Elena Athanasiadi(1), Abraham Pouliakis(1), Niki Margari(1), Magdalini Stamataki(1), Dionisios Aninos(1),
Ioannis Panayiotides(2) and Petros Karakitsos(1)
(1) Department of Cytopathology, University of Athens Medical School, “Attikon” University Hospital.
(2) 2nd Department of Pathology, University of Athens Medical School, “Attikon” University Hospital.
Burden of cervical cancer
Cervical cancer is the malignancy that has been most successfully monitored and controlled by population-based screening programs worldwide. Screening of population for cytological abnormalities and subsequent treatment of high grade precancerous cervical intraepithelial lesions appears to reduce cancer incidence. Cytological follow up at a 3-5 year interval is estimated to reduce incidence up to 80% [2, 3].
Yet, the estimated burden of neoplasia of the uterine cervix in the 27 EU member states sums up to more than 54000 new cases and 25000 deaths annually  thusremains a serious public health problem. Incidence and mortality rates present great variety among countries, as prevention policies implemented differ in terms of attendance and efficiency, or even lack in certain countries of Eastern Europe. The majority of these cases are diagnosed in Eastern European countries (31.013 new cases and 15187 deaths). Moreover, mortality rates compared with incidence, reflects lower survival resulting from delayed diagnosis and lower effectiveness of treatment in certain eastern European regions [5, 6].
It is nowadays clear that incidence reduction is only achieved when quality assurance is implemented throughout every step of the program, from information provided to the women to treatment strategies and clinical management of screen detected abnormalities .As a result, opportunistic screening is discouraged because it can jeopardize the aimed benefits, result to negative side effects due to poor monitoring  and unnecessarily increases costs.
European recommendations on cervical cancer screening were initially introduced in 1999, when the European Commission of experts in research, health care and cancer screening, agreed to the need of organized cervical cancer screening programs in all EU members . The first edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening, released in 1993, established the principles of organized population-based screening strategies. The second edition, released in 2008, focuses on policies for: adverse effects minimization, maximization of screening benefits and additionally examines future prospects of HPV testing and vaccination. Moreover, key performance indicators were presented in the summary document, as measures of quality assurance and program success .
The Greek action plan against cancer
Prevention and treatment of chronic diseases, with special attention to cancers, has been a strategic priority in policies formed by the Hellenic Ministry of Health as of the announcement of 16/12/2010 related to the opening of a public consultation process. Subsequently the first phase of this program was initiated.
The national action plan against Cancer 2011-2015 is an integrated set of interventions that covers all cancer related health policies, prominent to highlight preventive and early detection actions. Efforts are focused on delivering healthcare to all in an accessible, equal and highly scientific method, employing quality control in all steps. The national program for cervical cancer screening is the first intervention policy of preventive healthcare organized in Greece, attempting to establish a standardized call and recall monitoring system for cervical cancer disease. Similar programs are already enrolling in certain EU countries, but with fewer obstacles than those occurring in Greece due to the economic crisis and the financial cuts implied to all public sectors. It is therefore crucial that in order for the program to be able to remain financially viable, all policies are carefully examined in terms of cost-effectiveness and available resources should be maximized to achieve a high level of performance and availability.
The Greek screening program for cervical cancer
The National Cervical Cancer Screening Program was introduced in 1/7/2011, with the first health center officially participating during the pilot phase being the Sfakia health center in Crete. The screening program gradually embodied 140 health centers and community clinics and all public hospitals that can offer their services with cytopathology and pathology departments and/or colposcopy services.
The Program is monitored by the General Secretary of Public Health, under the authority of Greek Ministry of Health. Framed by a scientific advisory board of experts, the General Secretary of Public Health is responsible of implementing the screening policy. As policy framework was proposed the Greek Guidelines for Quality Assurance in Cervical Cancer Screening which are based on the European Guidelines , properly adjusted to the special features of the Greek population and the National Health System. Even though Greece lacked national cancer registry, a regional research project funded by Greece and EU, gave important information on epidemiological data of the screening population in order to incorporate the European policies concerning cervical cancer to an adjusted, national-oriented program structure .
Quality assurance controls are crucial in monitoring all aspects of services provided. Therefore key performance indicators have to be closely monitored. For that purpose, both epidemiological and clinical data are collected via in information technology platform [13, 14], which is used from trained personnel.
Fundamental points of the Greek cervical cancer screening guidelines
The main characteristics of the national screening program are summarized in the following:
- The screening program is a nationwide, population-based, public health program that reclaims and implements European recommendations on cancer screening.
- The target group consists of women aged 25-65 years and the population is divided into regions of 250000 citizens or more. There are created seven catchment areas, each occupies the geographic region of the related health district.
- The follow up intervals in case of normal test Papanikolaou result, is three years until the age of 55 years and every 5 years for the age range of 55-65. However there is special attention to the high risk population.
- The target coverage is estimated to be 80% three years after the full program implementation.
