|Year : 2018 | Volume
| Issue : 8 | Page : 184-189
Effect of smoking on high-grade cervical cancer in women on the basis of human papillomavirus infection studies
Jian-Hong Fang, Xue-Mei Yu, Shu-Hong Zhang, Yan Yang
Department of Obstetrics, Chengyang People's Hospital, Chengyang, Qingdao, Shandong, China
|Date of Web Publication||26-Mar-2018|
Department of Obstetrics, Chengyang People's Hospital, No. 600, Changcheng Road, Chengyang, Qingdao, Shandong 266100
Source of Support: None, Conflict of Interest: None
Purpose: We aimed, in the present study, to measure the risk related to the high-grade cervical intraepithelial neoplasia grade 3 (CIN3) or worse (CIN3+) or worse/high-grade squamous intraepithelial lesions with respect to changes in human papillomavirus (HPV) and smoking status.
Materials and Methods: A structured interview underwent for 7129 women. Then, we obtained their cervical cells and subjected to HPV testing. High-risk HPV infected and “no prevalent” cervical disease infected women were followed for cervical lesions up to 12 years (at baseline; n = 1531). Hazard ratios (HRs) for diagnosis of CIN3 (or worse) or worse/high-grade intraepithelial lesions were calculated along with the corresponding 95% confidence intervals (CIs).
Results: Among high-risk HPV-positive women, the conditions of long-term (more than 8 years) smokers and heavy (18 or more cigarettes/day) smokers are highly responsible for the increased risk for CIN3 or CIN3+. In the cases of persistent HPV-infected women, heavy smoking led to a higher risk for CIN3+ than those women who never smoked (HR, 2.31; 95% CI, 1.12–4.16).
Conclusion: We concluded here that smoking leads to an enhanced risk of high-grade cervical lesions in persistent high-risk HPV-infected women. This makes a good understanding of smoking's role in cervical cancer.
Keywords: Cervical cancer, high-grade, papillomavirus infection, smoking habit
|How to cite this article:|
Fang JH, Yu XM, Zhang SH, Yang Y. Effect of smoking on high-grade cervical cancer in women on the basis of human papillomavirus infection studies. J Can Res Ther 2018;14, Suppl S1:184-9
|How to cite this URL:|
Fang JH, Yu XM, Zhang SH, Yang Y. Effect of smoking on high-grade cervical cancer in women on the basis of human papillomavirus infection studies. J Can Res Ther [serial online] 2018 [cited 2019 Jun 20];14:184-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/184/179190
| > Introduction|| |
The most common sexually transmitted disease is high-risk human papillomavirus (HPV) infected cervical cancer. HPV is considered as a necessary but not a sufficient reason for cervical cancer because other factors, for instance, environmental factors, viral characteristics, and host characteristics  also play an important role. Nowadays, the attention is focused on the identification of the cofactors which modulates its progression to invasive disease and to high-grade cervical intraepithelial neoplasia (CIN). A persistent infection with high-risk HPV along with a single positive test for high-risk HPV is important factors in the exact prediction of CIN grade 3 (CIN3) or even worse (CIN3+).,,
Cigarette smoking , has been associated with increasing risk of cervical cancer and its precursor lesions, but it is difficult to prove this association because it is yet not clear whether smoking increases the risk of HPV persistence or the risk of HPV acquisition or works as an HPV cofactor which is responsible for risk of high-grade cervical disease as well as HPV. The high-grade cervical disease has been associated with smoking mainly in case–control studies , but less often in prospective cohort studies., Even in these cases, the results were based on a single measurement of both the transient and persistent HPV infected HPV.
On the basis of solitary isolated existence of HPV type in cervical cancer specimens, the genital HPV types have been bifurcated into two categories, “low-risk” and “high-risk.” HPV types 16, 18, and other related high-risk HPV types result in dysplastic lesions of the cervix as manifested by abnormal Pap smear More Detailss and these may lead to cervix cancer in the infected women., However, HPV 6 and HPV 11 are examples of low-risk types and are associated with proliferative, benign lesions (known as condylomata acuminate) and commonly referred to as genital warts., Thus, persistent high-risk HPV infection  and HPV cofactors dependent progression of cervical cancer should be studied in a cohort of persistently infected women.
