Background

Cervical cancer is the most common form of cancer in women in Papua New Guinea (Vallely et al 2011). The 2012 Australian Institute of Health and Welfare  report on cervical screening showed a declining trend in the new cases of cervical cancer in women aged 20-69 from the years 1982 to 2007 (AIHW 2012). The same trend was also seen in the mortality rates (AIHW 2012). These trends have been attributed to the national cervical cancer screening program using the Pap test introduced in 1991 (Vallely et al 2011). It is now established that high risk serotypes of Human Papilloma Virus (HPV) infection directly leads to the development of cervical cancer and efforts are also now targeting this virus (Ray and Ryan 2011). Analysis of early results of the use of the HPV vaccine in young women in Australia is promising (Brotherton et al 2011).

Current national efforts in Papua New Guinea (PNG) to control cervical cancer include, adhoc Pap test and the ‘see and treat’ approach based on visual inspection of the cervix with acetic acid plus cryotherapy (Vallely et al 2011). The introduction of the HPV vaccine in PNG is now being discussed (Vallely et al 2011). A national cervical screening using the Pap test has not been adopted in PNG because of inadequate laboratory infrastructure, shortage of cytotechnicians and cytopathologists, limited funding and difficulty in comprehensive clinic follow-up (Vallely et al 2011). Although a Pap test-based screening initiative was established in 1999 by a non-government charity organization the follow-up rate for high-grade epithelial abnormality has been between 30-50% (Vallely et al 2011). In an editorial titled “Achieving control of cervical cancer in Papua New Guinea: what are the research and program priorities?” published in the 2011 issue of the PNG Medical Journal, it was highlighted that research was need to “establish the performance, acceptability and operational feasibility of alternative approaches to cervical cancer screening and treatment of precancerous lesions” (Vallely et al 2011).  Advances in cytology diagnostics and information communication technology offer innovative solutions to the challenges of a national cervical screening program in PNG.

This pilot project proposes to evaluate the operational feasibility and acceptability of Citofem ®a liquid based cytology (LBC) test for use in cervical screening. Although LBC perform interchangeably with conventional cytology (Whitlock et al 2011), its main advantage is reduced rate of inadequate results compared to conventional cytology (Vega et al 2010). Smears from cellular material obtained using Citofem ® create a monolayer of cells on a single plane without debris, mucus or inflammatory cells (Vega et al 2010) making it easier to digitized the glass slide compared to smears made using conventional cytology method (Thrall et al 2011). Telecytology, a component of telepathology, is the interpretation of cytology material at a distance via the internet using digital images (Thrall et al 2011) and offers an alternative to the shortage pathologist in PNG. Because cytology material is difficult to image relative to histology, telecytology has been limited in its clinical applications (Thrall et al 2011). Conventional cytology material frequently contains significant elements of three-dimensionality and cellular material is widely and randomly distributed across glass slides (Thrall et al 20111). Liquid based cytology has the advantage of creating a single layer of cells making imaging easier. Lee and others evaluated the use of telecytology as a tool for quality assurance programs in screening cervical smears and found it to be reproducible and accurate compared to conventional microscopy (Lee et al 2003). These recent advances should prompt us to re-examine the use of cervical screening in PNG and evaluate an alternative cytology test in combination with recent advances in telepathology.

Problem Statement

Cervical cancer is the leading cancer among women in PNG. The role of cervical cancer screening using the Pap smear test has been proven in developed countries that have a publically funded cervical cancer screening program. National cervical cancer screening program has been difficult to implement in developing countries because of various challenges, the major ones being inadequate clinical follow-up, limited funding and inadequate laboratory infrastructure including shortage of pathologists. The Conventional method of cervical sample collection, processing and reporting using the Pap smear test has its limitations. Liquid based cytology (LBC) is proving to overcome these limitations although its costs are higher. Telepathology offers a short to medium term solution to the shortage of pathologists in developing countries. This pilot project will evaluate the feasibility, acceptability and operational requirements of a LBC for cervical screening and telecytology for reporting in two hospitals in PNG.

