Abstract
Background/Aim: Tobacco use is a recognized cofactor risk for cervical cancer induced by high-risk Human Papilloma Virus (HR-HPV). This study aimed to evaluate the specific influence of tobacco use on colposcopic examination results in women infected by HR-HPV.
Patients and Methods: HR-HPV-positive women undergoing a loop electrosurgical excision procedure (LLETZ) after colposcopic examination were considered for this study. A total of 819 patients from a regional screening program were included, of whom 320 were smokers and 499 non-smokers.
Results: Smokers were significantly younger (41.1 vs. 43.8, p<0.01), more frequently exhibited grade II colposcopic changes (63.9% vs. 53.3%, p<0.05), had worse histopathological outcomes (CIN2+: 75.7% vs. 67.9%, p<0.05; CIN3+: 51.4% vs. 44.0%, p<0.05), and higher rates of affected surgical margins, with borderline significance (22.6% vs. 17.8%, p=0.055). While no significant differences in viral clearance were observed at six months, smokers showed a trend toward worse outcomes at two years (p=0.07).
Conclusion: Smoking in any amount is associated with worse colposcopic and histopathological findings, and this occurs at younger ages.
Introduction
Tobacco consumption is known as a factor inducing numerous diseases, both benign and neoplastic. The mechanisms behind these diseases are based on both the carcinogenic effect of its metabolites and the indirect effects on target organs (1). Another mechanism involved in the oncogenesis of many tumors is infection (2). Both factors coincide in the case of oncogenesis induced by high-risk human papillomavirus (HPV-AR) (3).
However, cervical cancer is a preventable disease due to its well-known natural history. Screening programs have been able to identify precursor stages, which are treatable with minimal morbidity, and this, along with vaccination campaigns, results in a significant reduction in the incidence of this pathology (4).
One of the tools in managing preinvasive cervical pathology is colposcopy, which provides findings compatible with HPV infection (grade I changes) or suspected dysplastic, high-grade squamous intraepithelial/cervical intraepithelial neoplasia (HSIL/CIN2+) lesions (grade II changes), amenable to biopsy or direct treatment. One of the problems with colposcopy is the lack of sensitivity and its interobserver variability (5), as well as the relative lack of agreement between colposcopically directed biopsy and the final pathological result, as recently evidenced by our own group (6).
Smoking has been identified as a risk factor for developing cervical cancer. Tobacco smoke adducts act in synergy with HPV infection during this process (7, 8). Furthermore, smoking also worsens the prognosis of established disease (9). To the best of our knowledge, no previous study has correlated smoking with colposcopic findings in women infected by high-risk HPV.
Patients and Methods
We retrospectively analyzed a population of HR-HPV-positive women undergoing outpatient diagnostic-therapeutic LLETZ under colposcopic control (n=819) between January 2016 and September 2022.
All patients were recruited from the regional screening program of Cantabria. They were referred from their primary care centers after an HR-HPV-positive result, regardless of the corresponding cytology result, to the Cervical Pathology Unit of Hospital Universitario Valdecilla, Santander, Spain. The cervical swabs were analyzed using a PCR test (Genotypic variants 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68A-68B). For statistical analysis purposes, they were grouped into HR-HPV 16/18 and HR-HPV non-16/18.
Colposcopy was performed in a standardized manner, and colposcopic findings were categorized according to the current international nomenclature (10). Excision was performed under colposcopic control and local anesthesia (Lidocaine/Epinephrine 20 mg/ml + 0.0125 mg/ml injectable solution), excising the transformation zone completely using a 20 mm diathermy loop (Medtronic®, Minneapolis, MN, USA), applying monopolar 60 W energy.
The following variables were collected: age, parity, smoking habit, high-risk HPV genotype, colposcopic findings, histopathological biopsy results for pre-excisional CIN2+, histopathological results for CIN2+ and CIN3+ in the excised specimen, margin status, viral clearance, defined as negative PCR for HR-HPV at six months and two years.
All women reported their smoking status at the first visit (smokers: n=320; non-smokers: n=499). The smoker group was not categorized by years or intensity of consumption.
The professionals who performed the colposcopy were fully trained and accredited gynecologists. No evaluations or therapies were performed by residents in training. Patient assignment was random based on available time slots in consultation schedules.
Statistical analysis. Mean values ± 1 standard deviation values were studied and compared using the analysis of variance (ANOVA) test. Proportions were compared using the Chi-square (χ2) test. Differences were considered statistically significant when the p-value was equal to or less than 0.05. The statistical analysis was performed using SPSS V.25 software (IBM SPSS Statistics for Windows, Version 25.0., IBM Corp., Armonk, NY, USA).
