation with deprivation require further investigation.

Penile cancer and the HPV attributable fraction in Scotland; A retrospective cohort study.

BACKGROUND: Penile cancer (PeC) is a highly morbid disease which is rising in certain settings including Scotland. A component of PeC is associated with Human Papillomavirus (HPV) although its influence on clinical outcomes is debatable as is whether the fraction attributable to HPV is increasing. METHODS: A total of 122 archived tissue samples derived from patients diagnosed with PeC between 2006-2015 were collated and tested for HPV DNA using molecular PCR. HPV positivity was determined for the overall population and by calendar year of diagnosis to determine any temporal trends. The influence of age, deprivation, smoking, tumour stage and tumour grade on likelihood of HPV positivity was determined by logistic regression. In addition, the influence of HPV status and the other clinical and demographics variables on all-cause death and death from PeC was assessed. RESULTS: HPV was detected in 43 % (95 % CI: 34-52) of penile cancers and the majority of infections were HPV 16. The HPV component of PeC did not increase over the time period (p for linear trend - 0.226). No demographic or clinical variables were associated with HPV positivity neither was HPV status associated with improved all-cause or cancer-specific survival during the follow up period. CONCLUSION: The rise in PeC in Scotland may not be attributable to a rise in HPV-associated cancer; this is consistent with oropharyngeal cancer (OPC) in the UK where there is an increase in both HPV positive and negative cancer. This work calls for a larger multi centre study to enable further detailed investigation into the implications of HPV infection in PeC.

Staging and treatment outcomes in oropharyngeal squamous cell carcinoma: a single-centre UK cohort.

The 8th edition of the UICC TNM (UICC 8) staging rules for oropharyngeal squamous cell carcinoma (OPSCC) acknowledges dichotomous disease biology based on the human papillomavirus (HPV) tumour status. This retrospective study was undertaken to validate those staging rules in a single UK treatment centre. Given a recent resurgence of interest in primary surgery for OPSCC, a secondary objective was to identify subsets of patients who might benefit. Patients presenting with OPSCC between 2010 and 2017 to the South Glasgow head and neck multidisciplinary team were identified from a prospective database. Only patients managed with curative intent were included (n=272). Stage group allocation according to the UICC 8 resulted in appropriate hazard discrimination, in contradistinction to the UICC 7 staging rules. Locally advanced (cT3-4) disease had a relatively poor prognosis irrespective of HPV status. No clear benefit for primary surgery in any subgroup was demonstrated. A dichotomous disease biology based on the HPV status of tumour is confirmed in this cohort. Patients with HPV-positive T1 and T2 primary tumours have an excellent prognosis when treated with non-surgical treatment regimens. The use of surgery as the primary management for categories of patients presenting with OPSCC should be in the context of clinical trials.