About Cervical Cancer

Abstract:

Cervical cancer is the second most common cause of cancer death in developing countries. The cause of cervical cancer is the human papilloma virus (HPV). Cervical cancer has other risk factors, like: having multiple male sexual partners, starting to have sexual intercourse at an early age, having other sexually transmitted disease, having weak immune system and smoking.

Cervical cancer can be prevented by avoiding risk factors and undergoing regular screening tests. The most common methods used in cervical screening are Pap testing and HPV testing.

World Health Organization estimated that about 510,000 new cases of cervical cancer were diagnosed yearly. HPV testing is used as a primary screening method in some developed countries. Fewer amounts of tests required and better cost efficiency can be achieved by doing HPV testing first and Pap testing as a second test. Some studies suggested that HPV testing might be the effective cervical screening method and other studies did not suggest that. The study “HPV Screening for Cervical Cancer in Rural India” indicated that HPV testing was the most objective and reproducible of all other cervical screening tests. It seems to be a good study with well designed methodology and reliable results and conclusions, but it was criticized by R Marshall and Chengquan. They showed clearly that the study marred by test group biases and ethical concerns. More well designed studies are needed to clarify this issue and to show which method is proper to that country or to this geographical area.

Introduction:

Cervical cancer is the cancer of the lowest part of the uterus, which is known as cervix. Cervical cancer is very slow growing, but in some cases it can grow and spread quickly (Dolinsky & Hill-Kayser, 2009).

There are many types of cervical cancer. The most common type is called squamous cell carcinoma (figure 1), which found in about 80% of cervical cancer cases, whereas adenocarcinoma is the second most common type of cervical cancer (Dolinsky & Hill-Kayser, 2009). Cervical cancer is more common in developing countries than it is in developed countries. It is the second most common cause of cancer death in developing countries. It can affect young women who are 20 years old or some time younger than that (Dolinsky & Hill-Kayser, 2009).

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The cause of cervical cancer is the human papilloma virus (HPV) (figure 2) which was discovered by Harald zur Hausen who won the Nobel Prize in 2008 for this discovery (Nobel Prize organization, 2009). This virus is a sexually transmitted virus. It can cause genital warts which may or may not change to a cervical cancer (Dolinsky & Hill-Kayser, 2009).

The subtypes of HPV which have been confirmed to cause cervical cancer are 16, 18, 31 and 33 (Murray et al., 1998; Dolinsky & Hill-Kayser, 2009). Other researches suggested that subtypes 35 and 45 also can cause cervical cancer (NHS cancer screening programmes, 2009). A woman has HPV infection does not mean that she is going to have a cervical cancer (Dolinsky & Hill-Kayser, 2009).

Other risk factors for cervical cancer are: having multiple male sexual partners, starting to have sexual intercourse at an early age, having other sexually transmitted disease (herpes, syphilis, gonorrhea or Chlamydia), having weak immune system (HIV, organ transplantation or Hodgkin’s disease) and smoking (Dolinsky & Hill-Kayser, 2009).

The early stages of this disease usually do not have any symptoms, but as tumor increase in size, some non-specific symptoms for cervical cancer will occur, like: abnormal bleeding, abnormal vaginal discharge, pelvic or back pain, pain during urination and bloody stool or urine (Dolinsky & Hill-Kayser, 2009).

Cervical cancer can be diagnosed by Pap testing, HPV testing, liquid-base cytology and by taking a biopsy during Colposcopy. The biopsy is the only way to be sure if the patient has a cervical censer. Radiologic testing may also help in the diagnosing of this disease (Dolinsky & Hill-Kayser, 2009).

Cervical cancer can be treated by Surgery, radiotherapy and chemotherapy (Dolinsky & Hill-Kayser, 2009). It can be prevented by avoiding risk factors which have been discussed previously and undergoing regular screening tests (Dolinsky & Hill-Kayser, 2009).

In Islam religion for example, smoking and any sexual relationship not done between wives and husbands (reducing sexually transmitted diseases) are strictly forbidden, this can reduce the chance of having cervical cancer within Muslim societies (Adam, 2009). In addition, male circumcision which is a part of Islam religion has found to be a good factor in cervical cancer prevention as researches have found that the wives of circumcised men have less risk of getting this disease than the wives of uncircumcised (Mission Islam, 2009).

Moreover, many countries have started to do cervical cancer screening to diagnose this disease in its early stages. Pap testing (cytological testing), HPV testing and liquid-base cytology can be used in this screening programs which will be discussed later (Kufe et al., 2003; Jamison et al., 2006).

