Ayşe Didem Esen*, Alparsalan Baksu and Nimet Göker
Corresponding Author: Ayşe Didem Esen, Cemil Tascıoglu City Hospital, Department of Family Medicine, Istanbul, Turkey.
Received: May 10, 2022 ; Revised: 29, 2022 ; Accepted: June 01, 2022
Citation: Esen AD, Baksu A & Göker N. (2022) Evaluating the Risk Factors that Affecting Uterine Cervical Dysplasia Development. J Women Health Gynecol Res, 1(1): 1-9.
Copyrights: ©2022 Esen AD, Baksu A & Göker N. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Background: Cervical dysplasia describes a series of changes in the surface epithelium, from minor abnormalities to complete coverage of the squamous metaplastic epithelium with neoplastic cells.
Objective: This study investigates the effects of risk factors that play a role in the development of cervical dysplasia and neoplasia.
Material and methods: Cervicovaginal smear results of 225 patients randomly selected from patients who applied to Şişli Etfal Training and Research Hospital Obstetrics and Gynecology Clinic between 01 July and 31 October 2009 were retrospectively evaluated. A questionnaire about risk factors administered to the patients. Statistical analyzes were performed with NCSS 2007 package program. Descriptive statistical methods, independent t test chi-square test was used. The relative ratio (OR) was calculated. Logistic regression analysis was used to determine the factors affecting cervical dysplasia. The results were evaluated at a level of p <0,05, 95% confidence interval.
Results: No cervical premalign lesions were found in 168 of 225 patients, while one of the cervical premalign lesions was detected in 57 patients. There was no statistically significant difference between the mean age of the groups with and without cervical dysplasia. Logistic regression analysis revealed that cigarette use, human papillomavirus (HPV) positivity, number of partners and use of combined oral contraceptives (COC) were statistically significant in terms of risk of development of cervical dysplasia, while parity, abort and still COC use was not significant.
Conclusion: The increased number of sexual partners increases the risk of the transmission and exposure of HPV infection. Using combined oral contraceptives and smoking regardless of the duration were associated with increased cervical dysplasia.
Keywords: Uterine cervical dysplasia, Cancer of the cervix, HPV-16, HPV vaccines
Abbreviations: HPV: Human Papillomavirus; ASCUS: Atypical Squamous Cells of Undetermined Significance; ASC-H: Atypical Squamous Cells-cannot exclude HGSIL; AGS: Atypical Granular Cells; LGSIL: Low-grade Squamous Intraepithelial Lesions, HGSIL: High-grade Squamous Intraepithelial Lesions; CIN: Cervical Intraepithelial Neoplasia; COC: Combined Oral Contraceptives; IARC: International Agency for Research on Cancer
Cervical cancer is the fourth most common type of cancer among women and the third most common cause of death in women worldwide [1,2]. In developing countries, cervical cancer has a significant place among cancer-related deaths in women . 84% of all cervical cancer cases and 88% of all cervical cancer deaths occur in low-resource countries . Dysplasia describes a range of changes in the surface epithelium, from minor abnormalities in the squamous metaplasia epithelium to complete coverage of almost the entire thickness of the epithelium with undifferentiated neoplastic cells . Cervical premalignant lesions, namely cervical dysplasia, include atypical squamous cells of undetermined significance (ASCUS), atypical squamous cells-cannot exclude HGSIL (ASC-H), atypical granular cells (AGS), low grade squamous intraepithelial lesions (LGSIL), high-grade squamous intraepithelial lesions (HGSIL), and cervical intraepithelial neoplasia (CIN). In the development of cervical cancer, successive changes in the cervical epithelium are important in the early diagnosis of cervical cancer . Neoplastic changes begin at the squamocolumnar junction . Intraepithelial lesions and cancers of the cervix uterine are associated with human papillomavirus (HPV) infections . HPV induces uncontrolled cell proliferation through oncogenic gene expression .
More than 200 subgroups and different types of human papillomavirus is classified as low-risk and high-risk based on their clinical features. Nearly 13-15 genotypes make up the oncogenic subgroups that lead to cervical cancer . Common genotypes detected in uterine cervical lesions and cancers are HPV types 16 and 18 [9-11]. Thanks to the effective screening and vaccination practices against HPV in developed countries, there has been a decrease in the incidence of cervical intraepithelial cancer [12,1,13]. Cervical cancer screening is performed at regular intervals via HPV test and cytological smear (Pap-smear test) .
