Willingness to HPV self-sampling for cervical cancer screening and its predictors among women attending outpatient clinics in Meru District,Arusha Region,Northern Tanzania

BackgroundThe ability for women to self-collect human papillomavirus (HPV) samples can potentially reduce the risk of cervical cancer and increase screening coverage.ObjectivesTo assess the willingness to HPV self-sampling for cervical cancer screening and its predictors among women attending outpatient clinics in Arusha region, northern Tanzania.MethodsA hospital-based cross-sectional study was conducted among 706 women aged 18–55 years in Meru District Hospital and Usa River Health Centre from March to April 2019. Face-to-face intervies were conducted using a questionnaire. Data analysis was performed using Stata version 14.0. The log-binomial regression was used to determine factors associated with willingness to self-collection of HPV samples.ResultsMajority (70%) of the women were willing to self-collection of HPV samples for cervical cancer screening and was associated with attending Meru District hospital (PR=2.02, 95%CI 1.77–2.31); good knowledge about cervical cancer warning signs (PR=1.11, 95%CI 1.01–1.22), prevention (PR=1.13, 95%CI 1.04–1.20), and symptoms (PR=1.61, 95%CI 1.33–1.93); and having formal employment (PR=1.22, 95%CI 1.07–1.37).ConclusionThe majority of women were willing to self-collect HPV samples for cervical cancer screening. Self-collection is, therefore, an acceptable and viable means of screening for cervical cancer, which has great implications for Tanzania from a health policy perspective.     

Biomarkers in cervical cancer screening

In industrialized countries, population wide cytological screening programs using the Pap test have led to a substantial reduction of the incidence of cervical cancer. Despite this evident success, screening programs that rely on Pap-stained cytological samples have several limitations. First, a number of equivocal or mildly abnormal test results require costly work up by either repeated retesting or direct colposcopy and biopsy, since a certain percentage of high grade lesions that require immediate treatment hide among these unclear test results. This work up of mildly abnormal or equivocal cytological tests consumes a large amount of the overall costs spent for cervical cancer screening. Improved triage of these samples might substantially reduce the costs. Cervical cancer is induced by persistent infections with oncogenic human papilloma viruses (HPV). While HPV infection is an indispensable factor, it is not sufficient to cause cancer. The majority of acute HPV infections induce low grade precursor lesions that are cleared spontaneously after several months in more than 90% of cases, and less than 10% eventually progress to high grade lesions or invasive cancer. Progression is characterized by the deregulated expression of the viral oncogenes E6 and E7 in infected basal and parabasal cells. Novel biomarkers that allow monitoring these essential molecular events in histological or cytological specimens are likely to improve the detection of lesions that have a high risk of progression in both primary screening and triage settings. In this review, we will discuss potential biomarkers for cervical cancer screening with a focus on the level of clinical evidence that supports their application as novel markers in refined cervical cancer screening programs.     

Diagnosis analysis in breast cancer and cervical cancer screening

Assessment of the accuracy of diagnostic procedures has been made independent of the diagnostic criteria used by means of Relative Operating Characteristics (ROC) analysis. A ROC curve describes the mutual relationship between the sensitivity and specificity of a diagnostic decision on the basis of various diagnostic criteria. The construction of such ROC curves is made possible if diagnoses are graded into levels of certainty. The curve enables the choice of an operating point with predetermined sensitivity and specificity values for the diagnosis decision. The population-based breast-cancer and cervical cancer screening projects carried out in Utrecht demonstrated an excellent fit between actual data and the calculated ROC curves. Analysis of the accuracy or performance of cytological diagnosis uncovered a problem arising from the similarly graded histopathological reference criteria used to determine the 'truth' of the cytological diagnosis decisions. The proposed solution is a serial calculation of ROC curves, one for each level differentiating between the histopathological categories. The ensuing three-dimensional ROC hill may reveal a summit marking numerically advantageous diagnosis criterion levels for both the test and the disease to be detected, or a depression signalling locally below-standard detection performance.     