To the best of our knowledge, we have addressed the first study of its own kind to examine the risk of the development of high-grade cervical disease among persistent high-risk HPV infected women and its correlation to smoking. We have also explored the assessment of the role of smoking in the development of high-grade cervical disease in a population of high-risk HPV infected women and also in women of no prevalent cervical disease at entry level.
| > Materials and Methods|| |
The design and characteristics of the study population of participating women in a population-based cohort study of HPV (of the natural history) in China have been described elsewhere., Women aged 19–28 years, living in Beijing (n - 15,121) were recruited from our hospital and invited them to participate in the study. Women subjects who had moved out before contact (n - 1,719) were not found suitable for the study. The inclusion of 10,579 women was reported between June 1992 and March 1994 for the study. The women were invited to participate in a second examination after 2 years (December 1994 to March 1996; approximately) following the same original inclusion order; and thus finally, 7129 women participated in the study (participation rate, 67%).
At recruitment, each participant was gone through a standardized interview questionnaire that was verbally administered by trained female nurses containing questions about smoking behavior, reproductive factors, sociodemographic factors, sexual behavior, contraceptive use, and history of sexually transmitted infections. Approval of the Institutional Review Board at our hospital was obtained for the study. Written consent was obtained from each subject before her enrollment in the study as the copy of the signed consent form was given to the participant.
All participants underwent routine clinical procedures including history and physical examination. At each visit (and each follow-up visit), the women underwent a Pap smear test, and cervical swabs were obtained (or updated), as the gynecologic examination, stored at −80°C for subsequent HPV DNA detection.
Human papillomavirus DNA detection studies
Digene hybrid capture2 (HC2; Qiagen, Shanghai [China]) high-risk HPV DNA detection test was performed for all cervical samples, followed by a polymerase chain reaction-based genotyping method  for those samples which were positive with the HC2 assay. As per recommendation of the United States Food and Drug Administration, for the HC2 assay, the cutoff point of 1.0 pg/mL was used and at least 13 high-risk types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) were detected using only the high-risk probe. However, we conducted our genotyping as per a previous method  that allowed identification of 24 HPV types specifically in the high-risk types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68).
A pathology data type bank was made containing information on all cervical cytologic and histologic examinations (biopsies, cones, and hysterectomies; normal as well as abnormal diagnoses). An individual personal identification number was given to the subjects and used as the key identifier of each woman in the study population to obtain information about cervical cytology and histology from the bank during follow-up. After diagnoses, those were categorized and reported as mild, moderate, or severe dysplasia, atypia, carcinoma (in situ), or cancer. Specifically, the cytologic diagnoses carcinoma (in situ), severe dysplasia, and cancer were reported as high-grade squamous intraepithelial lesion (HSIL) or worse, while the histologic diagnoses of these lesions were categorized as CIN3 or worse.
We reported here about the study population of women who participated in both examinations (n - 7,129) to investigate the cervical outcomes of subsequent HPV DNA detection studies results. The women were followed up to the date of the second individual examination, defined as baseline, until April 16, 2006. On the basis of the positive results of HC2 test using the high-risk probe at the second examination, the analysis was restricted to the 1631 high-risk HPV infected women at the baseline. Due to inadequate baseline smear, 27 women were excluded while 42 women were excluded due to the absence of cervical examinations during follow-up. In addition to this, 31 women were also excluded due to moderate or worse dysplasia at baseline or 1 year before baseline. Thus, 1531 high-risk HPV-positive women were resulted at baseline in the overall study population. Women having high-risk HPV-presence (positive signal) at baseline and presence of the same high-risk HPV type (identified by the second test) at baseline and at the first examination were defined (n - 348). However, the high-grade cervical disease was developed in 292 women during follow-up in the overall study population (n - 1,531). Among these 292 women, 227 women were diagnosed of CIN3 or worse, and the rest women (n - 65) were diagnosed of HSIL or worse without histologic confirmation. For convenience, we called this combined group as CIN3+. During the second interview (at baseline), we discovered information with respect to smoking (never, former, and current) status, smoking duration, age at smoking initiation, and also the average number of cigarettes smoked/day (smoking intensity).
Statistical data analysis
On the basis of the fact that we were unaware of the exact date since cervical abnormality was developed, an accelerated failure time model (having interval-censored response variable) has been used for the estimation of the associated relation of the risk of developing CIN3+ and smoking. For this purpose, Weibull distribution method was used. In the final model, both the histologic and cytologic high-grade cervical lesions were included. The analysis was based upon PROC LIFEREG method from Statistical Analysis System Software (SAS Software, version 9.4; Shanghai [China]).
