Cervical cancer as malignant tumor and the classification of cervical cancer according to WHO also focused on risk factor by HPV as main cause and type of it.
Methods: Epidemiological distribution of disease and methods used in detection of HPV like, Pap cytology screening, HPV testing. Evaluate the efficacy of HPV testing as a primary screening tool in cervical cancer screening trails in Canada, Italy. Sweden, UK and the merits of HPV testing
Result: I evaluated the previous study in their result in screening trails and discuss their finding in HPV test Pap test and compared the sensitivity, specificity with Pap cytology screening test.
Conclusion: HPV test may be a critical screening test and could emerge a good predictive value in the future.
Cervical cancer is a malignant neoplasm of the cervical uterine or cervical area. It could present with vaginal bleeding but with symptomless occasionally until the cancer is in its advanced stages. Treatments contain a surgery in early stages and chemotherapy and radiotherapy in late stages of diseases (Kumar et al., 2007). However, the classification of cervical cancer has been change according to world health organization WHO to mild
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, moderate, and severe dysplasia or carcinoma in situ. The term, cervical intraepithelial neoplasia was progressed to involve on the spectrum of abnormality in these lesion. It classifies mild dysplasia as CIN1, moderate dysplasia as CIN2 and severe dysplasia as CIN3.However, the most recent classification is Bethesda system which divided all cervical precursor lesion into two groups , low grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL) (Demay ,2007).
As recent scientific studies show that the most important risk factor and main cause of cervical cancer is infection with human papilloma virus. It is a member of the papillomavirus family of viruses that enable of infecting human. HPVs establish productive infection only in stratified epithelium of the skin or mucous membrane, while the majority of the nearly 200 known types of HPV cause no symptoms, some types can cause wart (verrucae) , while others in minority of cases lead to cancers of cervix, vulva, vagina and anus in women or cancers of anus and peins in men (Schiffman & Castle, 2003). Moreover, as scientific papers illustrate that sexually active young men and women have the greatest risk of acquiring HPV. In addition, most types of HPV infect the mucosal and genital tract especially basal keratinocytes through micro abrasions in the skin or mucosa ; with viral DNA replication, the copy number of the virus is amplified to approximately 50 to 100 copies per cell ( Munoz et al ., 2006) .The initial genome amplification is followed by an episomal maintenance phase. Infected basal cell then enter the superabasal compartment, where abundant expression of early and late genes and productive genome amplification to high copy numbers is triggered in the terminally differentiating compartment, viral assembly occurs in the upper layer of the squamous epithelium, and then released and may infected adjacent tissue (Stanley, 2008).HPV type 16 and 18 cause approximately 70% of cervical cancers world wild. In contrast there is a cofactor related to the development of cervical cancer such as cigarette smoking , age , presence of other sexually transmitted diseases, and immune suppression (David et al ., 2008).
On the other hand, HPVs viral have sequence integrated into the cellular DNA. Some of the HPV early genes such as E6 and E7 are well define to act as oncogenes that promote tumor growth and malignant transformation (Ridge et al., 2008).In addition to that , the screening program of most cervical cancer is currently based on Pap smear that have ranging in sensitivity and specificity between 3%-70% and 86%- 100% respectively (Magdalena&Philip,2008).However, in terms of clinical efficacy , neither the incidence of invasive cervical cancer nor the rate of death due to cervical cancer many articles focused on the assessment as a trail end point for vaccines as preventing tool they developed two vaccines that were Gradasil and Cervarix (Jessica &Khan, 2009).
Figure 1: illustrates life cycle of human papilloma virus in the sqamous epithelium (Jessica &Khan).
Figure 2 : shows histology/ cytology correlation of cervical biopsy and Pap smear [Google images.co.uk, 2010]
The global Burden of Cervical cancer:
Cervical cancers represent a significant public health concern worldwide, it is the second most common malignancy among females in the United Kingdom. The rate of cervical cancer is highest in the Yorkshire and North West regions of England, Scotland. However, it's lowest in Eastern, South East and London regions, a recent report focused on the link between socioeconomic deprivation and inequalities in cervical cancer mortality in London. This relationship is consistently replicated even when controlling for access to medical care (Laura et al., 2990).Moreover, this type of tumor epidemiologically take about 80% of cervical cancer cases that occur in developing countries as scientific data published . Although the age standardized incidence rate is significantly lower in Asia than in central America, Asia account far more than half of the world cervical cancer cases and deaths due to its extensively population. However, the incidence and mortality rates were decreased dramatically in developed countries in past 25 years because of the screening program using Pap smear test (In addition to that as prior scientific papers illustrates that the highest incidence rates in South America and the Caribbean, Sub-Saharan, Africa and, Southern Asia , but the increasing of cervical cancer on developing countries is due to mainly lack of resources for cervical screening (Michael et al ., 2009).Many articles demonstrate that the mapping of uterine cancer mortality among 45 years indicates that the burden of cervical cancer is particularly high across the whole of Eastern Europe therefore they need specific attention from the health authorities of the countries concerned and the EU as a whole (Arbyn et al., 2007).