Known risk factors for the development of cervical dysplasia and cervical neoplasia include age, early coitus, multiple sexual partners, history of a high number of sexual partners, HPV infection, COC (combined oral contraceptive) use, parity, smoking, and other nutritional factors. [11,3,14] The aim of this study is to assess the impacts of risk factors that play a role in the development of cervical dysplasia and ultimately in the occurrence of cervical neoplasia.
MATERIALS AND METHODS
In this study, the cervicovaginal smear test results of a total of 225 patients were randomly selected from the patients who presented to the Gynecology and Obstetrics Polyclinic of Şişli Etfal Training and Research Hospital between 01 July and 31 October in 2009 were evaluated retrospectively. Patients of all ages who presented to the Obstetrics and Gynecology Polyclinic of our hospital for any reason with a Pap smear report for follow-up examination were included in the study. The study was conducted on a total of 225 patients, 168 of whom were not detected to have any cervical premalignant lesions based on the Pap smear results, and 57 of whom were detected to have cervical premalignant lesions (ASCUS, ASC-H, AGS, LGSIL, HGSIL, and CIN). All age groups were included in the study. Cases with invasive cervical neoplasia were excluded from the study.
By administering a questionnaire, the patients were questioned in terms of known cervical premalignant risk factors such as age at marriage, smoking, number of partners, number of partners of spouses, parity, contraception method, history of COC use, period of COC use, duration of COC withdrawal, and current use. Questionnaires were administered to the patients in the setting of the outpatient clinic. The patients were asked about the gynecological operations they had, how long they received the COC, how long it had been if they discontinued, and whether they still used it. Patients who had used COC preparations for at least six months once in their life were considered to have used COCs. Pap smear report results and dates were recorded along with the responses of patients to the questionnaire. Human Papilloma Virus (HPV) was considered positive or negative depending on whether HPV activity was detected in the cervicovaginal smear pathology report.
The cervicovaginal smear reports included in the study were composed of smear reports that were routinely taken with a cervical brush in the setting of outpatient clinic, spread on a slide, and then sent to the pathology laboratory and graded by the pathology specialists with the Bethesda system. The patients were divided into two groups as Cervical Dysplasia (+) and Cervical Dysplasia (-) based on the Pap smear results and statistical analysis was performed.
In our study, statistical analyzes were performed via the software of NCSS 2007. For the assessment of the data, the independent t-test was used for the comparison of cervical dysplasia groups, and the Chi-square test was used for the comparison of qualitative data, in addition to descriptive statistical methods (mean, standard deviation). The odds ratio (OR) was computed. Logistic regression analysis was used to identify the factors impacting cervical dysplasia. The results were considered significant at p<0.05, with a confidence interval of 95%.
A total of 225 patients, consisting of 168 patients without cervical premalignant lesions based on the Pap smear test results, and 57 patients with any cervical premalignant lesions (ASCUS, ASC-H, LGSIL, HGSIL, and CIN) were included in our study. The distribution of patients with cervical dysplasia regarding the types of cervical premalignant lesions is presented in Table 1.
The patients were compared statistically in terms of age, age at marriage, number of partners, parity, number of abortions, duration of combined oral contraceptive (COC) use, and mean duration of COC withdrawal.
Of 225 patients, 7.10% had HPV (+), 62.1% had never used COC preparations in their life, 37.9% had used COC preparations for at least six months in their lifetime. While 91.6% of them were not currently using COC preparations, 8.4% were using COC preparations. The percentage distribution of the patients in terms of risk factors is shown in Table 2.
The comparison of the groups with and without cervical dysplasia regarding the mean risk factors is tabulated in Table 3.
No significant difference was detected between cervical dysplasia (+) and cervical dysplasia (-) groups, in terms of mean age, mean age at marriage, mean number of partners, mean parity, mean abortion, mean duration of COC use, mean duration of COC discontinuation. The mean number for the history of sexual partners was determined to be significantly higher in the cervical dysplasia (+) group compared to the cervical dysplasia (-) group (p=0.022).
No significant difference was found between the two groups in terms of age, age at marriage, number of partners, parity, abortion, duration of COC use, and duration of COC withdrawal, whereas a significant difference was found between the mean number of partners (p=0.22).
