ABSTRACT

Objective: To determine the effect of tobacco consumption with the development in women of cervical intraepithelial neoplasia. Methods: A systematic review was conducted. The electronic search was carried out, using the research question: What is the association between smoking and the development of cervical intraepithelial neoplasia? whose PEO question was: Population: Women. Exposure: Tobacco use. Outcome: Cervical intraepithelial neoplasia. Articles published from January 1, 2014 to December 2019 were selected. Results: 71 articles were found, 55 being excluded because they did not meet the selection criteria, leaving 16 articles for this paper analysis. Those women who smoked tobacco had a significant association for the development of high-grade intraepithelial neoplasia (OR = 1.43, 95% CI = 1.14-1.80). Likewise, synergy was observed between severe smoking and the use of oral contraceptives, with a greater risk of grade II and III intraepithelial neoplasia (OR = 11.5; 95% CI, 1.88-70.40). Conclusion: The available evidence suggests the association between tobacco use and the development of cervical intraepithelial neoplasia, particularly high-grade cervical intraepithelial lesions.

Keywords: Cervical intraepithelial neoplasia; Tobacco use, Smoking, Smoking women, Lifestyle Medicine (fuente: MeSH NLM).

INTRODUCTION

Cervical intraepithelial neoplasia (CIN) constitutes a premalignant lesion that precedes the development of cervical cancer. Cervical cancer represents the second most frequent type of cancer that affects women worldwide, annually about 9 million women develop it from which 80% are in developing countries¹.

Cervical intraepithelial neoplasia is characterized microscopically by the presence of a series of manifestations that progress from cellular atypia to varying degrees of dysplasia. Among its conformation there are abnormal squamous cells that will be largely eliminated by the immune system, however, this will depend on the degree of cervical intraepithelial neoplasia (CIN).

It is very important to identify the degree of cervical intraepithelial neoplasia; Grade I is a mild dysplasia, which is why it is considered low grade, while Grade II and III constitute high-grade lesions, Grade II as a moderate dysplasia, and Grade III a severe dysplasia that can compromise all thickness of the lining of the cervix, being considered carcinoma in situ.

Among the risk factors involved in the development of cervical intraepithelial neoplasia are: genital HPV infection, where the most common infection mechanism is sexual transmission; It is estimated that approximately 80% of sexually active women at some time in their life will have contact with the human papillomavirus. In general, HPV infection represents the main factor of development, however, there are other factors that have been linked to being described in the literature, which contribute together to the development of squamous intraepithelial lesions at the cervix level and as a consequence they make women more likely to develop cervical cancer, among these factors are age, sociocultural condition, level of health knowledge, number of pregnancies, number of vaginal births, number of sexual partners, characteristics by the sexual partner, alcohol consumption, tobacco consumption, age of onset of sexual activity, hormonal planning, among others².

Currently, it has been shown that women who present smoking within their background are more predisposed to present atypical cells, as well as develop cervical cancer. According to the International Agency for Research on Cancer (IARC) 62 of the 5 000 components of tobacco have been considered, proving to be carcinogenic, placing cervical cancer among the most associated. It was obtained that there is a greater probability of mortality in 21% of women with cervical cancer and who have a history of smoking, which is why it is important to recognize the intervention of exogenous factors in the onset of cervical cancer^1,3.

Lifestyle factors are currently at the center of the prevention and treatment of chronic diseases, including cancer. The objective of this article was to determine the effect of tobacco consumption with the development in women of cervical intraepithelial neoplasia.

METHODS

In this work, a systematic review was made using articles in English and Spanish published from January 1, 2014 to December 2019, in PubMed, Scielo and Google Scholar. The PEO question was used: What is the association between smoking and the development of cervical intraepithelial neoplasia? Population: Women. Exposure: Tobacco use. Outcome: Cervical intraepithelial neoplasia. The key words were: "tobacco use" (MeSH Term) in combination with "cervical intraepithelial neoplasia" (used in PubMed); "Tobacco use", "tobacco", "smokers" in combination with "cervical intraepithelial neoplasia" (used in Scielo and Google Scholar). Mentioning the terms "tobacco use" refers to the use of tobacco through cigarettes. The syntax resulting from the advanced search was: ((((“Women” [mh] OR Girls * [tiab] OR Girl * [tiab] OR Woman * [tiab] OR Women's Groups * [tiab] OR Women Groups * [tiab] OR Women's Group * [tiab])) AND (“Tobacco Use” [mh] OR Tobacco Use * [tiab] OR Tobacco Chewing * [tiab] OR Tobacco Consumption * [tiab] OR smoking * [tiab] OR cigarrete * [ tiab])) AND (“Cervical Intraepithelial Neoplasia” [mh] OR Cervical Intraepithelial Neoplasm * [tiab] OR Cervical Intraepithelial Neoplasia * [tiab]).

The search strategy can be seen in Tables 1, 2, 3 and 4.