According to the length of schooling (≤8, 9–10, ≥11 years), the hazard ratio (HR) values were adjusted. Since the HPV 16, is strongly associated with cervical cancer progression, we adjusted the final model for non-16 high-risk HPV and HPV 16 at the baseline. Similarly, we also considered other factors, i.e., use of oral contraceptives, age at first intercourse, and lifetime number of sexual partners, initially but none of these confounders could affect the outcome; hence, these were not included in the final analysis models.
| > Results|| |
Age distribution and schooling
We found even age distribution in the study of high-risk HPV-presence women for various age ranges. For example, among 21–23, 24–26, and 27–31 years old ranges (in the study of high-risk HPV-presence women), it was 31.2%, 34.2%, and 34.6%, respectively [Table 1]. The comparative study of age distribution for the diagnosed CIN3+ cases and noncases of the women having high-risk HPV-presence and persistent high-risk HPV infection is shown in [Figure 1]. We also observed that more than 70% (70.9%) women had 11 or more schooling years (≥11); 17.3% women were mother (given birth); 41.6% were current smokers at baseline [Table 1]; and 57.6% women had <10 lifetime sex partners. Some data (in exact number; shown above in percentage) are not shown in [Table 1] to avoid awkwardness.
|Table 1: Diagnosis of high-grade cervical cancer (CIN3+; in terms of hazard ratios; followed up to 12 years) with respect to smoking among women (n=1531) having high-risk human papillomavirus-presence|
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|Figure 1: The age distribution (at baseline [in years]) comparison of the diagnosed CIN3+ cases (C1 and C2) and noncases (non-C1 and non-C2) for women having high-risk human papillomavirus-presence (1) and persistent high-risk human papillomavirus infection (2); (a and b) denotes ≥a to ≤b. CIN3+: Cervical intraepithelial neoplasia grade 3 worse|
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Risk of cervical intraepithelial neoplasia grade 3 worse versus smoking
CIN3+ was diagnosed in 276 women (18.0%) during the follow-up in the overall study population [Table 1]. Among the persistent HPV-infected women, CIN3+ was diagnosed in 112 women out of 348 [32.2%; [Table 2]. Cervical cytology examinations/year were followed up from the beginning until the end of the study among the women (having absence of abnormal cervical diagnoses), but no statistically significant different average values were obtained as per smoking status (current: 0.31; former: 0.30; never: 0.31; P= 0.460).
|Table 2: Diagnosis of high-grade cervical cancer (CIN3+; in terms of hazard ratios; followed-up to 12 years) with respect to smoking among women (n=348) having persistent infection of high-risk human papillomavirus|
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Risk of cervical intraepithelial neoplasia grade 3 worse among high-risk human papillomavirus-presence versus smoking
The diagnosis of the risk of subsequent CIN3+ with respect to smoking in the study of high-risk HPV-presence women (at baseline) is shown in [Table 1]. We observed an increased risk for CIN3+ (HR, 1.41; 95% confidence interval [CI], 1.07–1.85) in those women who had ever smoked in comparison to those who had never smoked (HR, 1.00). We subdivided the ever smoking women into former and current smokers and observed that likely to have a subsequent CIN3+ (HR, 1.44; 95% CI, 1.04–1.89; in the fully adjusted model) in comparison to former smokers. It was observed that those women who were smokers since more than a decade (≥10) were more likely to have CIN3+ (HR, 1.51; 95% CI, 1.09–2.11) than those who had never smoked (HR, 1.00). We also found that those women who began smoking in between 16 and 19 years of age had a significantly higher risk for CIN3+ (HR, 1.53; 95% CI, 1.11–2.09) than those who had never smoked. Heavy smokers (≥20 cigarettes/day) were also faced the enhanced risk of CIN3+ (HR, 1.58; 95% CI, 1.11–2.21).
Risk of cervical intraepithelial neoplasia grade 3 worse among persistent human papillomavirus infection versus smoking
[Table 2] shows the risk of a subsequent diagnosis of CIN3+ in accordance with smoking in persistent HPV infected women. In this case also those women who smoked heavily (≥20 cigarettes/day) were more likely to be diagnosed with CIN3+ (HR, 1.88; 95% CI, 1.08–3.37). However, the risk was increased with different smoking durations (current and even for a decade) but they could not get statistical significance.
