Evaluating the Association between Smoking Behaviors and Anal or Vulvar High-Grade Squamous Intraepithelial Lesion (HSIL) Recurrence

HPV-induced high-grade squamous intraepithelial lesions (HSILs) of the anus and vulva have high rates of recurrence after treatment. While many studies have demonstrated the positive association between smoking and primary lesion development, research on its association with anal and vulvar HSIL recurrence is limited. Methods: We used data from a randomized controlled trial assessing the impact of HPV vaccination on the risk of anal and vulvar HSIL recurrence to design a longitudinal study with smoking as the primary exposure. To assess HSIL recurrence, participants were established at baseline screening as HSIL-negative and biopsies during the study were used to diagnose new HSIL. Participants were categorized as never, former, and current smokers at enrollment, and unadjusted and adjusted Cox-Proportional Hazard models were constructed to compare risk of HSIL recurrence by smoking status. Additional smoking variables were investigated to evaluate the risk of HSIL recurrence among regular smokers. Results: During the study, there were 26 recurrences of anal HSIL and 11 recurrences of vulvar HSIL among the 188 enrolled participants. Current smokers accounted for 19.7% of the participants, 18.1% former smokers, and 61.7% never smokers. Compared to never smokers, current smokers had 60% increased risk of HSIL recurrence (aHR: 1.60, 95% CI: 1.02, 2.52), and the risk estimate was higher in analyses limited to anal HSIL participants (aHR: 2.73, 95% CI: 1.37, 5.43). Former smokers did not have increased risk of overall HSIL recurrence, compared to never smokers (aHR: 0.91, 95% CI: 0.58, 1.41). Smoking risks were further elevated among participants who reported higher numbers of cigarettes smoked per day and longer duration of lifetime smoking. Among ever smokers, smoking more than 20 cigarettes per day increased risk of overall HSIL recurrence, compared to smoking less than 10 cigarettes per day (aHR: 1.37, 95% CI: 0.51, 3.71), but this increase was not statistically significant. Comparing participants who smoked between 3-14 years, those who smoked between 15-24 and 25-34 years did not have increased risk of HSIL recurrence, but those who smoked between 35-45 years had a marginally elevated risk of overall HSIL recurrence (aHR: 2.32, 95% CI: 1.00, 5.36). Among anal HSIL participants, compared to smoking 3-14 years, smoking for more than 14 years significantly increased risk of HSIL recurrence (15-24 years aHR: 3.48, 95% CI: 0.95, 12.67; 25-34 years aHR: 4.79, 95% CI: 1.13, 20.34; 35-45 years aHR: 8.00, 95% CI: 1.61, 39.77). Increased total years of smoking was found to be associated with increased risk of anal HSIL recurrence (p = 0.05) but not vulvar HSIL recurrence (p = 0.38). Conclusions: Current smoking and total smoking years elevate the risk of anal and vulvar HSIL recurrence to varying degrees. Smoking is a modifiable risk and thus cessation should be highly encouraged, especially at primary lesion diagnosis.