Methods used to detect cervical cancer:
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Recently there is a different types of methods have been used to detect cervical cancer for instance Pap smear test as screening program , according to scientific data demonstrate that this test is far from a perfect screening test as is highly subjective in recognition of cytological abnormalities with ranging in sensitivity and specificity between 30% -87% and 86%- 100% respectively. The use of liquid-based cytology (LBC) and automated screening can lead to reduce the rate of false negative as well as the time taken to screen samples but without a loss of test specificity. However, the LBC test is cost more than the conventional Pap smear but this is compensated for by reductions in inadequate samples, repeat test and screening time together with the ability to perform additional test from the same cervical specimen (Magdalena & Philip, 2008)
As far as I concern cytological screening program are play vital role in decrease the incidence of cervical cancer in countries with organized screening. However, Europe in 1995 there stills an estimated 68,000 incident cases. Thus cytological screening has limited reproducibility in both meta-analyses and pooled analysis in testing of HPV which have higher sensitivity than cytology in detecting high grade cervical intraepithelial lesion (CIN), and that combined HPV and cytology testing has high negative predictive values for CIN regarding to previous data published (Joakin et al ., 2008).
Although there is a close relation between the infection with oncogenic HPV types and the progress of cervical intraepithelial neoplasia (CIN) and cervical cancer. DNA testing for onocogenic HPV types has been proposed for primary screening, either alone or combination of cytology, Pap smear, and it is useful for surveillance and management of patients after coloscopy. Introducing of HPV DNA test in screening programme with in national organized cervical cancer will gain benefit from it especially in high grade cervical lesions (CIN2, CIN3) and invasive cancer ( Marrit et al ., 2009) .
On the other hand the efficacy of HPV testing in primary screening has shown that higher sensitivity but lower specificity for the detection of CIN2 or higher (CIN2â€ ) compared with conventional cytology. The high sensitivity and high negative predictive value of HPV DNA testing for demonstration high-grade cervical lesions suggested that it could be extended screening intervals. However, the low specificity of HPV DNA test alone may conduce to rise numbers of follow-up test and colpscopy referrals that can increase the adverse effects of screening (Marrit et al., 2009).In addition, recent advance molecular biology for HPV testing has been proposed as primary screening test for cervical cancer, because of high detection rate that recommended for women aged over 30 combined with cytology (DNA Pap test) as prior scientific paper illustrated that (Wong et al ., 2008). Moreover. In term of merits the researcher found that an alternate strategy increased sensitivity, primary screening with DNA testing followed by cytological triage and repeat screening for persistent HPV type-specific infection had a considerably higher sensitivity for detecting high-grade neoplasia. Therefore, will become more important as use of the new vaccines, another benefit is that can track HPV infection over time as the vaccine comes into wider use also it be most effective methods of cervical cancer screening in low-resources setting it could reduce the incidence of invasive cervical cancer (Roxanne, 2009).
On the other hand, cervical cancer is highly amenable to screening because it has long preclinical phase with precursor lesions that can be identified by screening (Magdalena & Philip, 2008). However, large randomized trials are critical to investigate the value of incorporation HPV detection in population-based cervical screening programmes (Bekkers et al., 2006)
Randomized Trial In Italy (NTCC):
New technology for cervical cancer (NTTC) is a screening program for HPV in Italy. All women involved this study in aged group between 35-60 years. In this randomized trail they compared screening with conventional cytology with screening by HPV testing combination with liquid base cytology. In second phase of randomized trail they randomly assigned women to conventional cytology (n=24661) if cytology indicate any abnormality like a typical squamous cells or high risk of HPV, they referred to colposcopy and they did testing for HPV alone by Hybrid capture 2 (n=24535) with referral to colposcopy when the test was positive at concentration of HPV DNA 1 Pg/ml or greater .However. They investigated all cases histologically for cervical intraepithelial neoplasia of grade 2 or more (CIN2) then they calculated and compared sensitivity and positive predictive value (PPV). They found that HPV testing for detection of CIN2â€ at a cut off 1 Pg/ml vs conventional cytology was 1.92 (95% CI=1.28 to 2.87) and the relative PPV was 0.80. However, at the cut off 2Pg/ml HPV DNA, the relative sensitivity was 95% and the relative PPV was 95%. Therefore, in this group there was no evidence of heterogeneity between study phase.
