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INTRODUCTION - The characteristic features of Papanicolaou (Pap) tests collected from female-to-male (FTM) transgender patients on androgen therapy have not been well defined in the literature. FTM transgender patients require cervical cancer screening with the same recommended frequency as cis-gender females. Dysplasia remains challenging to differentiate from atrophy. Without pertinent history, the atrophic findings in younger transgender patients can be misinterpreted as high-grade dysplasia.
METHODS - A review of all cervical Pap tests of transgender patients receiving androgen therapy (2010-2017) was performed. Bethesda diagnosis, cytomorphological features, HPV testing and cervical biopsy results were reviewed.
RESULTS - Eleven transgender patients receiving androgen therapy were identified with 23 cervical Pap tests, 11 HPV tests and five cervical biopsies performed. A review of the Pap tests demonstrated: 57% negative for intraepithelial lesion; 13% unsatisfactory; 13% atypical squamous cells of undetermined significance; 13% atypical squamous cells - cannot exclude high-grade squamous intraepithelial lesion; and 4% high-grade squamous intraepithelial lesion. The rates of abnormal tests were higher than our age-matched cis-gender atrophic cohort rates of unsatisfactory (0.5%), atypical squamous cells of undetermined significance (7%), atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (0%) and high-grade squamous intraepithelial lesion (0.5%). The cytological findings from liquid-based preparations included dispersed and clustered parabasal-type cells, scattered degenerated cells, smooth evenly dispersed chromatin, and occasional mild nuclear enlargement and irregularity. Dysplastic cells had larger nuclei, hyperchromatic clumped chromatin, and more irregular nuclear contours.
CONCLUSIONS - The evaluation of dysplasia can be challenging on Pap tests from transgender patients on androgen therapy. The cohort evaluated had higher rates of unsatisfactory and abnormal Pap tests. Pathologists should be familiar with the distinctive cytomorphological changes in the Pap tests from patients on androgen therapy to evaluate them appropriately.
© 2018 John Wiley & Sons Ltd.

BACKGROUND - It is unknown why a minority of women fail to clear human papillomavirus (HPV) and develop precancer/cancer. Differences in T-cell receptor (TCR) repertoires may identify HPV16-infected women at highest-risk for progression to cancer. We conducted a proof-of-principle study nested within the Guanacaste HPV Natural History Study to evaluate the utility of next-generation sequencing for interrogating the TCR repertoires among women who cleared and failed to clear cervical HPV16.
METHODS - TCR repertoires of women with HPV16-related intraepithelial neoplasia grade 3 or higher (CIN3+; n = 25) were compared to women who cleared an incident HPV16 infection without developing precancer/cancer (n = 25). TCR diversity (richness and evenness) and relative abundance (RA) of gene segment (V [n = 51], D [n = 2], J [n = 13]) usage was evaluated; receiver operating curve analysis assessed the ability to differentiate case-control status.
RESULTS - TCR repertoire richness was associated with CIN3+ status (P = 0.001). Relative abundance (RA) of V-gene segments was enriched for associations between cases and controls. A single V-gene (TRBV6-7) was significantly associated with CIN3+ status (RA = 0.11%, 0.16%, among cases and controls, respectively, Bonferroni P = 0.0008). The estimated area under the curve using richness and V-gene segment RA was 0.83 (95% confidence interval: 0.73-0.90).
CONCLUSIONS - Substantial differences in TCR repertoire among women with CIN3+ compared to women who cleared infection were observed.
IMPACT - This is the first study to use next-generation sequencing to investigate TCR repertoire in the context of HPV infection. These findings suggest that women with HPV16-associated cervical lesions have significantly different TCR repertoires from disease-free women who cleared HPV16 infection.

Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.

BACKGROUND - Although the incidence of cervical cancer has been decreasing in the United States over the last decade, Hispanic and African American women have substantially higher rates than Caucasian women. The human papillomavirus (HPV) is a necessary, although insufficient, cause of cervical cancer. In the United States in 2013, only 37.6% of girls 13 to 17 years of age received the recommended 3 doses of a vaccine that is almost 100% efficacious for preventing infection with viruses that are responsible for 70% of cervical cancers. Implementation research has been underutilized in interventions for increasing vaccine uptake. The Consolidated Framework for Implementation Research (CFIR), an approach for designing effective implementation strategies, integrates 5 domains that may include barriers and facilitators of HPV vaccination. These include the innovative practice (Intervention), communities where youth and parents live (Outer Setting), agencies offering vaccination (Inner Setting), health care staff (Providers), and planned execution and evaluation of intervention delivery (Implementation Process).
METHODS - Secondary qualitative analysis of transcripts of interviews with 30 community health care providers was conducted using the CFIR to code potential barriers and facilitators of HPV vaccination implementation.
RESULTS - All CFIR domains except Implementation Process were well represented in providers' statements about challenges and supports for HPV vaccination.
CONCLUSION - A comprehensive implementation framework for promoting HPV vaccination may increase vaccination rates in ethnically diverse communities. This study suggests that the CFIR can be used to guide clinicians in planning implementation of new approaches to increasing HPV vaccine uptake in their settings. Further research is needed to determine whether identifying implementation barriers and facilitators in all 5 CFIR domains as part of developing an intervention contributes to improved HPV vaccination rates.

