26 27
Table 1. The Prevalence of the Age, Parity, Early Sexual Activity, and Social Economic Status in Cases and Controls
Risk Factors Cases N=50
Controls N=50 p
Mean SD
Mean SD
Age year 44,22
7,95 39,44
7,27 0,39
Parity 2,92
0,92 2,62
1,26 0,08
Sexual activity 20,52
2,87 20,72
2,94 0,89
Soc-Economic status 2,28
0,67 2,14
0,64 0,06
There were not a signiicant different for those variables p 0,05. So the age, parity, early sexual activity, and social economic status in cases and controls were homogeny.
The average age was 45 ± 8 year, the youngest was 29 and the oldest was 60 years. The wide
variety of age which was recommended by other studies, even there are a case of an 18 years old with cervical cancer stadium III found in Sanglah Hospital Denpasar. Although the trend of the age
decreased in the three last decades but the interval 35-50 years of age was consistent [7,27]. It may be related to the trend of HPV infection by the age and immunity status for speciic age [28,29].
The HPV infection was high in the age of 25, consistent in 25-35 years of age and increased in the age above 35 years old [30]. The L-SIL was most prevalence by year 25-35 [31] and H-SIL by year
over 35 [32,33]. The average parity was 3, the lowest was nuliparous and the higher was 6. That was wide variety of parity in cervical cancer and a similar reported by some studies [26,27,34].
The parity relected of more sexual activity and early sexual activity than labor hazards [30,35]. In addition, the producing of estrogen and progesterone were easy to infect and stabilize the HPV
oncoprotein [36,37]. The average of sexual activity was in the age 21 ± 3 years, the youngest was 15
and oldest was 29 years old. So it looks like the high risk for cervical cancer too. These phenomena related to antigenic of histon in semen [21]
and local immune response to the infection [36]. The middle and lowest of social economic status were found in this study that related to family nutrients
[40] and immune status [41,42]. It was not only lack of quantity but also the quality of micronutrient as zinc, folic acid, cuprum etc [3,30]. Meanwhile for Bali Province, the proile of health showed that
the 10,0 low birth weight, 21,0 lack of chronic calories, the prevalence of struma was 21.5 and nutrient anemia was 63.5 [40].
Based on it can be assumed that almost of the cervical cancer patient were high risk group, especially the lack of immune status.
4. The Prevalence of HPV, HPV Types 16 and 18, and p53 in Cases and Controls.
The distribution of HPV, HPV types 16 and 18, and p53 expression in the cervical cancer and non cervical cancer groups Table 2. In this study found that the prevalence of HPV cases was 84
which consist of 68 HPV type 16, 10 HPV type 18, and 8 other type of HPV. The prevalence was relatively high compared with the other reports in Indonesia, but the HPV type 16 was still the
higher prevalence [41,42,43]. The other reports from abroad found similar prevalence that HPV infection in the invasive of cervical cancer was about 80-90, even 100 [12,13,29]. It may be
related to the usage of the probe and proper technique or the prevalence was really higher. Other interesting result in this study was the prevalence of p53 positive in cervical cancer
which is not quite different. It may be related to the chaos of metabolism in cancer cell [19,44], HPV type [43,45], and cut of point [46]. Cancer cell has the pathologic metabolism itself and the
expression of p53 wild type may be impaired while the natural controlled by ubiquitin still exist [19,44]. HPV types 16 and 18 in Bali may be the variant because of very-very oncogenic. Some
studies reported that the HPV variant was more highly malignant than HPV type 16 [46,47]. If the cut of point change to be 10 [47], the ratio of the prevalence of p53 positive and negative was
logical. While in the controls, the HPV infection prevalence was 56 where is 36 HPV type 16 and 18. It must be carefully because it may be progressively change to be the invasive cervical
cancer for a few years later, event few months.
Table 2.The Prevalence of HPV, HPV Types 16 and 18, and p53 in Cases and Controls
Variables Cases
N = 50 Controls
N = 50 Total
p n
n HPV
positive 42
84,0 28
56,0 70
0,02 negative
8 16,0
22 44,0
30 HPV types 16
and 18 positive
39 78,0
18 36,0
57 0,001
negative 11
22,0 32
64,0 43
p53 positive
26 52,0
8 16,0
34 0,01
negative 24
48,0 42
84,0 66
There were a signiicant different for all variables p 0.05. It were continued to looked out the role of each variable.
Based on the data, the HPV may be infected 5-10 year post menorrhea, high oncogenic sub type of HPV types 16 and 18, and high risk by age of high viral load and persistent for long time.