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Although through women aged 25-60 the relative sensitivity for detection of CIN2 of HPV testing at cut off 1Pg/ml vs cytology was (95% CI=2.11-5.82), slightly larger (p=.019) than that observed in phase 1 at this age. Thus they achieved a substantial gain in sensitivity over cytology with only a little reduction in PHV that among women aged 35-60 years.
However, there is a large relative sensitivity of HPV testing compared with conventional cytology and the difference between relative sensitivity during phases 1&2 suggested that there is frequent regression of CIN2â€ that are detected by direct referral of younger HPV positive women to colposcopy . They conclude that HPV DNA- based approached to primary screening is a very useful option that should be actively progressed and assessed (Guglielmo et al., 2009).
Randomized Trail In Canada (CCCaST):
The Canadian cervical cancer screening trail focused on the false negative rate of Papanicolaou cytology which is an important issue and introduced DNA testing for DNA of oncogenic human papilloma virus could be crucial. The aim of this experiment to compare the performance (sensitivity, specificity, positive and negative predictive values) of HPV testing vs. They used CCCaST which is a randomized controlled trail (RTC) that compares HPV testing with Hybrid capture 2 and conventional Pap cytology as screening interventions to clarify intraepithelial high-grade cervical intraepithelial among women aged 30- 69 years in Montreal. They found that the sensitivity of HPV testing was higher (94%, 95%) than that of Pap cytology (55%, 95%) with a slightly lower specificity (Pap 96%.8, 95%) in HPV test (94%, 95%) specificity. In the light of this investigation they reached to the benefit from both test. However, HPV DNA has greater sensitivity compared to cytology and they recommended using HPV DNA in cervical screening cancer (Mayrand et al., 2007).
As far as I concern the scientific paper which have done in Rural India based on HPV screening for cervical cancer (Rengaswamy et al ., 2009). They used 52 clusters of village with total of 131,746 healthy women between ages 30-59 years, were randomly assigned to four groups of 13 clusters each. Each group did different screening, HPV (43,126 women), cytological testing (32,058) or visual inspection of the cervix with acetic acid (VIA) (34,074) or to receive standard care (31,488) control group, women who had positive results on screening underwent colposcopy and direct biopsies appropriate treatment, they prepared staff for training for nurse, doctors and technicians as well, they found that there were 34 death from cervical cancer in HPV testing group, 54 in the cytological testing group, 56 in the VIA group, and 64 in the control group .
As far as I concern the scientific paper which have done in Rural India based on HPV screening for cervical cancer (Rengaswamy et al ., 2009). They used 52 clusters of village with total of 131,746 healthy women between ages 30-59 years, were randomly assigned to four groups of 13 clusters each. Each group did different screening, HPV (43,126 women), cytological testing (32,058) or visual inspection of the cervix with acetic acid (VIA) (34,074) or to receive standard care (31,488) control group, women who had positive results on screening underwent colposcopy and direct biopsies appropriate treatment, they prepared staff for training for nurse, doctors and technicians as well, they found that there were 34 death from cervical cancer in HPV testing group, 54 in the cytological testing group, 56 in the VIA group, and 64 in the control group ( Rengaswamy et al ., 2009).
Randomized Trail in UK (ARTISTIC):
In the UK, a randomized trial in screening to improve cytology (ARTISTIC) was conducted within the routine national cervical screening program, to evaluate the effectiveness of HPV testing for primary cervical screening ,to evaluate the effectiveness of HPV testing for primary cervical screening (Magdalena & Grce , 2008). In this trail , women aged 20-64 years were screened with LBC and HPV testing (HC2) at entry, the prevalence of moderate dyskaryosis was found to be 20-30 times higher and sever dyskaryosis was over 100- times higher in HPV positive women compared with those who were HPV negative (Magdalena & Grce , 2008). Although the majority (87%) of women aged under 38 year with mild dyskaryosis were HPV positive , the proportion dropped down to 58% for those aged 30 49 years and to 28% for those over 30 years ( Kitchener et al ., 2006). The study also illustrated that 96% of women with sever dyskartyosis or worse and 86% of those with moderate dyskaryosis were HPV positive , whereas HR-HPV prevalence ranged from 18.5% in women aged over 30-34 years to 6.0% in women over 55 years with the author sum up that HPV testing would be practicable for routine primary screening of women aged over 30 years( Magdalena & Grce , 2008 ).