Now a day, the vaccine Gardasil is used to prevent cervical cancer in women who are not exposed to HPV (Dolinsky & Hill-Kayser, 2009).

This study is aimed to discus the importance of HPV screening in the control of cervical cancer and clarifies the most appropriate method for cervical cancer screening.

The Global Burden of Cervical Cancer and the Available Methods for Controlling the Disease:

Cervical cancer is the second most common cancer among females worldwide with about 493,000 new cases and 274,000 deaths in 2002. Cases occur in developing countries are estimated to be about 83% (Bosch et al., 2009). Thomas Rohan and others stated that opportunities for cervical cancer prevention have been created by our understanding of the cause, particularly the role of HPV infection (Rohan et al., 2003). In addition, World Health Organization estimated that about 510,000 new cases of cervical cancer were diagnosed yearly. In Africa, about 68,000 new cases are reported every year, whereas 77,000 new cases are reported in Latin America and 245,000 in Asia (Pagliusi, 2009).

In United Kingdom, about 25.51 millions females who are 15 years old are at risk of having a cervical cancer during their life. This kind of cancer is ranked as the 11th most common cancer in females in UK and the 2nd most common cancer in females between 15 and 44 years old. In addition, about 8.9% of females in the population of UK are estimated to have HPV infection at a given time. Currently in UK, it is estimated that about 3181 females are reported with a cervical cancer yearly and about 1529 deaths (Bosch et al., 2009).

Many researches suggested that the decline in incidence and mortality of cervical cancer which have been observed in the last 50 years in developed countries can be related to the introduction of screening programs (Kufe et al., 2003).

The most common methods used in cervical screening are Pap (cytological) testing and HPV testing (Kufe et al., 2003). The most widely used method in the world is the Pap testing. This method is simple, cheap and some times is used as a secondary screening method. It basically involves exfoliating epithelial cells collection from the squamocolumnar junction of cervix or transformation zone (Walker et al., 1990; Kufe et al., 2003).

In addition, HPV testing is used as a primary screening method in some developed countries. It is used mostly to distinguish between a high risk women group and others (Kufe et al., 2003).

The study of Joakim Dillner and others suggested that HPV testing as a screening method is safe and effective when it is done every six years (Dillner et al., 2008) and it should be done for women who are 30 years old or older because they are typically past the peak age of self-limited infection (Castle, 2008).

HPV DNA testing might be a more clinically effective method than cervical smear, but its specificity is low because it could lead to unnecessary repeated screening and follow up (Nelson (I), 2009).

Fewer amounts of tests required and better cost efficiency can be achieved by doing HPV testing first and Pap testing as a second test (Medscape Medical News, 2009; Nelson (I), 2009).

Existing Randomized Controlled Trails Investigating the Use of HPV Testing in the Control of Cervical Cancer:

Many randomized controlled trails have been done to investigate the use of HPV testing in the control of cervical cancer. Some studies suggested that HPV testing might be the effective cervical cancer screening method (Grce and Davies, 2008; Rebar, 2008; Nelson (II), 2009). On the other hand, other studies suggested that HPV testing does not improve cervical cancer screening (Brown, 2009; NHS cancer screening programs, 2009).

In Italy, the second recruitment phase of the study titled: New Technologies for Cervical Cancer Screening (NTCC), women to conventional cytology (24,661 women) with referral to colposcopy if cytology indicated a typical squamous cells of undetermined significance or more sever abnormality or to HPV DNA testing alone by Hybrid Capture 2 (24,535 women) with referral to colposcopy if the test was positive at a concentration of HPV DNA 1 pg/mL or greater were randomly assigned. It has been concluded that HPV testing with a cutoff of 2 pg/mL achieves a substantial gain in sensitivity compared to cytology with only a small reduction in Positive Predictive Value among a group of women aged 35 to 60 years. In contrast, for women aged 25 to 34 years, it is suggested that there is a frequent regression of CIN2+ that is detected by direct referral of younger HPV testing-positive women to colposcopy as a result of the large relative sensitivity of HPV testing compared with conventional cytology (Ronco et al., 2008).

In addition, the results from a 6-year prospective study in Rural China demonstrated that a single oncogenic HPV DNA testing is more effective than cytology in predicting future CIN2+ status (Shi et al., 2009).