Inclusion criteria::

• Articles published during the last 5 years.
• Articles that contain any of the following combinations of keywords both in the title or abstract: Cervical intraepithelial neoplasia along with smoking, tobacco or smoking; "Cervical intraepithelial neoplasia" next to "tobacco use" or "tobacco" or "smoking".

Exclusion criteria::

• Studies that are not directly related to this topic.
• Articles that do not have an author or Digital Object Identifier (DOI).

The study protocol was registered in Biomedical Sciences Research Institute of Ricardo Palma University.

RESULTS

71 articles were found, excluding 20 for not being within the last 5 years, 32 because they did not comply with the combination of keywords in their structure, also 3 were excluded because they were not directly related to the subject to be reviewed. In the end, 55 articles were excluded, so there were 16 articles left for this paper analysis, including one article for theoretical and conceptual purposes.

The study selection diagram can be seen in Figure 1



Evidence from prospective studies:

In the work carried out by Sánchez J. et al, a population of 807 patients were studied, of which 629 (77.9%) denied to be smokers and 178 (21.1%) they to be smoke, taking occasional smoking criteria as exclusion criteria. The smoking rate of the smoking patients was calculated, resulting in: 148 (83.1%) had a mild degree of smoking, 20 (11.3%) a moderate degree of smoking and 10 (5.6%) an intense degree of smoking. Regarding the results of Pap smears, 9 (5%) cases presented low-grade intraepithelial lesions, 3 (1.68%) high-grade intraepithelial lesions. At the time of calculating the odds ratio (RM) 1.90 was obtained with a 65% probability for the presence of cellular atypia in smoking women; also, in relative risk the result was 1.58 higher to have cervical-vaginal atypia in patients who smoked while those who did not had a protective relative risk of 0.63¹.

Fang JH. et al. conducted a study to measure the risk related to the presence of high-grade intraepithelial neoplasia and regarding the changes produced by the human papillomavirus (HPV), as well as smoking, where it was obtained that those women smokers in the long term (more 8 years) and those who were severe smokers (18 or more cigarettes per day) had an increased risk for grade III intraepithelial neoplasia than those women who never smoked, having a HR of 2.31 with a 95% CI, 1,12 to 4,16 ⁴.

Evidence from retrospective studies:

In the work done by Min KJ. et al., it was obtained that passive smoking in those non-smoking patients was associated with an increased risk for the development of cervical intraepithelial neoplasia grade I (OR = 1.53, 95% CI, 1.07-2.18), the risk increased regarding to the longest time exposed to this factor (P for trend <0.0003); the multivariate probabilities of <2 hours = day of passive smoking and ≥2 hours = day of passive smoking was 2.48 (95% CI, 1.49-4.14) and 2.28 (95% CI, 1.21-4.26) for cervical intraepithelial neoplasia^2,5. Oh HY et al., report that those patients who had a history of severe smoking and long-term use of oral contraceptives (OR = 11.5; 95% CI, 1.88-70.4) had a higher risk of grade II and III intraepithelial neoplasia⁶.

Xu H. et al., Obtained that in those women who used tobacco during the study had a significant association for the development of grade II and III intraepithelial neoplasia (OR = 1,43, 95% CI = 1,14-1.80)⁷. Wudtisan J. et al., observed that among all the associated factors was the presence of smoking history (OR = 2,95; 95% CI, 1,10-7,93; P = 0,032) with significance for development of cervical intraepithelial neoplasia in women under 30 years of age⁸. Daily LR. et al., refers that women with an average age of 22,5 years, where the proportion of smokers was 36,1%, it was determined that the history of smoking (OR = 1,64, 95% CI = 1,2-2-25) was associated with a history of high-grade cytology (OR = 2,06, 95% CI = 1,02-4,01) such as cervical intraepithelial neoplasia grade II and III⁹. Lee CH. et al., when assessing the risks for the development of cervical intraepithelial neoplasia, obtained that despite the high DNA load of the human papillomavirus, the main predictor of grade I and II intraepithelial neoplasia, factors such as age, age of Sexual onset and active or passive smoking are involved in the development of these lesions¹⁰.

Feng RM. et al., studied the role of smoking, as well as passive exposure to tobacco smoke at home, associated with the risk of infection with human papillomavirus (HPV) and grade II cervical intraepithelial neoplasia. The adjusted OR in those who once smoked versus those who never smoked was 1,45 (95% CI = 1,10-1,91) for HPV infection and 1.89 (95% CI = 1,03-3,44), with respect to cervical intraepithelial neoplasia grade II. Regarding active smokers such as passive smokers, they had an increased risk of 1.57 times (95% CI = 1,14–2,15) of HPV infection and a 1.99 times risk (95% CI = 1,02–3,88) of developing grade II intraepithelial neoplasia¹¹. Pérez R. et al., obtained that low-grade cervical intraepithelial neoplasms (CIN 1) (n = 115; 48,94%) and grade II cervical intraepithelial neoplasia (n = 76; 32,34%) predominated, it was observed that there was a greater correlation between the lesions and the smoking rate (Rho Spearman 0,84; P <0.0001)¹². Cifuentes LY. et al., had a population where the age range was from 16 to 71 years, whose mean is 42,2 (SD = 14,57); finding that 11,3% were smokers, with an OR = 12,1 (5% CI, 4,0-36,3)(p<0.001)¹³.