The epidemiology of human papillomavirus infection and cervical cancer

Cervical cancer has been recognized as a rare outcome of a common Sexually Transmitted Infection (STI). The etiologic association is restricted to a limited number of viral types of the family of the Human Papillomaviruses (HPVs). The association is causal in nature and under optimal testing systems, HPV DNA can be identified in all specimens of invasive cervical cancer. As a consequence, it has been claimed that HPV infection is a necessary cause of cervical cancer. The evidence is consistent worldwide and implies both the Squamous Cell Carcinomas (SCC), the adenocarcinomas and the vast majority (i.e. > 95%) of the immediate precursors, namely High Grade Squamous Intraepithelial Lesions (HSIL)/Cervical Intraepithelial Neoplasia 3 (CIN3)/Carcinoma in situ. Co-factors that modify the risk among HPV DNA positive women include the use of oral contraceptives (OC) for five or more years, smoking, high parity (five or more full term pregnancies) and previous exposure to other sexually transmitted diseases such as Chlamydia Trachomatis (CT) and Herpes Simplex Virus type 2 (HSV-2). Women exposed to the Human Immunodeficiency Virus (HIV) are at high risk for HPV infection, HPV DNA persistency and progression of HPV lesions to cervical cancer.     

Genotyping and follow-up of HR-HPV types detected by self-sampling in women from low socioeconomic groups not participating in regular cervical cancer screening in France

BackgroundHPV vaginal self-sampling can be an alternative for women refusing cytological screening.ObjectivesTo describe HR-HPV types in 35–69 years old women from low socioeconomic groups not attending regular cytological screening in Marseille, France.Study designA cervical screening campaign using HR-HPV self-sampling including 22,702 women aged 35–69 years living in low socioeconomic districts of Marseille was organized. A cytological and/or histological follow-up was undertaken for a subset of women harboring HR-HPV types. Abbott RealTime High Risk HPV test was used for screening, while INNO-LiPA HPV Genotyping Extra assay was used for genotyping.Results4245 self-samplings were performed (participation rate, 18.7%) out of which 609 (14.3%) were HR-HPV+ by the screening test including 114HPV 16 (18.7%), 41HPV 18 (6.7%), 454HR-HPVnon-16/18 (75.4%). A sample of 260 out of the 454HR-HPVnon-16/18 were genotyped by INNO-LiPA which revealed HPV52 (35%), 66 (22.6%), 51 (19.6%), 31 (15.7%), 39 (13%), 56 (10.4%), and 53, 35, 59, 33, 58, 82, 45, 68, 73 (<10% each). At month 12, a 2nd self-collection kit was sent to 274 of 609HR-HPV+ women who did not have a Pap-test previously performed on them. Of these 274 women, 130 provided a sample for HPV testing; one was uninterpretable, 56 were HPV negative, and 73 were HR-HPV+ (10HPV16+, 3HPV18+, 60HR-HPVnon-16/18+). Of the 345 women with cytological and/or histological follow-up 19 (5.5%) had ≥CIN2 lesions, (11 were HPV16+ and 8 were HR-HPVnon-16/18).ConclusionThis study illustrates the potential efficacy of self-sampling as a cancer screening strategy for socioeconomically deprived women who do not participate in regular Pap screening programs.     

Vaginal self-sampling is an adequate means of screening HR-HPV types in women not participating in regular cervical cancer screening

In France, about 40% of women aged 25–65 years do not participate in regular screening and thus are at high risk (HR) of cervical cancer. Human papillomavirus (HPV) vaginal self-sampling is a valuable alternative in this population. This study aimed to assess the prevalence of HR and LR (low-risk) HPV infection in 3767 women aged >35 years from mid-socioeconomic backgrounds who carried out HPV vaginal self-sampling at home. HPV vaginal self-sampling was better accepted than the Pap-test in women aged 35–69 years who were previously non-responders to individual invitation. From the 933 self-collected swabs studied (24.7%), 62 were HPV-infected (6.6%), and 73 HPV types were found. HPV 16 was the most frequently found (43.5%), followed by 53 (23.2%), 18 (12.3%), 66 (12.3%), 31 (6.8%), 33 (5.4%) and 58 (2.7%). Ten women (16.2%) were infected by multiple HR-HPV types. Median HPV 16 load was 104.000 copies/10⁶ cells and median HPV 18 load was 833 copies/10⁶ cells. Six women (9.3%) harboured LR-HPV types. The 12-month follow-up of 43 HR-HPV positive women (69.3%) revealed CIN2–3 lesions in three women (6.9%), all HPV 16 infected, and harbouring an HPV 16 load >5 log₁₀ copies/10⁶ cells. Women harbouring HR-HPV types other than HPV 16/18 were older than women harbouring HPV 16/18 types (55 years vs. 46.9 years, p 0.0008). The high frequency of HR-HPV types in women >50 years deserves further investigation to elucidate the mechanism involved (re-infection or reactivation).     