The study “Human Papillomavirus DNA versus Papanicolaou Screening Tests for Cervical Cancer” which was done in Canada, conducted a randomized trial comparing the two methods, found that HPV testing has greater sensitivity than Pap testing for the detection of cervical intra-epithelial neoplasia (Mayrand et al., 2007).

The Population Based Screening Study Amsterdam (POBASCAM) which is a population based randomized controlled trial for implementation of hrHPV testing by GP5+/6+ PCR-enzyme immunoassay (EIA) with a classical cytology as a control group was done between January 1999 and September 2002. It was done among 44,102 women aged between 29 and 61 who participated in the regular Dutch screening program. This study (POBASCAM) indicated that large scale hrHPV testing is accepted by both participating women and general practitioners, is practically feasible and yield highly reproducible results (Bulkmans et al., 2004).

In 1997, a 10-year study “Randomized Controlled Trial of Human Papillomavirus Testing in Primary Cervical Cancer Screening” (SWEDESCREEN) was started. This study aimed to investigate whether HPV-based cervical cancer screening which is known to increase sensitivity for detection of high grade cervical intraepithelial neoplasia (CIN) is represent overdiagnosis or a protective effect. It included 12,527 women aged between 32 and 38 years and were randomized (1:1) to HPV testing and cytology testing (intervention arm) or cytology only (control arm). Its conclusion indicated that HPV testing with a cytology testing is more sensitive than cytology testing alone (U.S. National Institute of Health, 2009).

In another study, titled “Randomized Controlled Trial of Human Papillomavirus Testing Versus Pap Cytology in the Screening for Cervical Cancer Precursors”, the Canadian Cervical Cancer Screening Trial (CCCaST), randomized women aged between 30 and 69 years were categorized in to Pap testing group and HPV testing group. The findings at recruitment phase of this study indicated that HPV testing is more sensitivity and less specificity than Pap cytology testing (Mayrand et al., 2006).

An Overview on the Methodology, Results and Conclusions of the Study: “HPV Screening for Cervical Cancer in Rural India”:

Rengaswamy and others began their study “HPV Screening for Cervical Cancer in Rural India” in 1999 and finished after 8 years. In this study, 52 clusters of villages with a total of 131,746 healthy women aged between 30 and 59 years were randomly assigned to 4 groups of 13 clusters each. These groups assigned to go through screening by:

1. HPV testing group (34,126 women) (27,192 were screened and 2812 (10.3%) had positive results).
2. Cytology testing group (32,058 women) (25,549 were screened and 1787 (7.0%) had positive results).
3. Visual Inspection of the Cervix with Acetic Acid (VIA) group (34,074 women) (26,765 were screened and 3733 (13.9%) had positive results).
4. Standard care group (control) (31,488 women) (not offered screening but were advised on how to seek screening) (only 1946 (6.2%) requested screening and that means (93.8%) stayed without screening.

Women who had positive results went through colposcopy and biopsies were taken and those with cervical precancerous lesions or cancer received appropriate treatment (Sankaranarayanan et al., 2009).

The results of this study showed that: 

1. In HPV testing group: cervical cancer was diagnosed in 127 women and 34 deaths occurred.
2. In Cytology testing group: cervical cancer was diagnosed in 152 women and 54 deaths occurred.
3. In VIA group: cervical cancer was diagnosed in 157 women and 56 deaths occurred.
4. In Control group: cervical cancer was diagnosed in 118 women and 64 deaths occurred.

In addition, this study indicated that of the 131,806 women, 60 died or migrated before the study began. The study groups were equally distributed in terms of household type, religion, occupation, marital status and number of pregnancies. The well balanced study will help to remove any biases to any group of the study. The results of this study showed also:

1. Invasive cervical cancer developed in 8 (0.033%) of 24,380 HPV negative results women.
2. Invasive cervical cancer developed in 22 (0.093%) of 23,762 cytology negative results women.
3. Invasive cervical cancer developed in 25 (0.109%) of 23,032 VIA negative results women (Sankaranarayanan et al., 2009).

The protocol of this study was reviewed and approved by the scientific and ethical review committees of the International Agency for Research on Cancer (IARC), the Tata Memorial Center (TMC) and the Nargis Dutt Memorial Cancer Hospital (NDMCH). It was supported by the Bill and Melinda Gates Foundation through the Alliance for Cervical Cancer Prevention (Sankaranarayanan et al., 2009).

This study concluded that a single round of HPV testing was associated with a significant decline in the rate of advanced cervical cancers and associated deaths compared with the unscreened control group, whereas there was no significant reduction in the rate of death in either the cytology testing or the VIA group compared with the control group. Previous conclusions indicated that HPV testing was the most objective and reproducible of all other cervical screening tests (Sankaranarayanan et al., 2009).