Iwata T. et al., Studied the profile of cytokines present in the cervical mucosa of Japanese patients with cervical intraepithelial neoplasia, obtaining significantly lower levels of cytokine macrophage inflammatory protein-1β (MIP-1β) (P = 0.018) in smoking patients, however, they concluded that this habit further facilitates persistent infection with human papillomavirus (HPV)¹⁴. ). Roura E. et al., conducted a study to evaluate the association between smoking and the risk of cervical intraepithelial neoplasia grade III; smoking status, duration and intensity showed a twice-greater risk of cervical intraepithelial neoplasia grade III, while in those who quit smoking, the time elapsed since they stopped smoking was associated with a twice-lower risk¹⁵. Andrade CE. et al., studied the risk factors of recurrence for cervical intraepithelial neoplasia in patients who had undergone surgical treatment, following up with a median time of 22.6 months; in the multivariate analysis, the only independent risk factor for recurrence was tobacco use (HR = 3,5, CI = 95%, 1,6-7,6, P = 0.002)¹⁶.

The designs and results of the studies are found in Tabla 5.





DISCUSSION

Through this systematic review it was observed that there is an association between smoking and the development of cervical intraepithelial neoplasia, which has been evidenced by various authors^1,3,4,5,14. Cohort studies, cases and controls, as well as cross-sectional studies could be reviewed.

Within cohort studies, it was observed that in the work carried out by Sánchez JM et al. in Mexico, those women who smoked had an increased risk of cervical-vaginal cell atypia; also, Fang JH et al. in China, reported a higher risk for grade III cervical intraepithelial neoplasia in severe smokers^1,4.

In case-control studies, the relationship between tobacco consumption and the three degrees of cervical intraepithelial neoplasm could be shown, observing tobacco consumption was present, resulting in one of the factors that increases the risk of intraepithelial cervical lesions in 32% of cases. This effect is greater in relation to the age of onset, whose average age range is between 15 and 19 years, as well as the time of consumption^7,9,12.

Interestingly, in a case-control study it was observed that the risk for cervical intraepithelial neoplasia grade II and III decreased in ex-smokers (p-trent = 0.004), showing a benefit in relation to the time they stopped using tobacco⁷.

Regarding the findings on the use of oral contraceptives, in a study conducted by Oh HY et. al, it was observed that those patients who had a history of severe smoking and concomitant use of oral contraceptives as a consequence had a higher risk of grade II and III intraepithelial neoplasia⁶.

Currently, the role of inflammation, within the study of the tumor microenvironment, is one of the main fields of cancer research. There is evidence for a strong link between chronic inflammation and cancer. Inflammation has been implicated in initiation and progression of tumors, as well as elimination of cancerous cells.

Many lifestyle habits produce low but constant levels of inflammation that can increase the risk of cancer. Highlights include food, tobacco, alcohol, infectious agents, obesity, among others. In women, both HPV related to sexual habits and smoking related to socially accepted toxic habits, produce chronic inflammation and meta-inflammation, constituting targets for the prevention and treatment of CIN with Lifestyle Medicine. Numerous anti-inflammatory agents including those identified from natural sources have been shown to exhibit chemopreventive activities.

There is limited publication on clinical trials related to tobacco and CIN. The present work is one of the first systematic reviews on the association between smoking and cervical intraepithelial neoplasia. Our study included an important number of heterogeneous studies. Additionally, inherently it has the recognized limitations of the observational studies.

Overwhelming evidence exists from multiple sources that cigarette smoking significantly increases the risk of multiple chronic diseases including heart disease and stroke, diabetes, and cancer.

Despite the widespread recognition of the important role of lifestyle medicine measures and practices as a key component of the treatment and cancer prevention, scant progress has been made in improving the habits and actions of the women population. Working on the preventive model of cancer with Lifestyle Medicine is essential for both the medical community and decision makers in public health.

CONCLUSION

The available evidence supports the association between tobacco use and cervical intraepithelial neoplasia. Likewise, it was evidenced that smoking is not only associated with cervical intraepithelial neoplasia, but particularly high-grade intraepithelial lesions. Finally, more attention should be given to those patients who use oral contraceptives and consume tobacco, since this combination can increase the risk of cervical intraepithelial neoplasia, so it is necessary to deepen further studies.

ACKNOWLEDGMENTS

First of all, we thank God for his blessings and opportunities, as well as the people who supported us in carrying out this work.

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