- Cervical cytology remains the cornerstone of the prevention program, thus ut is the primary screening test, however innovative technologies are always under consideration .
Organisation, monitoring and evaluation
Existing social services, already available at municipalities are responsible for the program advertisement to promote women for arranging an appointment to the local center of health services registered to the program. Invitation letters for follow up of women with negative results is designed to be sent every 3 years for those aged 25-55 and every 5 years for those aged 55-65 (in cases of normal test Papanikolaou). The initial phase of the program introduced inclusion criteria for certain groups of women. The criteria established included women with difficulty in accessing health services, attributed to either the distance between their residence and hospitals (women living in distant villages, small islands etc.) or women with low socioeconomic profile, potentially facing social exclusion.
Women that underwent primary screening having abnormal smears are informed and requested to refer to the nearest health center offering colposcopy facilities for further examination. All data available (personal data, clinical information, examination results, appointment availability/records) are registered in the information system, which is available only to the trained and authorized personnel. Collected data is processed in order to monitor the program and indicators concerning attendance.
Screening tests and innovative technologies
Test Papanikolaou is the mainstay for cervical screening. Both methods of cytology (conventional and liquid based) are equally accepted. The availability of both cytological methods allows the laboratories to offer services without need to change neither their routine nor producing excessive costs in equipment. This approach will offer the opportunity to perform low cost randomized control trials and to evaluate both techniques in terms of diagnostic accuracy and cost effectiveness. Nevertheless, the scientific committee has encouraged the use of liquid based cytology, based on already published evidence of reduction in unsatisfactory smears and the possibility of reflex testing for HPV, from the remaining biological material in the vial .
The fact that Human Papilloma Virus (HPV) is causally associated with cervical cancer is a factor that has led scientific committees worldwide to examine the potential benefits of introducing certain molecular tests in the screening guidelines. So far, DNA tests that aim to detect presence of viral genome are developed and their potential clinical application is located in primary screening, in the triage of minor cytological abnormalities and in post-op follow up [16-19]. Additionally, HPV tests show significantly improved sensitivity but much worse specificity in primary screening and its potential use in large scale application could be cost effective in specific age groups . The Hellenic Program is taking into consideration all new evidence concerning molecular tests and ongoing research in the field and is examining its potential introduction if enhanced effectiveness is reassured, together with requisite quality control. For that purpose, the advisory committee has officially suggested a randomized control trial with pragmatic data from the program with at least for two rounds of follow up and a cost benefit analysis of the outcomes. Such trial would give all necessary information to enhance a policy of introducing DNA based techniques to the screening policies. Such transition would of course require a period of adjustment for the enrolled laboratories.
Computer assisted screening of cytological smears is a rather innovative technology provided by scanning devices currently on market. Their usage is enabling faster screening by cytopathologists, effective handling of laboratory workload, reduction of misinterpreting due to human afctor and even better quality control as more slides are reevaluated without time consuming efforts [21-23]. Insufficient evidence available for these systems is complicating extensive usage in the Greek cervical cancer screening program until now, but ongoing research about these systems is of great importance.
Out of more than 100 subtypes, HPV 16 and 18 are identified in approximately 72% of cervical cancers and HPV subtypes 6 and 11 in 90% of anogenital warts . Two vaccines, one quadrivalent and one bivalent (for HPV 16 and 18) have completed large scale Phase III vaccine trials proving their effectiveness in protection against high grade intraepithelial lesions and adenocarcinoma in situ associated with the targeted types in women that weren’t infected prior to vaccination [25, 26]. The vaccines are safe, well tolerated and efficacious. Both vaccines are available in Greece, especially, women aged 12-26 can be vaccinated with cost covered by the Social Insurance System, without being a mandatory vaccination policy.
According to national regulations, midwifes, nurses, cytopathologists and gynecologists are authorized to take Papanikolaou smears. Their role in the national program is considered highly important, not only because of the critical decisions they are required to make, but also because they are largely involved in communicating the program to the target population and reassuring accessibility of services to the women.
Quality assurance of the smears, sample taking process as well as sample transportation guidelines is considered in the Greek guidelines.
At present, cytopathology laboratories of the Greek National Health System, that fulfill basic criteria concerning both human resource and infrastructure requirements, are participating in the program. According to national laws, only specialized cytopathologists medical doctors are authorized for smear interpretation and reporting. The reporting scheme is according to the Bethesda System for Reporting Cervical Cytology. Although certain laboratories are already certified with ISO 9001, efforts are being made so that in the near future the majority of laboratories are accredited with ISO 15189.
Quality control is designed in respect to maintain a balance between manageable control of costs and low false negative/positive rates. Thus, methodologies for internal quality control of cytology are regularly followed including rescreening of slides, correlation of cytological to histological and/or colposcopic evidence, monitoring of ASCUS/LSIL and HPV typing/ASCUS ratios. In addition to internal quality control, internal continuing education and external quality controls are important aspects of the program implementation that need to be on focus of health policies.