Randomized Trail in Sweden (SWDENSCREEN):
In Sweden screen trail they tend to evaluate primary cervical screening with both HPV DNA testing and cytological examination of cervical cells with a Pap test ( cytology) screening strategies that use HPV DNA testing as the primary test may be more effective ( Pontus et al ., 2009). They used the database from the intervention arm of population based randomized trail double screening with cytology and HPV DNA testing to assess the efficacy of 11 possible cervical screening strategies that were based on HPV DNA testing alone, cytology alone, and HPV DNA testing combined with cytology through women aged 32-38, the main outcomes were sensitivity for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3â€ ) within 6 months of enrollment or at colposcopy for women with a persistent type-specific HPV infection and the number of screening test and positive predictive value (PPV ) for each screening strategy ( Pontus et al ., 2009 ). They compared with screening by cytology alone, double testing with cytology and for type-specific HPV persistence they found that resulted in a 35% rise in sensitivity to demonstrate CIN3â€ , without a statistically significant reduction in the HPV but twice as many screening tests needed, they resulted in reduce PPV compared with cytology" (Pontus et al., 2009). Correlate with cytology , primary screening with HPV DNA testing followed by cytological triage and repeat HPV DNA testing of DNA positive women with normal cytology increased the CIN3â€ sensitivity by 30%, conserved a high PPV and resulted in mere 12 % increase in the number of screening tests. Therefore, primary HPV DNA based screening cytology would be the most achievable cervical screening strategy (Pontus et al., 2009).
In cytojournal paper they argued and excoriated the study in Rural India which show some misleading in their interpretation of data in each arm of study ( Marshall & Chengquan, 2009 ). They discussed the death rate in the HPV-negative group of HPV arm was 0% as compared to 40%.9 among clinically detected cancer patient in the cytology-negative group of cytology arm according to their figure in initial paper table 3. Remarkably the 0% death rate occurred in HPV group despite the fact that 62.5% of HPV test-negative cervical cancer was advanced stage. They animadvert and focused on other outcome differences, the numbers of cervical cancers in both screen -detected groups were essentially the same (HPV 87, cytology 88), more favorable stage IA screen detected cancers were detected in the cytology arm (58) than in HPV (45), also fewer unfavorable stage 11â€ cancers were detected in the cytology arm (10) than in the HPV arm (14). Even after identifying the higher negative predictive value of HPV testing that pointed in table 3 , deaths in the HPV arm were unexpectedly one third lower (12) than in the more stage favorable cytology arm (18). Another carp reported that "the most common from treatment of invasive carcinoma in the intervention arm was radical hysterectomy followed by radical radiotherapy". My opinion based on their argued and it corresponding with cytojournal letter they reported "no data are reported on the extent of similarities or differences in cancer treatment between the test group arms. Personally I believe that there is a significant change and reductions as their data analysis shown in table 4. Another observation in my view in terms of training in cytology screening which were trained only 3 months I think that is no enough and need at least one year intensive cyto screener training . Therefore to introduce accurate data need good quality in all part of study either in training program or in analytic data.
HPV testing seems to be a predictive test which tends to introduce with HPV cytology test as primary screening program. To evaluate the merits and demerits of HPV test we need to compare between the classical screening & HPV test to demonstrate the efficacy of this test.
As the previous paper illustrated that there is benefit gain from this test especially in high grade cervical lesion (CIN2 or CIN3), and invasive cancer also the efficacy of HPV DNA testing in primary screening has shown that higher sensitivity but lower specificity for detection of CIN2 or higher (CIN2â€ ) compared with conventional cytology. The high sensitivity and higher negative predictive value of HPV DNA testing for detection of high grade cervical lesions, they suggested that it could be possible to extend screening intervals. However, the low specificity of HPV DNA test alone may conduce to raise number of follow-up test and colposcopy referrals that can increase the adverse effects of screening. In addition to that, there is a co-relation between the occurrence and progression of CIN and the sensitivity and specificity with age (Marrit et al., 2009)
The HPV DNA test could be a crucial in screening program for human papilloma virus and useful; in interpretation of the molecular of the disease. well organized of data that shown in HPV screening for cervical in Rural India and identify the accuracy of sensitivity and specificity with ethical approval consideration could improve the HPV screening in the future