This study seems to be a good one with well designed methodology and reliable results and conclusions, but it is clear that about 93.8% of the control group did not do any cervical screening during the 8 years which may raised an ethical issue might affecting the approval of this study if it was done in different country.

Further more, the courses and training period given to different staffs who participated in this study may be not enough to give them good experience in order to have less chance of error during the diagnosis.

An Overview on the Criticizing Article Titled: “Test Group Biases and Ethical Concerns Mar New England Journal of Medicine Articles Promoting HPV Screening for Cervical Cancer in Rural India”: 

A few months after the publication of previous study, R Marshall and Chengquan had criticized it. They suggested that unexpected biases might have occurred in some of the test groups of the study. The study stated that “the positive predictive value for detecting CIN 2-3 was 19.3% in the cytology testing group, higher than 11.3% in the HPV testing group and the study results indicated that essentially the same number of cervical cancers was detected after positive screening test results in the cytology group (88 women) and in the HPV group (87 women)” (Austin & Zhao, 2009).

Also, they observed that in the report of 2005, this study indicated that the detection rates of HPV testing did not show any improvement over cytology, but its conclusion of 2009 indicated different findings (Austin & Zhao, 2009). I think this is not a problem as findings and conclusions of scientific studies usually change over time.

In addition, of 54 cervical cancers related deaths in the cytology group, 27 deaths were in the “assigned but not screened” group and another 18 deaths were in patients who had abnormal cytology results. In HPV group, 19% fewer cervical cancer deaths (22 women) were in the “assigned but not screened” group and 33% fewer deaths (12 women) occurred in women with abnormal HPV testing results. These data supported the hypothesis that biases were introduced in the study groups. (Austin & Zhao, 2009). I think it is possibly true, because these data can show that the follow up and treatments were not equally effective in the two groups. So, even when cytological detection is successful, women can still die from cervical cancer due to inappropriate management.

In addition, these data also can show that the effectiveness of cytology as a cervical screening method is depended on its acceptance by women. 

R Marshall and Chengquan have raised questions about the partnership between AACP’s coordinating organization and the HPV test manufacturer (Austin & Zhao, 2009). I think this partnership if it is real, it can affect the final results and conclusion in way that show the advantages of HPV testing in order to increase the income of the manufacture.

Also they stated that it is not fare to allow a large number of control group to go without any screening during the study (Austin & Zhao, 2009). I think it is true that it is not fare to leave women in the control group without any screening and this can lead to ethical concerns.

In addition, cytology screeners were trained for only three months, which was very short period. They concluded that cytology screening is better than HPV screening according to the results of the previous study (Austin & Zhao, 2009).

In my opinion, the criticizing letter might be in the correct direction. From a brief reading and viewing of the study, the reader might believe that its finding indicated that HPV testing as a cervical cancer screening method is better than other tests, but deep reading will show him the limitation errors of this study which were firstly published by R Marshal and Chengquan. They showed clearly that the study marred by test group biases and ethical concerns. The study might try to cover and exclude some facts which can show that cytology testing was better than HPV testing.

Use or Not to Use HPV Testing as a Primary Screening Test for Cervical Neoplasia:

It has been argued that HPV testing is the best method for cervical cancer primary screening. I think that HPV testing is a good method to be used in cervical cancer primary screening in developing countries as well as in developed countries to reduce the incidence and mortality rates of cervical cancer. Studies which concluded that HPV testing is better than cytology testing are more than those which showed the opposite.

The high cost of HPV testing can be overcome by the support of WHO and privet sector companies in these developing countries. Also, the high cost of HPV testing can be overcome by the selective use of HPV testing, e.g. in the over 30s.

Many studies suggested that Human Papillomavirus is found in most of cervical cancer cases if not all. So, the use of HPV DNA testing in a well designed screening program may help in diagnosis early stages of cervical cancer, giving better chance for treatment compared with Pap testing which may give false negative results.   

In conclusion, it is clear that different results and findings were gathered from different studies which try to find the proper method for cervical cancer screening. These differences may be occurred because the studies done in different countries. And is it known that each country has its own geography, rate of mortality, rate of incidence and other factors which may affect the burden of cervical cancer disease.

So, more well designed studies are needed to clarify this issue and to show which method is proper to that country or to this geographical area in order to save women’s lives.

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