The statistical comparison of the risk factors of the groups with and without cervical dysplasia in terms of patient number distribution is presented in Table 4.
Participants having more than 2 partners was significantly higher in the cervical dysplasia (+) group (n=6) (10.5%) compared to the cervical dysplasia (-) group (n=5) (3%) (p=0.022) (Table 4). The risk of developing cervical dysplasia was found to be 3.83 (1.12-13.09) times higher in the group with a partner history of >2 (Table 4).
No significant difference was observed between the cervical dysplasia (+) and cervical dysplasia (-) groups, regarding the distribution of the number of spouses' partners (p=0.255) (Table 4). The presence of smoking (+) was found to be significantly higher in the cervical dysplasia positive group (n=21) (36.8%) compared to the cervical dysplasia (-) group (n=35) (20.83%) (p=0.02). The risk of developing cervical dysplasia was determined to be 2.21 (1.15-4.26) times higher in smokers (Table 4).
The presence of HPV (+) was found to be significantly higher in the cervical dysplasia (+) group (n=12) (21.10%) compared to the cervical dysplasia (-) group (n=4) (2.4%) (p=0.001) (Table 4). The risk of developing cervical dysplasia was found to be 10.9 (3.36-35.5) times higher in the HPV (+) group (Table 4).
The use of COC preparation was determined to be significantly higher in the cervical dysplasia (+) group (n=22) (59.5%) compared to the cervical dysplasia (-) group (n=39) (31.5%) (p=0.002) (Table 4). The risk of developing cervical dysplasia was found to be 3.2 (1.5-6.8) times higher in the (+) group using COC Preparation (Table 4).
No significant difference was observed between the cervical dysplasia (+) and cervical dysplasia (-) groups (p=0.918), regarding the distributions of COC use (Table 4). The risk of developing cervical dysplasia was found to be 1.05 (0.36-3.09) times increased in the (+) group currently using COCs (Table 4).
No significant difference was observed between the age distributions of cervical dysplasia (+) and cervical dysplasia (-) groups (p=0.759) (Table 4). The risk of developing cervical dysplasia was found to be 1.35 (0.61-2.99) times increased in the 31-45 age group, while this risk was found to be 1.24 (0.51-2.9) times increased in the group over 45 years old (Table 4).
Logistic regression analysis was used to determine the factors impacting Cervical Dysplasia.
The results of the logistic regression analysis are shown in Table 5. As a result of logistic regression, smoking, HPV positivity, the number of partners, and the use of COC preparations were found significant. It was determined that smoking increased the risk of cervical dysplasia development 1.198 times (0.64-2.24), and the number of partners increased 2.228 (0.137-36.158) times, while HPV (+) increased 4.796 (2.33-9.936) times, and COC preparation use increased 1.7 (0.513-5.638) times.
Cervical dysplasia disproportionately impacts women in less developed countries [15,3]. The development of invasive cervical cancer is primarily caused by oncogenic strains of the virus called Human papillomavirus (HPV), which is a sexually transmitted infection [16,17].
Many other concomitant factors affect the development of low-grade and high-grade lesions or the formation of cervical cancer, yet the impact of these factors is controversial. These include factors such as early first coitus, a history of many sexual partners, oral contraceptive use, high fertility, low socioeconomic status, poor diet, smoking, immunosuppression, and spouses' history of having a large number of sexual partners [3,14].
Cervical cancer ranks third in cancer-related deaths among the female population. In 2019, nearly 569,847 new cases of cervical cancer were detected and there were more than 311,365 deaths .
Thanks to the effective HPV vaccinations and organized use of HPV screening tests in developed countries, a decrease has been observed in HPV infections as well as in the incidence of cervical cancer [12,16,13,18,19].
Human Papilloma Virus (HPV) infection is considered the main risk factor for cervical cancer and premalignant lesions.  HPV has more than 220 genotypes and is graded as low-risk and high-risk [13,7,20]. HPV 16 and 18 are seen in 70% of cervical cancers, while HPV 6 and 11 are culpable for genital warts and condylomas [13,21]. It is well-documented that HPV 16 has the highest prevalence worldwide. HPV 18 is the second most common type among Western countries, while HPV 52 and 58 are common in Asia [17,22].