Ethics. The study was approved by the Ethics Committee of the Valdecilla Health Research Institute (IDIVAL) with code 2021.405 on February 11, 2022.
Results
The smoker group was significantly younger (41.1 vs. 43.8, ANOVA F=11.7, p<0.01) and had a higher number of pregnancies (1.7 vs. 1.4; ANOVA F=4.6, p<0.05) (Table I). No differences were found regarding HPV genotype 16/18 (58.1% vs. 54.0%; χ2=1.3, p>0.1) or HSIL cytology findings (52.1% vs. 50.0%; χ2=0.8, p>0.1) (Table II).
Clinical variables.
Pre-excisional variables.
Regarding colposcopic findings, grade II colposcopic changes were significantly more frequent in smokers compared to non-smokers (63.9% vs. 53.3%; χ2=6.4, p<0.05). No differences were observed between both groups in pre-excisional CIN2+ histopathological findings (85.2% in smokers vs. 82.8% in non-smokers; χ2=0.6, p>0.1) (Table II). However, significant differences were observed in the definitive post-excisional pathological results (CIN2+: 75.7% in smokers vs. 67.9% in non-smokers; χ2=5.7, p<0.05 and CIN3+: 51.4% in smokers vs. 44.0% in non-smokers; χ2=4.3, p<0.05) (Table II). Regarding margin status, free surgical margins were observed in 77.4% of smokers compared to 82.2% in non-smokers, with findings at the borderline of statistical significance (χ2=2.8, p=0.055). Regarding viral clearance at six months, a negative PCR for HR-HPV was found in 59.9% of smokers vs. 64.6% of non-smokers, with no significant differences (χ2=0.8, p>0.1), while there was a trend toward statistical significance in favor of non-smokers at two years (58.6% in smokers vs. 66.1% in non-smokers; χ2=3.1, p=0.07) (Table III).
Post-excisional results.
Discussion
Our study highlights two key facts: First, it is more common to find worse and more suspicious colposcopic findings, described as grade II changes according to standardized terminology (10), in smokers compared to non-smokers (63.9% vs. 53.3%). This finding, unlike previous epidemiological (8, 11) and clinical (9, 12) studies, correlates for the first time colposcopic findings subject to specific colposcopy terminology with smoking habits in HPV-AR-infected women and suggests that these findings occur earlier in smokers.
This first finding is supported by the second observation, where tobacco use is associated with worse histopathological outcomes in specimens obtained after complete excision in our cohort. These worse histopathological results agree with data from previous studies (8, 9, 11, 12).
Furthermore, we also observed worse results in the surgical margin status, with a higher incidence of affected margins in smokers compared to non-smokers (22.6% vs. 17.8%), although this was at the statistical significance threshold (p=0.055). A negative margin is a therapeutic goal that should be achieved with a free margin rate of 80% or higher, and an affected endocervical margin rate of less than 15% (13). Our data could suggest that changes found in the cervical epithelium of smokers make it more difficult to achieve this goal.
Additionally, the smoker population was significantly younger (41.1 years vs. 43.8 years), which suggests that tobacco is an aggressiveness factor, accelerating the clinical course and reducing viral clearance compared to non-smokers. In support of this hypothesis, Collins et al. showed in their cohort that young smoker women are at a higher risk of developing HSIL/CIN2+ than non-smokers, and non-smokers achieve greater viral clearance (12).
Negative PCR for HR-HPV is the best criterion for defining post-excisional prognosis. In our sample, tobacco was not a differential factor at six months (59.9% vs. 64.6%). However, at two years, the differences found (58.6% vs. 66.1%) were at the significance threshold (p= 0.07). These results agree with those found in the literature (15).
Conclusion
Colposcopic findings in smokers infected by HR-HPV were significantly worse, regardless of the number of cigarettes consumed. These findings occurred at significantly younger ages. Similarly, the rate of high-risk lesions, even invasive carcinomas, found in excised surgical specimens (LLETZ) was significantly higher in the smoker group.
Footnotes
Authors’ Contributions
Diego Erasun supervised data collection and conducted statistical analyses. Ana Vázquez del Campo, Alazne de Castro, and Alberto Muñoz Solano collected data from medical records. José Schneider designed and supervised the study and wrote the final article. All Authors critically reviewed and discussed the article.
Conflicts of Interest
All Authors declare no conflicts of interest in relation to this study.
- Received January 23, 2025.
- Revision received February 17, 2025.
- Accepted February 18, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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