Elsevier

Gynecologic Oncology

Volume 128, Issue 2, February 2013, Pages 265-270
Gynecologic Oncology

The role of co-factors in the progression from human papillomavirus infection to cervical cancer

https://doi.org/10.1016/j.ygyno.2012.11.003 Get rights and content

Abstract

Objective

Co-factors for cervical cancer, including oral contraceptive (OC) use, smoking and multiparity have been identified; however, the stage at which they act in cervical carcinogenesis is not clear. We compared established risk factors among women with CIN2 and CIN3 to evaluate the heterogeneity of these factors in precancer and also assessed their role during cervical carcinogenesis.

Methods

The current analysis included 2783 women with various stages of cervical disease who were enrolled in the Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED) and the Biopsy Study. Associations of co-factors within cervical precancer and at different stages of cervical carcinogenesis were estimated using logistic regression.

Results

Long-term OC use (10 + years vs. never: OR = 2.42, 95% CI: [1.13–5.15]), multiparity (3 + births vs. nulliparous: OR = 1.54 [1.04–2.28]), smoking (ever vs. never: OR = 1.95 [1.48–2.58]), and no Pap test in the previous five years (2.05 [1.32–3.17]) were positively associated with CIN3 compared to CIN2. We observed that long-term OC use, parity and smoking were associated with an increased risk of CIN3 compared to < CIN2 (1.97 [1.12–3.46]; 2.23 [1.59–3.11]; 2.60 [2.04–3.30], respectively), whereas associations were not significantly different (OC use, parity) or showed decreased risk (smoking) when comparing cancer to CIN3.

Conclusions

Differences in established risk factors suggest that CIN3 is a more specific definition of precancer than CIN2. Hormonally-related factors and smoking play a role in the transition from human papillomavirus infection to precancer.

Highlights

► CIN2 and CIN3 are heterogeneous with respect to known cervical cancer risk factors. ► Hormonal factors are important for the progression from HPV infection to precancer. ► Smoking promotes progression from HPV infection to precancer.

Introduction

Cervical carcinogenesis is defined by a multistage progression model where persistent infections with carcinogenic human papillomavirus (HPV) types lead to cervical precancer, which if left untreated can become invasive carcinoma [1], [2]. The risk factors that influence the first stage of this model, infection, are well studied and are related to sexual behavior. Pooled analyses of epidemiological studies have established several co-factors for cervical cancer, including long term oral contraceptive (OC) use, smoking, multiparity and lack of cytology-based screening [3], [4], [5]; however, with the exception of screening, the mechanisms by which these factors increase risk are not clear. In addition, these studies have focused on comparing women with cancer to those without disease and little is known about how these co-factors potentially influence risk at different stages of cervical carcinogenesis.

Evaluating associations of risk factors during cervical carcinogenesis requires an accurate definition of cervical precancer. This can be challenging when working with the existing framework for histologically classifying precancerous lesions, which combines cervical intraepithelial neoplasia-2 (CIN2) and CIN3. Whereas CIN3 is a clear precursor lesion for cancer, CIN2 suffers from limited reproducibility and frequent misclassification [6], [7], [8]. Despite these limitations, recent recommendations for the histological diagnosis of cervical disease proposed a two-tiered approach, combining CIN2 and CIN3 for treatment decisions [9], [10]. However, it remains important to understand potential differences in risk profiles among these disease categories in order to better define cervical precancer and limit overtreatment.

In the current study, we used cross-sectional data from a large referral population in Oklahoma to compare established cervical cancer risk factors (OC use, smoking, multiparity, and screening history) in women diagnosed with CIN2 and CIN3. In addition, we assessed the role of these factors at the transition stages of the cervical carcinogenesis model.

Section snippets

Study population

Women with a recent abnormal Pap smear or biopsy diagnosis of CIN referred to the colposcopy clinic at the University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK were invited for enrollment in either SUCCEED between 2003 and 2011 or Biopsy Study between 2009 and 2011. Details of the SUCCEED and Biopsy Study design, inclusion and exclusion criteria have been described elsewhere [11], [12]. Briefly, women were excluded if they were less than 18 years of age, pregnant at the time

Study population

Characteristics with regards to demographics and distribution of cervical cancer risk factors based on histological diagnoses of the study population are presented in Table 1.

Risk factor associations in CIN2 and CIN3

We evaluated potential differences in risk factor associations to determine whether CIN2 and CIN3 should be combined as precancer in this population. Compared directly to CIN2, CIN3 was positively associated with long-term OC use (10 + years vs never: OR = 2.42, 95% CI [1.13–5.15]), multiparity (3 + live births vs. nulliparous:

Discussion

Pooled analyses of case–control data have established several risk factors for cervical cancer, including OC use, parity, smoking and lack of cytology-based screening [3], [4], [5]. Most studies to date have compared cancer cases with controls, and there is limited data about how these factors act at different stages of cervical carcinogenesis. The few reports that have evaluated co-factors have only reported associations at the early transition to cervical precancer and did not compare

Conflict of interest statement

The authors declare that there are no conflicts of interest.

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