In a study conducted on 315 cases on HPV prevalence and genotypes in the Cukurova region of Turkey, HPV positivity was determined to be 69.8% in women with abnormal cytology while it was 39.7% in women with normal cytology. In this study, the most dominant HPV genotype was found to be HPV16 among HPV positive cases with abnormal cytology, followed by HPV 56, HPV 18, HPV 52, and HPV 68 Among HPV positive cases with normal cytology, the most common types were detected to be HPV 16, HPV18, HPV 45, HPV 56, HPV 68, and HPV 52, respectively . In our study, albeit HPV positivity was determined to be significant for the development of cervical dysplasia, HPV positivity was 21.10% in the group with abnormal cytology, while it was 2.40% in the group with normal cytology. HPV type was not evaluated in our study. The presence of koilocytes in Pap smear imaging alone was considered as HPV positivity. Due to the method used in our study, HPV positivity rates may have been found to be lower than in the general population. Besides, HPV typing was not performed in our study. In a recent study conducted in our country, HPV positivity was detected in 44.7% of 76 women who presented with ASCUS and above pap smear results, and HPV positivity percentages were 35%, 51.9%, and 77.7% in ASCUS, LSIL, and HSIL patients, respectively. HPV 16 was found to be the most common type. In the same study, HPV positivity was found in 57.8% of cervical neoplasia cases detected by biopsy, and the most common type was again HPV 16 (54.5%) among these cases .
In a study by Milagros Bernal et al., the odds ratio (OR) was found to be 6 in CIN I and 10 in CIN II for HPV positivity and early lesions of cervical neoplasms, while it was found 16 in CIN III and 55 in invasive carcinoma for high-risk lesions. However, earlier lesions such as ASCUS were not included in this study . In our study, ASCUS, ASC-H, AGH, LGSIL, HGSIL, and CIN subgroups were included and all of them were considered as the group with cervical dysplasia, where the OR for HPV positivity was found to be 10.9 (%95 GA 3,36-35,5). Our study was consistent with the previous study, though subgroups were not differentiated in cervical abnormal cytology, and cases with cervical invasive cancer were not included.
Some studies have revealed the relationship between cervical cancer and hormonal contraception. It has been found out that parity has a significant impact on the risk of disease development, based on the data from studies conducted by the International Agency for Research on Cancer (IARC). There was no increased risk among those using hormonal contraception for less than 5 years, but this risk became evident after 10 years . In another study, as a result of a reanalysis of data from 24 epidemiological studies, it was determined that the risk of invasive cervical cancer is increased among current oral contraceptive users (5 years or more) compared to non-users. The risk decreased after discontinuing hormonal contraception, falling to the same level as those who had never used it after 10 years or more. The same pattern was observed in both invasive cancer and carcinoma in situ . In a previous study, it was suggested that the use of long-term hormonal contraception may be a risk factor for the development of carcinoma in situ (CIS) . Based on recent data from studies, the International Agency for Research on Cancer (IARC) concluded that hormonal contraception can be classified as carcinogenic for the cervix as well as for the breast . The trophic effect of estrogen, exposure to this hormone at normal levels increases this development. According to some studies, cervical HPV infection is more common among women with high estrogen receptor transcript levels, and this estrogen binds to specific DNA fragments in the transcriptional regulator regions of HPV DNA . It is also well-known that E6 and E7 proteins of HPV 18 are activated by interacting with estrogen . Cervical ectopia is common among women using hormonal contraception, increasing susceptibility to HPV infection . Moreover, the use of hormonal contraception increases exposure to infections due to the less use of barrier methods during sexual contact . In our study, having used oral contraceptives at any time in life was found to be effective for the development of cervical dysplasia, but using it currently as well as durations of withdrawal and receiving were not found to be effective. Precisely accurate results may not have been obtained, since our study was conducted in a limited population, the use of hormonal contraception was not common in the population we studied, and the duration of oral contraceptive use was not long enough. More comprehensive and further studies are needed to assess the impact of oral contraceptives on cervical dysplasia.
According to a study by Deacon  a woman's detectable HPV infection was found to depend on the number of sexual partners and how long she had had a new partner, and it was noted that many relationships that ended years ago can cause temporary episodes of infection and recurrences of latent infection. It has been observed that HPV acquired from the new partner acts like a new-onset infection. The primary risk factor for CIN III among infected women was considered as the age at first coitus, possibly because the duration of exposure was thought to be the main risk factor for neoplastic development. The fact that the number of partners does not increase the risk of CIN III indicates that the risk does not increase with reinfection if the partner has already been infected . In our study, the number of partners was found to be significant for cervical dysplasia, whereas the age at first coitus was not significant. However, in our study, HPV positivity was categorized as a separate risk factor. Our study was not conducted only to investigate CIN III and included cervical dysplasia subgroups as well.
