Paper 5 Short Communication
2.15 Alternative cervical cancer screening tools to cytology
While the Pap smear is known to be an effective tool for the prevention, detection and management of cervical cancer it is not the most accurate test due to sampling errors and diagnostic errors (DeMay 1997; DeMay 1996) For a Pap smear to be a valuable tool in the diagnosis of cervical cancer, the following steps need to be followed: the smear needs to be properly collected so that it is well preserved and adequate (having the correct representation of cells from the cervix). Thereafter, the smear must be properly prepared or stained for cytological assessment and finally it must be correctly diagnosed by the cytologist (DeMay 1997). Three common diagnostic problems are that results from smears are issued without them being fully representative, or result are issued from an unsatisfactory smear and the issuing of
“false negative” results (DeMay 1997). Cancer could be missed on a Pap smear if there are only few cells present or compared to the biopsy which is the gold standard, lesions may not be within reach of the sampling device used (Koss 1993). Cytology as a discipline requires concentration since screening many slides can lead to fatigue and human error (Koss 1993).
Another common problem is the fact that there is a shortage of cytologists, and the capacity to provide results within a short period of time is limited in developing countries. Furthermore, it is a huge challenge in developing countries to get a woman to have a Pap smear, and expecting her to return for results after some time is also problematic. Not being able to interpret the cells correctly is another source of error. There are however, some alternatives to conventional cytology in addition to LBC cytology, which are available, and these include options such as visual examination and HPV testing and vaccination.
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HPV DNA tests and genotyping: HPV originates from the papilloma virus family, there are several HPV types which have been identified in humans (Bibbo and Wilbur 2008). Some of these cause no symptoms in humans while others are sexually transmitted and potentially carcinogenic. Viral particles enter the body via small abrasions on the skin or mucous membranes. Viral replication occurs mainly in the nucleus, but the effects are seen in both the nucleus and cytoplasm. On the vulva, HPV causes multiple, warty, cauliflower-like (verrucous) lesions (Bibbo and Wilbur 2008). Histologically, HPV causes proliferation and thickening of the squamous epithelium. In the genital tract the following types of lesions have been identified:
subclinical papillomavirus infection: flat warts, exophytic warts/ condyloma acuminatum, endophytic warts (Bibbo and Wilbur 2008).
With the discovery that HPV is central to the development of cervical cancer, scientists have been developing molecular diagnostic tests for detecting HPV (Walboomers et al. 1999). There is potential for HPV testing in screening programmes, both as an adjunct to cytological screening and in primary screening (Schiffman et al. 2007). The proposed uses of HPV testing in cervical cancer prevention programmes include the identification of HPV in areas where Pap smear findings show ASCUS (cells that are atypical but not definitely dysplastic) and to test for high-risk types of HPV so that such women may be identified, monitored and treated accordingly. In addition, testing may be used as a means of surveillance for women after treatment for high grade lesions (Schiffman et al. 2007).
HPV genotyping is an important tool in determining the oncogenic potential of the virus. Many strains of HPV, types 16, 18, 31, 33 and 45, are thought to have a high oncogenic potential (Clifford et al. 2006). The worldwide prevalence of HPV in cervical cancer is 99.7%, and the association of so-called high-risk (likely oncogenic) HPV with cervical cancer makes HPV the highest attributable factor that is specific for any major human cancer (Walboomers et al. 1999).
A global review conducted to assess the age specific prevalence of HPV in females, found that the most high-risk oncogenic HPV are types 16 and 18 (Louie, De Sanjose and Mayaud 2009).
HPV vaccines have been developed and are aimed at protecting against oncogenic strains of HPV with the stimulation of antibody production among humans. The introduction of HPV vaccines in developing countries where cervical cancer is a huge burden could be a possible solution, however HPV vaccination is only effective in prevention among women who have no present or past HPV infection. HPV vaccination would therefore be more effective in pre- adolescent girls (Cutts et al. 2007).
Molecular Markers p16: Immuno- markers may be used in order to identify oncogenic strains of HPV that are likely to progress, thus preventing over treatment or misdiagnosis by using the Pap diagnosis only (Lesnikova et al. 2009). The diagnostic test for the immune-marker p16 can be conducted on LBC samples as can the HPV DNA testing. HPV has been established as the common causative agent in cervical cancer since it is able to alter gene or protein expression in the host cells. There are different strains of HPV, some have a high risk oncogenic potential which results in cervical cancer. Two proteins caused by high risk HPV infection are E6 and E7 (Saqi et al. 2002). E7 binds to the retinoblastoma gene product (RB) resulting in its functional inactivation. The E7 HPV oncogenes inhibit the effect of tumour suppressive proteins, protein P53 and RBp respectively thus increasing the risk of mutations. Since the p16 is under negative feedback control of functional RBp, overexpression of the p16 gene occurs in cells infected by high risk HPV (Cuschieri and Wentzensen 2008). Because the p16 protein is detectable by immunocytochemistry it is a surrogate marker for HPV since this protein is not expressed in normal tissue (Lesnikova et al. 2009). It is observed in the nucleus and the cytoplasm of cells. In young populations, such as the present study population such an assay may be of value in identifying those young women with high risk for cervical cancer.
Visual inspection with acetic acid (VIA): Visual examination instead of cytology as the initial screening technique has been implemented in areas where resources are particularly scarce (World Health Organization 2012). The method entails a primary health care worker carrying out a visual examination of the cervix, using a speculum cervix which is swabbed with acetic acid, abnormal areas react with the acid and turn white. Once identified, these areas can be treated with cryotherapy or biopsy. This approach is advantageous since it is a “see and treat”
approach. One of the limitations to this approach is that it is not always accurate in identifying pre-cancerous conditions. It has been found that VIA is promising in low-resource settings since it is a relatively simple, “low-tech” approach that is minimally dependent on infrastructure for its adequate performance, provided that treatment services are in place. Due to low cost, easy applicability and immediate results, it has been suggested that VIA could be a useful screening test in developing countries compared to Pap smear screening (World Health Organization 2012). Over-treatment may result in additional health risks to women as well as overburdening the health care system. VIA is less effective for screening women in their fifties because of the tendency for the squamo-columnar junction to recede into the cervical canal, making observation more difficult. Despite these drawbacks it is recommended that VIA be considered as an option for identifying pre-cancerous lesions in many settings, either in conjunction with or as an alternative to other screening approaches.
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