Management of screen detected abnormalities and follow up
Women with abnormal cytology are referred to further examination. For women with smears classified as ASCUS or Low Grade Lesions during their routine screening, policies suggesting either immediate referral to colposcopy or surveillance with HPV DNA test or repeat smears are considered acceptable. If the colposcopy findings are suggestive of a more severe lesion, PBs or diagnostic LLETZ excisions are options, depending on woman’s profile (age, wish to childbearing etc). Women with high grade cytological diagnoses are referred to immediate colposcopy and histological confirmation of the severity of the lesion and subsequent treatment, due to the significant risk of progression to malignancy.
There is not a method of treatment proven superior for eradicating CIN or reducing the risk of future malignancy, after a treatment for high grade intraepithelial lesion [27-30]. As a result, 15% of women treated for high-grade cervical intraepithelial neoplasia (grade 2 or 3) develop high grade lesions or cervical cancer, usually within 2 years of treatment . Therefore, post operational surveillance is extremely important, thus this group of women is closely monitored. The surveillance includes consecutive test Papanikolaou at 6 months intervals.
Histopathological confirmation of a cytological diagnosis currently constitutes the golden standard and provides the final diagnosis, upon which all subsequent clinical decisions (including invasive treatments) are based. As such, histologic examination is the most accurate quality control indicator for both cytology and colposcopy, as well as for the evaluation of the entire screening program.
Ensuring quality assurance in service delivery within a Department of Pathology comprises compliance with both quality requirements and quality standards. The Department must be ISO15189 accredited or equivalent, certified and documented, preferably by a national accreditation body. All data must be protected and procedures must comply with relevant national and European legislation. All personal data must be protected in terms of confidentiality throughout all operations. Appropriate room is mandatory for sample reception, cut-up, processing, reporting etc. Safety must be ensured for both biological specimens and laboratory personnel. In addition, personnel must be qualified for the positions they hold, according to national requirements. Finally all procedures concerning staff qualifications specimen reception, sample processing, slide staining, microscopy and archiving must be clearly documented and closely monitored.
Information and Communications Technologies support
According to the European Guidelines, the support of the program by an information and communication technologies (ICT) system is extremely important, as it is essential tool for managing the screening program, computing the indicators of attendance, compliance, quality and impact; and providing feedback to involve health professionals, stakeholders and health authorities. Cervical cancer screening programs are nationwide applied, involve numerous users of divergent disciplines and affect the majority of the population, therefore there are numerous parameters that should be taken to account during a careful design and development. The ICT system is decided to be developed into two steps: at first a lightweight system has been rapidly implemented in order to support immediately the program activities, subsequently, as the program progresses another system should replace it. The second system will be implemented from scratch or based on the chosen technologies of the initial, possibly by replacement of critical components and by the addition of improved features, all user, usage and patient data will be transferred to the new system.
The initial software system [13, 14, 32, 33] supports the basic program requirements. It is web based, thus accessible via the Internet and has a multi-tier architecture based on open source software, namely the Apache Tomcat application server  and the MySQL database . The semantics of the system include: the case (i.e. the screened woman) along with numerous contact details, invitations, rendezvous, visits, samples, examinations such as cytological, colposcopy, histology, therapy, other data such as demographic details and history, entities involved for sample taking and examination, users and numerous other entities such as users roles and rights and management authorities.
The system has been implemented and is under deployment and continuous evaluation. System deployment requires user training and additionally initial problems resolution. It has been selected a hierarchical deployment method : initially there are trained information technology specialists of the seven regions that the Hellenic national health system is composed, this training involves all software aspects, and subsequently user training of each region is performed by these specialists. To resolve initial problems and additionally to collect user requirements and ideas for the system optimization there has been implemented an electronic reporting mechanism. The proposed hierarchical system deployment and user training strategy has more advantages against other methodologies. User training is performed by professionals that are already in contact with the users and are aware of user capabilities and the hardware and networking limitations. The reporting mechanism proved to be a useful tool not only for bug detection but for further system development according to the everyday user needs.
Feedback from data collected from the first phase of pilot implementation of the national screening program is more than important. Analyzing the results from the first 19292 pap-tests the incidence of CINII, CINIII and cervical cancer cases was remarkably high. In particular, 439 women were referred to colposcopy and biopsies detected 138 cases of CINII+ lesions out of which 17 cervical cancer cases. These rates are by far increased from those reported in published literature, however explained by the fact that these women were never examined before since the vast majority consisted of women with limited access to organized health services. It is worth mentioning that the program is supported entirely by already existing personnel with no prolonged working hours or additional equipment, thus well fitted to the stringent economic situation that Greece faces during last years. Since the economic turbulence is massively challenging national budgets and health services, it is crucial to realize the benefits derived from this ongoing effort to establish an organized screening program and promote prevention.
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34. Apache Tomcat [http://projects.apache.org/projects/tomcat.html]
35. MySQL [http://www.mysql.com/]