The low social economic status, improper of nutrient may be caused the low immune response status. The inluence of local culture and some traditional aspect may be the important factors have
to be considered for better prevention. If the incidence of the cervical cancer in Bali about 150- 200 per year and almost of them were invasive and late stadium with lack of education and low
understanding to this disease for those reproductive and productive women will be died for the next view year. It was very bed news for her family and for Bali people at all, especially women.
The Risk of Cervical Cancer in HPV types 16 and 18 Infections
Table 3.The Risk of Cervical Cancer in HPV types 16 and 18 Infections Cervical Cancer
Odds Ratio
Ci 95 p
positive negative
HPV types 16 and 18
positive 39
18 6,03
2,60-15,25 0,001
negative 11
32
28 29
HPV types 16 and 18 increased the risk of cervical cancer 6 times than with out HPV infection. The study found that the risk of cervical cancer in HPV types 16 and 18 infections were 6 times in
the case without HPV infection. The other studies reported that similar results but odds ratio was higher than this study as far as 43.5 for HPV type 16 and 24.8 for HPV type 18 [49,50]. In the abroad
studies, the average odds ratio were 16-20 times for HPV oncogenic high risk group compared to that without HPV infection [34,49,51]. Therefore, the hypothesis that the risk of cervical cancer in
case with HPV types 16 and 18 infections was higher than the case without HPV infection has been proven.
The Risk of Expression of p53 in HPV Types 16 and 18 Infections
Table 4. The Risk of Expression of p53 in HPV Types 16 and 18 Infections HPV types16 and 18
Odds Ratio
Ci 95 p
positive negative
p53 positive
28 6
5,95 2,75-16,29
0,001 negative
29 37
HPV type 16 and 18 infection increased the risk of expression of p53 was 6 times than that with out HPV infection.
The study found that the risk p53 expressions in HPV types 16 and 18 infections were 6 times and 3
times more than the case without HPV infection respectively. The abroad studies reported that the
p53 increased in HPV type 16 infections were 14-26 times [50,52,53]. Some studies found that the high viral load and persistence correlated to the incidence of cervical cancer in situ [21,54].
Therefore, the risk of the detection of p53 expression in the case with HPV types 16 and 18 infections were higher than the case without HPV infection have been already proven.
The Risk of Cervical Cancer in p53 positive
Table 5.The Risk of Cervical Cancer in p53 and pRB positives Cervical cancer
Odds Ratio
Ci 95 p
positive negative
p53 positive
26 24
5,68 2,22-14,52
0,001 negative
8 42
P53 positive increased the risk of cervical cancer 6 times and 4,5 times respectively. This study found that the risk p53 positive increased the risk of cervical cancer were 6 times more
than the case with p53 negative. The other studies reported that the p53 concentration was low in cervical cancer. It related to the natural degradation still worked [29,40], improperly metabolism
of cancer cell [45,55], and the carcinogenesis may be ended [37,51]. Otherwise in precancerous lesions, the p53 was higher than in the invasive cervical cancer [49,51,54]. It can be understood
that during process of the p53 wild type still exist and the oncoprotein E6 in precancerous or pre integration phase was not over expressed. Therefore, the risk of cervical cancer in the case with p53
expression higher than the case without p53 expression have been already proven. Based on the three proven results of this study, the carcinogenesis mechanism in HPV types 16 and
18 infections may be as below: The HPV infected the basal cell caused by α-6 integrin receptor for L1 HPV. The natural life
cycle of HPV followed the cell differentiation. Protein E1 and E2 expressed early and stimulated immunity host response to a both early proteins. Meanwhile, the new viral forming was rolled
by L2 continuing well undergo and immune host response to the L2 was not effective because of the completely virion was in exfoliate supericial cell. The cell was broken by E5 function and
the trauma during sexual intercourse and the HPV become infectious. The natural life cycle was continuing forever and reinfected the basal cell. The E6 and E7 were expressed too but not as high
as and it did not cause the function of p53 wild type to be impaired. Molecularly, instability of gene and immune response were performed. Histopathologically, the cervical lesion were the varieties
of the dysplasia phases. When the viral load 50.000 and low expression of E1 and E2, to propose the integration between viral DNA to host DNA. And after integration, E6 and E7 oncoproteins
over expressed and make E6-p53 and E7-pRB complexes. The complexes formation caused to the degraded of p53 and pRB functions. So the p53 can not control the damage gene, differentiation of
cell, and apoptosis. The pRB-E7 complex caused E2F transcription factor freely and worked itself without any controlled of pRB. In addition, dysfunction of pRB inactivated c-myc
and c-ras that kept the pathological coniguration of DNA. The E2F copied the pathologic gene or cervical cancer
gen. Therefore the carcinogenesis of cervical cancer in HPV types 16 and 18 has been elucidated.
5. Conclusion and Recomendation