We compared the HRs (in the unadjusted model) of CIN3+ diagnosed cases among women having high-risk HPV-presence and persistent high-risk HPV infection with respect to smoking events [Figure 2] to explore our results.
|Figure 2: Comparative study of HRs (in the unadjusted model) for CIN3+ diagnosed cases among women having high-risk human papillomavirus-presence and persistent high-risk human papillomavirus infection (shown in bold) with respect to smoking events as (a) smoking duration (years); (b) smoking initiation age (years old) and; (c) smoking intensity (tobacco cigarettes/day); (a and b) denotes >a to ≤b. CIN3+: Cervical intraepithelial neoplasia grade 3 worse, HR: Hazard ratio|
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| > Discussion|| |
The aim of our study was to explore the smoking effect on the risk of subsequent development of CIN3+ in high-grade cervical disease as well as in persistent high-risk HPV infection. Earlier works , have shown that the significant increment in the risk of subsequent CIN3 or worse with persistent high-risk HPV positivity in various studies. We have shown the first of its own kind longitudinal study of HPV cofactors to discover the resultant risk of high-grade cervical cancer (having persistent HPV). However, smoking was also shown as an increased risk for CIN3+ in those women who were high-risk HPV positive (as per single HPV measurement).
It has been previously ,, found that current smokers and ever smokers had an enhanced risk for high-grade cervical disease during the studies of (single HPV measurement based) HPV-positive women. Several studies have also shown the relation of increased risks with reference to long-term smoking and heavy smoking. Nevertheless, another study  could not find any dose-dependency with respect to smoking initiation, intensity, or duration status. In this study of HPV-positive women (based on single HPV measurement), we found similar results that current smoking and ever smoking has statistically significant association with an enhanced risk for CIN3+. Particularly, we found that the increased risk is strongly associated with women having long-term smoking habit [Figure 2]a and having heavy smoking habit [Figure 2]c. We can see in [Figure 2]a that in the cases of women having high-risk HPV, the increased risk is strongly associated with long duration of smoking, but in the cases of persistent high-risk HPV infection, the same trend has not been followed strictly. On the other hand, strong association of increased risk in heavy smoker women is being observed in both the cases [Figure 2]c. Besides, we studied the effect of duration of smoking and amount of smoking among former smoker women and current smoker women and found the similar patterns as observed in the case of ever smokers, but we observed statistically significant associations only for current smokers' cases. In the case of high-risk HPV-presence women whose smoking initiation age was in between 16 and 19 years had a significantly higher risk for CIN3+ than those who had never smoked while in the case of persistent high-risk HPV infection women who began below 15 years of age, we observed very high-risk of CIN3+ [Figure 2]b.
In our present case study, we observed that the percentage of CIN3+ developed women in the study of (single HPV measurement based) high-risk HPV-positive women [18.0%; [Table 1] is lower than those in persistent HPV-infected women [32.2%; [Table 2]. In the case of analysis of the risk of CIN3+ among persistent high-risk HPV infected women, we observed that never smokers had lower risk than heavy smoker women. This result clearly indicates that smoking is strongly related to an increased risk for progression even in the presence of strong characteristic of the persistent HPV infection.
We found few shortcomings and limitations in our study. Since we had a shortage of sufficient statistical efficiency for HPV cofactors with respect to cervical cancer, we were forced to study immediate precursor lesions. Besides, we were lacking of the cervical HPV infection timings with respect to smoking initiation and its effect on cervical cancer progression, and that is why we could not find any relation between HPV infection and time of smoking in the reference of subsequent risk of CIN3+. Further studies are required for answer to these aspects.
| > Conclusion|| |
We may say that our outcome leads us to the fact that smoking is a contributing factor (as HPV) in the progression of cervical cancer and hence our work would be excellent for cervical cancer based future studies. We also found that persistent high-risk HPV infected women had expressed a remarkable enhance in the risk for high-grade cervical cancer disease. Finally, in this study, we reported a first-ever result showing cervical persistent HPV infected carcinogenesis' dependence on smoking.
Financial support and sponsorship
The work has been supported by Department of Obstetrics, Chengyang People's Hospital, China.
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Bosch FX, Qiao YL, Castellsagué X. Chapter 2 The epidemiology of human papillomavirus infection and its association with cervical cancer. Intl J Gynaecol Obstet 2006;94:S8-S21.