2400例宫颈细胞脱落标本HPV筛查及荧光PCR基因分型和定量

目的建立快速、灵敏的HPV筛查方法及探讨HPV基因型与宫颈癌之间的关系.方法用细胞涂片法和传统PCR对2400例年龄在18～65岁的厦门郊区妇女进行筛查,对PCR阳性标本进一步进行荧光PCR基因分型和定量.结果 2400例宫颈脱落细胞普查中有宫颈原位癌4例、CIN(癌前病变)Ⅰ～Ⅲ级7例;PCR定性筛查这些标本中有84例阳性,阳性率为3.5%.对这84例阳性标本进行荧光基因分型和定量,发现13例HPV-16、18型阳性,其中HPV-16型阳性8例(占9.52%),HPV-18型阳性5例(5.95%),并且HPV-DNA拷贝数在3.6×103到5.6×107之间.在HPV-16、18型阳性的患者中宫颈原位癌3例(占75%)、CINⅠ-Ⅲ级5例(占71%).结论 HPV-16、18型与宫颈癌之间有高度相关性.     

Comparison of FFPE histological versus LBP cytological samples for HPV detection and typing in cervical cancer

Human papillomavirus (HPV) infection is closely associated with cervical cancer. This study analyzed HPV genotype prevalence in 75 cases of formalin-fixed paraffin embedded (FFPE) tissue samples from patients diagnosed with cervical cancer. Genotype prevalence was assessed using Reverse Blot Assay (REBA) and quantitative polymerase chain reaction (qPCR), which target the HPV L1 and HPV E6/E7 genes, respectively. HPV DNA chip tests were also performed using liquid based preparation (LBP) cytological samples from the same patients who provided the FFPE histological samples. We observed a slight difference in HPV genotype distribution as assessed by DNA chip versus REBA. One possible explanation for this difference is that normal regions could be mixed with lesion regions when cytological samples are extracted from each patient with cancer. For the detection of moderate dysplasia, the main target of diagnosis, this difference is anticipated to be greater. We also made several unexpected observations. For example, HPV multi-infection was not detected. Moreover, the rate of HPV positivity varied radically depending on the cancer origin, e.g. squamous cell carcinoma versus adenocarcinoma.Our results imply that it is important to determine whether cytological specimens are suitable for HPV genotyping analysis and cervical cancer diagnosis. Future research on the mechanisms underlying cervical cancer pathogenesis is also necessary.     

The human papillomavirus (HPV) vaccine,HPV related diseases and cervical cancer in the post-reproductive years

Prophylactic HPV vaccines have demonstrated high efficacy against a range of HPV related diseases. They have been widely adopted as population health interventions in many jurisdictions and their routine use has been endorsed by the WHO. The development of these vaccines comes after an increased understanding of the natural history and epidemiology of HPV infection and disease in both males and females. Persistent HPV infection with oncogenic types induces malignant transformation in a range of epithelia including the cervix, anogenital regions, the penis and a number of head and neck sites. In relation to HPV disease prevention in the post-reproductive years, most infections occur soon after commencement of sexual activity but new infections do occur throughout the age spectrum. This reduces the likely impact of prophylactic vaccines in this population. The major impact on HPV related disease in this age group will come from advances in screening and early detection of HPV and neoplastic precursors. The most appropriate prevention for any individual man or women in this age group will be an individualised combination of vaccination, screening and early detection depending on the individual's own circumstances.     

膜杂交技术检测HPV基因分型联合液基细胞学在宫颈癌筛查中的应用

目的采用膜杂交法对人乳头瘤病毒（HPV）进行基因分型,液基细胞学检测细胞分级,用作宫颈癌筛查手段的临床价值和意义。方法采用膜杂交法检测23个HPV基因型别（低危型：HPV6、11、42、43、45和高危型：HPV16、18、31、33、35、39、45、51、52、53、56、58、59、66、68、73、83、MM4）和液基细胞学（TCT）作为宫颈癌和癌前病变的筛查。结果781例临床样本中,HPV阳性360例;占46.02%,其中单一型HPV感染中,低危型占34%、高危型占60%、二型和二型以上混合感染占6%。TCT检查≥ASCUS 184例占27%。结论本地区宫颈疾患人群中,存在较高的HPV感染率;随着TCT级别的升高,HPV感染率、特别是高危型的感染率明显升高。HPV基因分型检测是有价值的辅助诊断技术,与细胞学联合,是最佳的宫颈癌筛查的方案。     

Role of cervical screening in older women

Objective

To review the literature concerning the role of cervical screening in women 60 years and older.

Methods

Literature review was conducted using PubMed and the search terms cervical neoplasm, cancer, middle aged, elderly, aged, postmenopausal, cervical cytology and screening. To be included in the review, the article must have been in the English language. The search focused on publications from 2000 forward.