In one study, high-risk HPV infection was associated with never having been pregnant, having had children before, and age at first pregnancy, but not the number of children and cesarean sections. Pregnancy resulting in childbirth and first gestational age above 20 were associated with a lower risk of infection . Unlike our study, this study was conducted on women with high-risk HPV infections. In our study, HPV infection was considered an independent risk factor. Likewise, in our study, the risk of cervical dysplasia was not found to be associated with the number of births and cesarean sections.
According to one study, early coitus was found to be a risk factor for cervical cancer. It was found out that the adjusted odds ratio for cervical cancer increased with the increasing number of sexual partners. The adjusted odds ratio for cervical cancer was found to be significant as 1.7 (1.2-2.2) in women with four or more lifetime partners .
Again, the information obtained from 21 separate epidemiological studies conducted by the Cervical Cancer Epidemiological Working Group to investigate the relationship between cervical cancer and sexual behavior patterns was reanalyzed and the relative risks for invasive cancer and CIN III were estimated by situational logistic regression analysis. The risk of invasive cervical carcinoma was found to be increased with the growing number of lifetime sexual partners. Moreover, the risk of invasive cervical cancer was determined to be increased with earlier age at first coitus CIN III carcinoma in situ showed a similar correlation with the number of sexual partners acquired during the lifetime, but showed a weaker correlation with age at first coitus . In our study, the number of partners was found to be effective for the occurrence of cervical dysplasia, thus for the III development, whereas age at first coitus was not found to be effective. This finding is consistent with the results in the literature.
In a longitudinal analysis of Collins S. et al. to determine the risk of developing high-grade cervical intraepithelial lesion regarding the presence of HPV and smoking status, it was observed that current smoking frequency increases the risk of high-grade CIN. Compared to non-smokers, the hazard ratio (HR) was found to be 2.21 (95% CI 1.19-4.12) for those who smoked 10 or more times a day. Accordingly, current smoking prevalence was observed as an independent risk factor for the occurrence of high-grade CIN in young women . In a study by Kjeliberg it was found out that smoking increased the estimated risk for CIN 2 and 3 in both HPV positive and HPV negative groups. A dose-dependent correlation was observed depending on the number of cigarettes smoked per day. Besides, it was observed that CIN regressed when smoking was quitted. It was concluded that smoking could be an independent risk factor for CIN 2 and 3 . In another study, a slightly increased risk of developing cervical dysplasia was found in current smokers, independent of the duration of smoking when compared with never-smokers . In our study, smoking was found to be a risk factor for all cervical dysplasia, consistent with the literature.
Age, multiple sexual partners, HPV type, smoking, early initiation of sexual activity were determined as risk factors for cervical lesions İn a study by Fernandes JW et al., which was conducted in northeastern Brazil to determine the prevalence of Human papillomavirus (HPV) infection according to cervical cytology and to determine other risk factors for low- and high-grade intraepithelial lesions (LGSIL, HGSIL). It was found that age, multiple sexual partners, and being infected with HPV 16 increased the risk for both LGSIL and HGSIL, while early initiation of sexual activity and smoking increased the risk only for HGSIL . In our study, having multiple sexual partners and smoking increased the risk of developing cervical dysplasia for all cervical dysplasia’s, but early sexual activity was not associated with increased risk. High- and low-grade intraepithelial lesions under the name of cervical dysplasia were included in our study, but subgroups were not studied in terms of risk factors.
Epithelial factors in the cervical region are known to cause cervical precancerous lesions. HPV infection is considered the primary risk factor for cervical cancer and premalignant lesions. The high number of sexual partners acquired throughout life increases the transmission and exposure of HPV infection, thus increasing the risk of developing cervical dysplasia and neoplasia. Having used oral contraceptives at any time in life was effective for the development of cervical dysplasia, and smoking was associated with increased cervical dysplasia regardless of duration. More comprehensive and further studies are needed to assess the impact of oral contraceptives on cervical dysplasia.
Authors are very grateful for patient’s participation and obstetrics and gynecology department team in this time period for their support.
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