AIM - Appraisal of cancer trends is essential for future cancer control, but relevant studies in China are scarce due to a lack of long-term data. With 40-years of cancer registry data, we sought to evaluate secular time trends in incidence and mortality of gynaecological cancers in an urban Chinese population.
MATERIALS AND METHODS - Data on incidence and mortality of invasive cervical, uterine and ovarian cancer were collected by the Shanghai Cancer Registry. Age-standardised incidence and mortality rates were calculated for women aged 20-84 in urban Shanghai between 1973 and 2012. Age-period-cohort Poisson regression models were used to evaluate age, period and cohort effects. Overall linear trends, interpreted as the estimated annual percentage change (EAPC), were derived from the net drift in age-drift models.
RESULTS - Overall, cervical cancer incidence and mortality substantially decreased (EAPC = -4.5% and -5.5%, respectively); however, an upward trend was apparent among younger women (age <60). Uterine cancer incidence increased slightly (EAPC = 1.8%), while mortality decreased over time (EAPC = -2.4%). Ovarian cancer incidence and mortality both increased, although the increase in incidence (EAPC = 1.8%) was larger than mortality (EAPC = 0.6%). While cohort effects were most evident for cervical cancer incidence and mortality, significant age, period, and cohort effects were found for all three gynaecological cancers evaluated.
CONCLUSIONS - These secular trends in incidence and mortality of gynaecological cancers in Shanghai likely reflect changing risk factor profiles and improved cancer prognosis over time, and suggest new priorities and call for additional efforts for gynaecological cancer prevention and control for women in China.
Copyright © 2016 Elsevier Ltd. All rights reserved.

BACKGROUND - Cervical cancer screening efforts linked to HIV/AIDS care programs are being expanded across sub-Saharan Africa. Evidence on the age distribution and determinants of invasive cervical cancer (ICC) cases detected in such programs is limited.
METHODS - We analyzed program operations data from the Cervical Cancer Prevention Program in Zambia, the largest public sector programs of its kind in sub-Saharan Africa. We examined age distribution patterns by HIV serostatus of histologically confirmed ICC cases and used multivariable logistic regression to evaluate independent risk factors for ICC among younger (≤35 years) and older (>35 years) women.
RESULTS - Between January 2006 and April 2010, of 48,626 women undergoing screening, 571 (1.2%) were diagnosed with ICC, including 262 (46%) HIV seropositive (median age: 35 years), 131 (23%) HIV seronegative (median age: 40 years), and 178 (31%) of unknown HIV serostatus (median age: 38 years). Among younger (≤35 years) women, being HIV seropositive was associated with a 4-fold higher risk of ICC [adjusted odds ratio = 4.1 (95% confidence interval: 2.8, 5.9)] than being HIV seronegative. The risk of ICC increased with increasing age among HIV-seronegative women and women with unknown HIV serostatus, but among HIV-seropositive women, the risk peaked around age 35 and nonsignificantly declined with increasing ages. Other factors related to ICC included being married (vs. being unmarried/widowed) in both younger and older women, and with having 2+ (vs. ≤1) lifetime sexual partners among younger women.
CONCLUSIONS - HIV infection seems to have increased the risk of cervical cancer among younger women in Zambia, pointing to the urgent need for expanding targeted screening interventions.