Aims of Proposed Project

• Evaluate operational feasibility and acceptability of the LBC cytology test for cervical cancer screening at PMGH and Popondetta General Hospital.
• Evaluate operational feasibility and acceptability of a telecytology service specific for cervical cancer screening at PMGH and Popondetta General Hospital.

Objectives of the proposed project

• Determine and document operational requirements and acceptability of the LBC test.
• Determine and document operational and infrastructure requirements for a telepathology service for cervical cancer screening.
• Determine the costs of the LBC for cervical cancer screening.
• Determine the costs of a telecytology service for cervical cancer screening.

Significance of the proposed project

Pap test for cervical cancer screening has a proven benefit. But use of this test for cervical screening in a national publically funded cervical smear program in PNG has been limited due to a number of factors. The major limiting factors have been inadequate laboratory infrastructure, inadequate number of pathologists and high rates of loss for clinical follow-up for abnormal smears. The Pap test also has limitations inherent with the test such as high rate of inadequate smear results which results in increase repeat test rates. Liquid based cytology test has fewer inadequate smear results. In addition cervical cell smears from LBC have less debris, inflammatory cells and mucous making reporting easier. Smears from LBC can also be easily digitized and produce clearer image, a feature that is not possible with smears from conventional Pap test. Because the smears can be photographed easily and digitized, the images can be sent via internet to a pathologist geographically located elsewhere for viewing and reporting hence improving result turnaround time. It also allows increased number of number of smears to be reported by distributing workload to many participating pathologists.

The results of this pilot project will determine the laboratory infrastructure, technical capability and other operational requirements for a LBC test for cervical screening. Such information will also be important for laboratory managers and medical directors who plan to introduce this test into their hospitals. This pilot project will also determine the hardware, software and other infrastructure requirements for establishing a telecytology unit within a hospital and provide baseline data for further research into telepathology in PNG and its role in cervical cancer screening. It is hoped that data from the pilot project will be the basis for follow-up studies exploring the application of telepathology/telecytology not only for cervical cancer diagnosis and prevention in PNG but for other diseases of that require cytology for screening or diagnosis such as breast cancer and tuberculous lymphadenitis.

Literature Review

Population based cervical smear screening has contributed to the decline in morbidity and mortality from cervical cancer in developed countries. The commonly used screening test for cervical screening is the Pap test or Pap smear test. Recently the development and introduction of the Human Papiloma Virus (HPV) vaccine is proving to be effective and will play a major role in the prevention of cervical cancer. And for developing countries such as PNG (Papua New Guinea) considering preventative strategies against cervical cancer, the HPV vaccine may be a cost-effective solution. This is because a population based cervical screening program has been evaluated and thought not to be cost-effective. Other factors such as inadequate laboratory infrastructure, shortage of cytotechnicians and pathologist and inability to clinically follow-up abnormal smear results has also limited a national cervical screening program in PNG.

The conventional Pap test involves the collection of ectocervical and endocervical cells using a wooden spatula or brush and transferring the cells onto a glass slide by making a smear. The glass smear is then fixed with 70% alcohol. The remainder of the cellular material on the sampling device is discarded. The fixed smears are later transported to the laboratory, stained with specific stains and the glass slides are viewed by a pathologist using a microscope and reported. Sample collection in a liquid based cytology test (LBC) is similar to the Pap test but the collection brush has a removable head that is placed in its entirety with sampled cellular material into a container with a fixing solution. This ensures all sampled cellular material is obtained and dispersed in the fixing solution for processing later in the laboratory. At the laboratory, sampled cells are concentrated and obtained selectively using either filters or centrifugation. Inflammatory cells, mucus or cellular debris are also eliminated in this process. The resulting smear slide is clearer containing a monolayer of cells and less or no debris making slide reading easier for the pathologist. The creation of the monolayer of cells also makes it easier for the slide to be photographed and digitized, a feature not possible with cervical smear slides made from conventional Pap test. In terms of diagnostic capability for detecting abnormal cells, the conventional Pap test and LBC test appear to perform equally. However, the LBC test has less repeat and inadequate test results, a feature common with the Pap test. This is an obvious added benefit for patients although it may cost more for the LBC test.

