We observed an association between OC use and SCC risk, with a duration-related increase among women who used OCs ≥25 years before diagnosis. In addition, among these women, we detected an interaction with the Lys751Gln polymorphism in the DNA repair gene XPD.
Estrogen-induced keratinocyte malignancies could arise through similar pathways that are thought to influence the risk of other cancers, including cellular proliferation, metabolism leading to the generation of free radicals, and DNA adduct formation from estrogen-quinone metabolites (Zhu and Conney, 1998
; Cavalieri et al., 2000
; Hilakivi-Clarke et al., 2002
). Clinically, skin changes after the intake of OCs, including melasma, suggest that individuals have an enhanced response to UV exposure when taking OCs (Resnik, 1967
; Mathison and Haas, 1970
; Horkay et al., 1975
; Sedee and Beijersbergen van Henegouwen, 1985
; Cooper and George, 2001
). Thus, there may be additional pathways to consider for SCC. Furthermore, estrogen binds to the estrogen receptor, a transcription factor, influencing gene expression in cells (Urano et al., 1995
; Verdier-Sevrain et al., 2004
). If the expression profiles of cells change, this may alter susceptibility to UV carcinogenesis. Our findings of an interaction between the DNA repair gene, XPD
, and OC use on SCC risk are consistent with this hypothesis. Furthermore, the direction of the XPD
results are consistent with previously published NER findings, where no elevated risk was observed among those with variant alleles. As described earlier, this was expected as keratinocytes with a variant allele likely have more unrepaired DNA damage, and thus undergo apoptosis. However, with exposure to OCs and proficient repair, an increased SCC risk was observed.
Although plausible, a relationship between OCs and risk of SCC requires further study, as very few epidemiological studies have evaluated this question. A cohort study among women in England and Scotland reported no association between OCs and a loosely defined category of all skin cancers other than malignant melanoma (Vessey et al., 2000
). A weakness is that the study relied on self-reported skin cancers without histological confirmation, increasing the likelihood of incomplete ascertainment and diagnostic misclassification. A clinic-based study of all malignant and non-malignant skin cancers combined reported no difference in the percentage of controls compared with skin cancer cases who reported ever using OCs (Wei et al., 1994
). However, the lack of histological distinction between skin cancers limits the opportunity to observe an association, particularly as these cancers arise from different cell types. Overall, results from these previous studies cannot be readily compared with our analysis in which we studied histologically confirmed, incident cases of SCC.
Findings of an excess SCC risk in relation to OC use conceivably could be confounded by the associations between OC use and sun-seeking behavior, that is, if women who took OCs were more likely to spend time in the sun. Indeed, among controls in our study, OC users had a history of more sunburns and reported more episodes of sunbathing than non-users (data not shown). However, after adjustment for sunburns, additional UV exposure variables such as sunbathing or other recreational UV exposures did not change our risk estimates. Another issue is whether individuals who were more susceptible to the effects of UV while taking OCs (e.g., melasma) were more likely to either cease taking them or change their sun-exposure behavior (e.g., by avoiding UV, applying sunscreens). We were unable to answer these questions directly; however, few participants in this study reported experiencing melasma (four controls and seven SCC cases), and their duration of OC use did not differ from those who did not experience melasma (data not shown). Age and education also related to both OC use and SCC. To examine the possibility of residual confounding, we restricted to those born in 1940 or later, but the association between OCs and SCC was, if anything, stronger, and the association remained even after restricting to women who had had some college education (data not shown). Furthermore, we examined the association within age strata but found that the relationship between time since last use and SCC showed a doubling in risk (data not shown). Nonetheless, residual confounding and chance cannot be ruled out entirely.
The potencies of the estrogen and progestin components used in OCs have changed over time along with a decrease in the overall dose. Furthermore, there are variations in the formulation across a 1-month cycle. A stronger association for women who used OCs ≥25 years before diagnosis could reflect the use of earlier compositions of OCs, which contained the highest levels of estrogen (e.g., ≥50 μg of estrogen); however, unfortunately we were not able to evaluate specific doses of OCs used in this analysis. Epidemiological studies involving complete OC histories could help elucidate the nature of the relationship with SCC and may provide insight into the effect of estrogen content and dose, as well as disease latency. Additional research is needed to determine whether more recent compositions of OCs may also be associated with SCC.
A potential limitation of our analysis is recall bias, for example, that cases may have better recall of their OC history than controls. In a case–control study of breast cancer (Nischan et al., 1993
), investigators compared self-reporting of OC use with medical records data. They found no significant differences for breast cancer cases and controls in their ability to report on duration of use, time since first use, and time since last use. Given that SCC is a less-severe cancer than breast cancer, there should be less of a concern about reporting bias for these same variables in this study. Alternatively, a concern may be that an association reflects greater detection of SCCs among women who took OCs because they may be seeking more medical treatment, in general, than those who did not take OCs. Although this possibility exists, there were few current users of OCs and the association of interest was among women who last used OCs at least 25 years ago; thus, reducing the likelihood for this potential bias.
Our findings raise many questions regarding whether the use of OCs is a potential risk factor for SCC among women. More epidemiological research is needed to examine whether the findings observed here can be replicated. In addition, a better mechanistic understanding of OCs on keratinocyte carcinogenesis would shed light on whether OC use is contributing to the rising incidence rates of SCC among women in many regions of the world.