BACKGROUND - HIV infection is associated with a higher incidence of precancerous cervical lesions and their progression to invasive cervical cancer (ICC). Zambia is a global epicenter of HIV and ICC, yet the overall burden of cervical pre-cancer [cervical intraepithelial neoplasia 3 (CIN3)] and ICC among its HIV positive adult female population is unknown. The objective of this study was to determine the burden of cervical disease among HIV positive women in Zambia by estimating the number with CIN3 and ICC.
METHODS - We conducted a cross-sectional study among 309 HIV positive women attending screening in Lusaka (Zambia's most populated province) to measure the cervical disease burden by visual inspection with acetic acid enhanced by digital cervicography (DC), cytology, and histology. We then used estimates of the prevalence of CIN3 and ICC from the cross-sectional study and Spectrum model-based estimates for HIV infection among Zambian women to estimate the burden of CIN3 and ICC among HIV positive women nationally.
RESULTS - Over half (52 %) of the study participants screened positive by DC, while 45 % had cytologic evidence of high grade squamous intraepithelial lesions (SIL) or worse. Histopathologic evaluation revealed that 20 % of women had evidence of CIN2 or worse, 11 % had CIN3 or worse, and 2 % had ICC. Using the Spectrum model, we therefore estimate that 34,051 HIV positive women in Zambia have CIN3 and 7,297 have ICC.
CONCLUSIONS - The DC, cytology, and histology results revealed a large cervical disease burden in this previously unscreened HIV positive population. This very large burden indicates that continued scale-up of cervical cancer screening and treatment is urgently needed.

UNLABELLED - Tanzania has the highest burden of cervical cancer in East Africa. This study aims to identify perceived barriers and facilitators that influence scale-up of regional and population-level cervical cancer screening and treatment programs in Tanzania. Convenience sampling was used to select participants for this qualitative study among 35 key informants. Twenty-eight stakeholders from public-sector health facilities, academia, government, and nongovernmental organizations completed in-depth interviews, and a seven-member municipal health management team participated in a focus group discussion. The investigation identified themes related to the infrastructure of health services for cervical cancer prevention, service delivery, political will, and sociocultural influences on screening and treatment. Decentralizing service delivery, improving access to screening and treatment, increasing the number of trained health workers, and garnering political will were perceived as key facilitators for enhancing and initiating screening and treatment services. In conclusion, participants perceived that system-level structural factors should be addressed to expand regional and population-level service delivery of screening and treatment.
IMPLICATIONS FOR PRACTICE - Tanzanian women have a high burden of cervical cancer. Understanding the perceived structural factors that may influence screening coverage for cervical cancer and availability of treatment may be beneficial for program scale-up. This study showed that multiple factors contribute to the challenge of cervical cancer screening and treatment in Tanzania. In addition, it highlighted systematic developments aimed at expanding services. This study is important because the themes that emerged from the results may help inform programs that plan to improve screening and treatment in Tanzania and potentially in other areas with high burdens of cervical cancer.
©AlphaMed Press.

BACKGROUND - Very few efforts have been undertaken to scale-up low-cost approaches to cervical cancer prevention in low-resource countries.
METHODS - In a public sector cervical cancer prevention program in Zambia, nurses provided visual-inspection with acetic acid (VIA) and cryotherapy in clinics co-housed with HIV/AIDS programs, and referred women with complex lesions for histopathologic evaluation. Low-cost technological adaptations were deployed for improving VIA detection, facilitating expert physician opinion, and ensuring quality assurance. Key process and outcome indicators were derived by analyzing electronic medical records to evaluate program expansion efforts.
FINDINGS - Between 2006-2013, screening services were expanded from 2 to 12 clinics in Lusaka, the most-populous province in Zambia, through which 102,942 women were screened. The majority (71.7%) were in the target age-range of 25-49 years; 28% were HIV-positive. Out of 101,867 with evaluable data, 20,419 (20%) were VIA positive, of whom 11,508 (56.4%) were treated with cryotherapy, and 8,911 (43.6%) were referred for histopathologic evaluation. Most women (87%, 86,301 of 98,961 evaluable) received same-day services (including 5% undergoing same-visit cryotherapy and 82% screening VIA-negative). The proportion of women with cervical intraepithelial neoplasia grade 2 and worse (CIN2+) among those referred for histopathologic evaluation was 44.1% (1,735/3,938 with histopathology results). Detection rates for CIN2+ and invasive cervical cancer were 17 and 7 per 1,000 women screened, respectively. Women with HIV were more likely to screen positive, to be referred for histopathologic evaluation, and to have cervical precancer and cancer than HIV-negative women.
INTERPRETATION - We creatively disrupted the 'no screening' status quo prevailing in Zambia and addressed the heavy burden of cervical disease among previously unscreened women by establishing and scaling-up public-sector screening and treatment services at a population level. Key determinants for successful expansion included leveraging HIV/AIDS program investments, and context-specific information technology applications for quality assurance and filling human resource gaps.