Liquid based cytology test for cervical screening is now being used in the United States, England, Scotland and New Zealand although it has not been accepted for public funding in the national cervical screening program in Australia. Combining telecytology with LBC test for cervical cancer screening is being evaluated and there is increasing evidence to support this approach where there is shortage of pathologists. Reading concordance between telecytology and conventional microscopy for cervical screening is about the same as well although this requires proper training and a good quality assurance program. Screening for HPV can be done with the left over sample from LBC also. These added advantage of LBC and developments in telepathology should prompt us to re-evaluate our position on the use of a population based cervical cancer screening program in PNG for the prevention of cervical cancer. The challenge of clinical follow-up for abnormal test results also needs re-visiting and innovative options need exploring, for example use of mobile phones for alerting patients using automated text messaging solutions. Introduction of the HPV vaccine appears to be way forward for PNG and this option is currently being discussed but it will also require proper planning and funding to incorporate it into the national PNG vaccine guidelines. As a pre-requisite for HPV introduction, epidemiological surveys on HPV stain prevalence also needs to be determined and the LBC sampling method has the advantage of adjunct HPV testing using the sample. Numerous studies have demonstrated that HPV testing is more sensitive than cytology but with reduced specificity. But when coupled with reflex cytology on positive HPV results, there is increased detection rate of CIN3 and CIN 2. This may result in increased referrals for coloposcopy or biopsy procedures. Therefore the net effect of primary HPV testing will need to be determined. Limitations to the use of a population based cervical smear program, including challenges in clinical follow-up in PNG have been documented but recent diagnostic and technological advances such as telepathology should prompt us to re-visit and explore application of these advances in cervical cancer prevention strategies.

Citofem ® is a liquid based cytology test kit used in screening for the presence of atypical cervical cells for the prevention of cervical cancer. After endocervical and ectocervical cells are obtained using the Rovers ® Cervex-Brush ® combi, the handle is disconnected and the head inserted into the preservative Citofem ® cell preservative fluid vial. The vial is later transported to the laboratory for further processing. No sample is discarded allowing for 100% of sampled cells to be analysed and adjunct tests to be done on the sample. Citofem ® can also be utilized for non-gynaecological samples such as sputum, aspirate fluid, urine and cerebrospinal fluid. Compared to other LBC such as ThinPrep ® and SurePath ®, Citofem ® does not require additional expensive laboratory equipment or reagents for sample processing. After staining the cells are fixed with a resin, Culiq ®, that ensures high optical quality and eliminates use of Xylene and cover clips. Although numerous studies have compared LBC to conventional cytology, there is limited data evaluating the performance of Citofem ® against other LBC tests commercially available. When Citofem ® is compared to conventional Pap test, Citofem ® has a slight advantage over Pap test at a comparable cost indicating non-superiority of Citofem ®. Citofem ® also has the advantage of adjunct or co-testing for HPV without further processing of the collected sample, a step required in other LBC tests. All these make Ciofem ® a suitable LBC test for cervical screening for developing countries considering LBC tests in cervical cancer prevention strategies.

Telecytology is a component of telepathology and can be defined as the digitization of cytology images and transmission of these images via a telecommunication network to a remote viewing location for diagnosis, storage or education. Establishing a telepathology unit will require considerable financial investment. A cost-benefit analysis will have to be done in a feasibility study before a final infrastructure investment decision can be made. Experiences from other countries such as China and Japan shows telepathology can be a medium term solution for histopathological diagnostic limitations. The long-term solution for PNG will always be to have hospital based pathologist but this will not be possible in the foreseeable future.  If a telecytology unit is set up for cervical screening, other diagnostic services will have to be incorporated into this service so that establishing such a unit is cost-effective. For example, using a telecytology-based cervical screening program as the platform, other diagnostic services from fine needle aspiration biopsies will need to be considered such as for probable tuberculous lymph node or breast lumps for investigating breast cancer. A major limitation on the routine use of telecytology in clinical diagnosis has been its low diagnostic accuracy which is affected by field selection (sampling error) and inadequate magnification. These challenges can now be overcome with whole slide digitization systems and a pathologist trained in the use of this technology. With appropriate training and a good quality assurance program, accurate diagnosis and reproducibility can be achieved with telecytology systems.

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