Castellsagué X, Muñoz N. Chapter 3: Cofactors in human papillomavirus carcinogenesis – Role of parity, oral contraceptives, and tobacco smoking. J Natl Cancer Inst Monogr 2003;31:20-8.
Kjaer SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: Role of persistence. J Natl Cancer Inst 2010;102:1478-88.
Castle PE, Rodríguez AC, Burk RD, Herrero R, Wacholder S, Alfaro M, et al.
Short term persistence of human papillomavirus and risk of cervical precancer and cancer: Population based cohort study. BMJ 2009;339:b2569.
Schiffman M, Glass AG, Wentzensen N, Rush BB, Castle PE, Scott DR, et al.
A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the portland kaiser cohort study. Cancer Epidemiol Biomarkers Prev 2011;20:1398-409.
Plummer M, Herrero R, Franceschi S, Meijer CJ, Snijders P, Bosch FX, et al.
Smoking and cervical cancer: Pooled analysis of the IARC multi-centric case–control study. Cancer Causes Control 2003;14:805-14.
International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, Berrington de González A, Colin D, Franceschi S, et al.
Carcinoma of the cervix and tobacco smoking: Collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer 2006;118:1481-95.
McIntyre-Seltman K, Castle PE, Guido R, Schiffman M, Wheeler CM; ALTS Group. Smoking is a risk factor for cervical intraepithelial neoplasia grade 3 among oncogenic human papillomavirus DNA-positive women with equivocal or mildly abnormal cytology. Cancer Epidemiol Biomarkers Prev 2005;14:1165-70.
Gargano JW, Nisenbaum R, Lee DR, Ruffin MT 4th
, Steinau M, Horowitz IR, et al.
Age-group differences in human papillomavirus types and cofactors for cervical intraepithelial neoplasia 3 among women referred to colposcopy. Cancer Epidemiol Biomarkers Prev 2012;21:111-21.
Bosch FX, de Sanjosé S. Human papillomavirus in cervical cancer. Curr Oncol Rep 2002;4:175-83.
Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev 2003;16:1-17.
Brown DR, Schroeder JM, Bryan JT, Stoler MH, Fife KH. Detection of multiple human papillomavirus types in Condylomata acuminata lesions from otherwise healthy and immunosuppressed patients. J Clin Microbiol 1999;37:3316-22.
Gissmann L, Wolnik L, Ikenberg H, Koldovsky U, Schnürch HG, zur Hausen H. Human papillomavirus types 6 and 11 DNA sequences in genital and laryngeal papillomas and in some cervical cancers. Proc Natl Acad Sci U S A 1983;80:560-3.
Schiffman M, Wentzensen N, Wacholder S, Kinney W, Gage JC, Castle PE. Human papillomavirus testing in the prevention of cervical cancer. J Natl Cancer Inst 2011;103:368-83.
Kjaer S, Høgdall E, Frederiksen K, Munk C, van den Brule A, Svare E, et al.
The absolute risk of cervical abnormalities in high-risk human papillomavirus-positive, cytologically normal women over a 10-year period. Cancer Res 2006;66:10630-6.
Woodman CB, Collins S, Winter H, Bailey A, Ellis J, Prior P, et al.
Natural history of cervical human papillomavirus infection in young women: A longitudinal cohort study. Lancet 2001;357:1831-6.
Iftner T, Villa LL. Chapter 12: Human papillomavirus technologies. J Natl Cancer Inst Monogr 2003;31:80-8.
Klug SJ, Molijn A, Schopp B, Holz B, Iftner A, Quint W, et al.
Comparison of the performance of different HPV genotyping methods for detecting genital HPV types. J Med Virol 2008;80:1264-74.
Wang SS, Zuna RE, Wentzensen N, Dunn ST, Sherman ME, Gold MA, et al.
Human papillomavirus cofactors by disease progression and human papillomavirus types in the study to understand cervical cancer early endpoints and determinants. Cancer Epidemiol Biomarkers Prev 2009;18:113-20.
Castle PE, Wacholder S, Lorincz AT, Scott DR, Sherman ME, Glass AG, et al.
A prospective study of high-grade cervical neoplasia risk among human papillomavirus-infected women. J Natl Cancer Inst 2002;94:1406-14.
[Figure 1], [Figure 2]
[Table 1], [Table 2]