Results

The case control and modeling studies that addressed the role of cervical cytology screening in women 60 and older were reviewed. The outcomes of interest included: (1) the benefits of screening in terms of decrease rate of cervical cancer incidence (6 studies) and mortality (3 studies); (2) the duration of protection of the last screening test (4 studies); and (3) the harms of screening older women including false positive test results and cost.

Conclusions

Cervical cytology screening is beneficial for women over 60 years in terms of preventing the occurrence and death from cervical cancer. A negative cytology test appears to have 5 years of protection in this age group. Age of last screen with in an organized screening program may differ compared to the goals and wishes of individual women.     

Implementing targeted cervical cancer screening videos at the point of care

Objective

To develop and implement educational videos to improve cervical cancer health literacy for patients within a safety net healthcare system.

Methods

Testimonial-style videos were developed with the goal of describing the Pap test to low literacy patients and motivating them to participate in regular cervical cancer screening. Nurses were trained to use the electronic medical record to identify patients due or past due for a Pap test according to the current screening guidelines. They played the video for all eligible patients as they waited to be seen by their physician in clinical examination rooms.

Results

Four 2-minute videos were developed in English, Spanish, and Vietnamese. Videos were made available on desktop computers in 458 exam rooms at 13 community health centers.

Conclusion

Integration of educational videos into the workflow of high-volume community health centers is feasible. Future work will focus on optimizing uptake of the videos as well as assessing their efficacy for improving cervical cancer health literacy.

Practice Implications

Integrating targeted videos into patient flow may be a feasible way to address health literacy barriers to cervical cancer screening within a busy workflow environment.     

Toll样受体在人乳头瘤病毒感染致宫颈癌中的作用

高危型人乳头瘤病毒(high-risk human papillomavirus,HR-HPV)持续感染是宫颈癌发生的明确病因,但并非所有HR-HPV感染都会导致宫颈癌,说明多种因素参与调节HR-HPV的致病性。Toll样受体(Toll-like receptors,TLRs)是一类模式识别受体,能特异性识别病原体相关...     

Human papillomavirus genotypes in Iranian patients with cervical cancer

The aim of this study was to determine the frequency of HPV genotypes isolated from cervical intra-epithelial neoplasia grade III and invasive carcinomas of Iranian patients.A total of 94 cases were selected in five years from 2003 to 2007. After nucleic acid purification, real-time PCR was performed by means of GP5+/GP6+ primers. Subsequently, PCR products were sequenced, on the basis of which a phylogenetic tree was constructed. Negative samples and twelve randomly selected positive samples were also typed by reverse hybridization to increase the sensitivity and to confirm the results.Of 94 evaluated samples, 7 were negative for internal control gene and were excluded from the study. The overall genotyping results of phylogenetic analysis and hybridization methods were as follows: HPV 16: 75% (65/87); HPV 18: 3% (2/87); HPV 31: 1% (1/87); HPV 45: 1% (1/87).High frequency of HPV 16 and low frequency of HPV 18 were found in this study. Information about HPV genotype distribution is important in cervical cancer screening and prevention.     

HPV逃避宫颈癌宿主免疫应答的机制

人乳头瘤病毒(HPV)使用不同的方法逃避宿主的免疫识别。近期研究发现宫颈上皮为HPV病毒摧毁宿主免疫应答提供了一个保护的微环境,例如子宫颈缺乏炎性环境使宫颈部位的树突状细胞(DCs)和朗格罕式细胞(LC)对HPV抗原产生耐受;CD4+T细胞在上皮内瘤变的退行中起关键作用,而CD8+T细胞在浸润性癌中其关键作用;CD8+T淋巴细胞中的信号分子TCRzeta链表达减少;宫颈癌和宫颈上皮内瘤变患者表达NKG2D的NK细胞和T细胞数量减少;宫颈癌患者CD4+CD25+FoxP3+调节性T细胞频率增加;Nrp-1+Treg表现出较强的抑制活性;肿瘤细胞中的Treg网络和吲哚胺2,3-双加氧酶使肿瘤细胞易于产生免疫逃逸等。此篇综述阐述了宿主免疫系统在清除HPV感染中的作用及HPV摧毁宿主免疫应答所采取的策略。了解HPV的逃逸机制将有助于分析宫颈癌免疫治疗中的困难并设计出更好的治疗策略。     

Shp2 expression is upregulated in cervical cancer,and Shp2 contributes to cell growth and migration and reduces sensitivity to cisplatin in cervical cancer cells

Src homology phosphotyrosine phosphatase 2 (Shp2) has been found to be overexpressed in cervical cancer tissues. However, the influence of Shp2 on the biological behavior and sensitivity to cisplatin of cervical cancer cells remains unclear. We aimed to assess Shp2 expression in cervical tissues and cell lines and to detect the influence of Shp2 knockdown and overexpression on the biological behavior and sensitivity to cisplatin in cervical cancer cells. We found that Shp2 expression was significantly upregulated in cervical cancer tissues and cell lines, and Shp2 overexpression was associated with lymph node metastasis and a high human papillomavirus (HPV) DNA load. Shp2 knockdown inhibited cell growth and migration and enhanced sensitivity to cisplatin in the HeLa and SiHa cervical cancer cell lines. In contrast, Shp2 overexpression had the opposite effects. These tumor-promoting effects of Shp2 may be partly related to Akt signaling. In conclusion, Shp2 is involved in the occurrence and development of cervical cancer and may confer cisplatin resistance in cervical cancer. Shp2 blockade may be a new strategy for cervical cancer treatment.     

子宫颈癌预防研究的里程碑

子宫颈癌是常见的妇科恶性肿瘤,其发病率在女性恶性肿瘤中居第二位。据2002年数据统计,全球估计有49万的子宫颈癌新发病例,27万多妇女死于该病。半个多世纪以来,人类试图努力用巴氏涂片来消灭子宫颈癌。子宫颈癌的病因学研究在80年代取得的显著进展,明确了人乳头瘤病毒与子宫颈癌病因学联系。而HPV预防性疫苗研制的成功则是子宫颈癌预防研究的里程碑。     

MICA and KLRK1 genes and their impact in cervical intraepithelial neoplasia development in the southern Brazilian population

Cervical carcinoma and cervical intraepithelial neoplasia (CIN) are associated with persistent infection by oncogenic subtypes of HPV (Human Papillomavirus). Factors linked to immunity, genetics and others like oral contraceptive use, sexual behavior, coinfections with other microorganisms and smoking seem to influence the mechanisms that determine regression or progression to CIN and cervical cancer. We investigated the effect of the MHC class I chain-related gene A (MICA) and Killer Cell Lectin Like receptor K1 (KLRK1) genes on cervical cancer and CIN lesions susceptibility in a group of 195 patients from southern Brazil. There were found a significantly higher number of ex-smokers in the control group (p = 0.005). There were more oral contraceptives (OC) users in the patient group. MICA*008:01/04 allele showed a significant difference between patient and control groups (p = 0.03; OR = 0.63, 95% CI 0.41–0.96), as well as MICA*018:01(p = 0.004, OR = 0.15, 95% CI 0.03–0.64) and MICA*002:01/020 (p = 0.01; OR = 0.60, 95% CI 0.40–0.88). We also analyzed cases and controls according to the MICA-129 genotypes (Met/Val). There was found a difference (p = 0.02) with the Met/Val genotype in a higher frequency in controls and Val/Val and Val/MICA del at a higher frequency in the patient group. For the KLRK1 gene there was no significant difference between groups.     

Evaluation of a new solid media specimen transport card for high risk HPV detection and cervical cancer prevention

BackgroundSolid media transport can be used to design adaptable cervical cancer screening programs but currently is limited by one card with published data.ObjectiveTo develop and evaluate a solid media transport card for use in high-risk human papillomavirus detection (HR–HPV).Study designThe Preventative Oncology International (POI) card was constructed using PK 226 paper^® treated with cell-lysing solution and indicating dye. Vaginal samples were applied to the POI card and the indicating FTA (iFTA) elute card. A cervical sample was placed in liquid media. All specimens were tested for HR–HPV. Color change was assessed at sample application and at card processing. Stability of the POI card and iFTA elute card was tested at humidity.Results319 women were enrolled. Twelve women had at least one insufficient sample with no difference between media (p = 0.36). Compared to liquid samples, there was good agreement for HR-HPV detection with kappa of 0.81 (95% CI 0.74–0.88) and 0.71 (95% CI 0.62–0.79) for the POI and iFTA elute card respectively. Sensitivity for ≥CIN2 was 100% (CI 100–100%), 95.1% (CI 92.7–97.6%), and 93.5% (CI 90.7–96.3%) for the HR–HPV test from the liquid media, POI card, and iFTA elute card respectively. There was no color change of the POI card noted in humidity but the iFTA elute card changed color at 90% humidity.ConclusionsThe POI card is suitable for DNA transport and HR–HPV testing. This card has the potential to make cervical cancer screening programs more affordable worldwide.