Role of Dietary Factors in the Development of Basal Cell Cancer and Squamous Cell Cancer of the Skin

Diet may play a substantial role in the development of many cancers and it has been estimated that ∼35% of all cancers are due to dietary factors (1). Although the influence of diet on the development of skin cancer is of considerable interest (2), the results of all salient epidemiologic studies have not been systematically reviewed.

Keratinocytic cancer is the most commonly occurring cancer among light-skinned populations and includes two types of cancer with distinct clinical, pathologic, and genetic features: basal cell cancer (BCC) and squamous cell cancer (SCC; refs. 3, 4). The key factor responsible for development of keratinocytic cancer is UV radiation (5). Other factors, including diet, may play an important role (2, 6) and dietary factors are hypothesized to act at many points in the multistage process of carcinogenesis (7, 8).

UV radiation induces skin cancer through the formation of DNA mutations or lesions induced by the absorption of UV photons and damage to various immune mechanisms (9-12). UV-induced free radicals can also damage cellular proteins and cell membrane carbohydrates and fatty acids, thus influencing the process of carcinogenesis through altered cellular communication (11), changes to cell receptor functioning (7), and alterations in DNA repair systems and cell proliferation pathways.

This review focuses on the role of fats, retinol, carotenoids, vitamin E, vitamin C, and selenium in the development of BCC and SCC and aims to evaluate the available epidemiologic evidence for these dietary factors. These particular dietary factors have been hypothesized to play a role in skin cancer development based on the results of animal and in vitro studies and have been the focus of epidemiologic research in humans (7, 8, 11, 13-22). Table 1 summarizes the potential mechanisms by which these dietary factors may act in the development and prevention of skin cancer. Although there are other nutrients that may potentially influence skin cancer development, such as folate and polyphenols, to date, few studies have examined their role.

All published human studies investigating dietary exposure to fats, retinol, carotenoids, vitamin E, vitamin C, and selenium in relation to BCC or SCC of the skin were reviewed. Literature searches were conducted via Medline (23) and the reference lists of relevant articles were cross-checked and any additional studies were identified. Studies were included if they investigated dietary intake or if they used biomarkers of dietary exposure, such as plasma/serum biomarkers.

The studies were reviewed according to their study design, including details of the case ascertainment and whether the diagnosis of BCC or SCC was based on self-report, clinical or histopathologic diagnosis, and aspects of the exposure measurement, such as the dietary assessment method and the timing of the biomarker measurement. Other considerations included selection of the study population, the number of skin cancer cases, and the management of potential confounding factors. A few studies did not distinguish between the two types of keratinocytic cancer; that is, they combined BCC and SCC in the analysis and this limitation has been highlighted as necessary.

The results of each study were considered in the context of a hierarchy of epidemiologic evidence. Case-control studies provide the weakest evidence of a relationship between an exposure and disease compared with other study designs and, in particular, hospital-based studies because of inherent selection bias compared with population-based designs. Methodologically sound cohort and nested case-control studies provide good evidence and sound intervention studies are considered to provide the best evidence (24).

A total of 26 studies investigating BCC and SCC risk in relation to the specific dietary factors of interest were identified in the literature, published between 1983 and 2004. This included six case-control studies (five hospital-based and one population-based), five cohort studies, seven nested case-control studies, and eight intervention studies as summarized in Tables 2, 3, 4, and 5 respectively. The findings for each dietary factor have been considered separately.

There have been three cases-control studies (two hospital-based and one population-based), two cohort studies, and two intervention studies investigating the relationship between dietary fat and keratinocytic cancer in humans (15, 25-30).

Overall, the studies suggest there may be a possible relationship between fat intake and keratinocytic cancer risk. One cohort study showed a significant positive association between long chain n − 3 fatty acids and BCC and an inverse relationship with total fat and monounsaturated fat (30), whereas the remaining two hospital-based case-control studies (26, 29) and one cohort study (28) showed no significant effects for BCC. There was no association found between dietary fat intake and SCC in the hospital-based case-control study by Hakim et al. (27).

There have been two intervention studies showing a reduction of keratinocytic cancer risk (BCC and SCC combined) with a reduction of fat intake (15, 25). These intervention studies provide stronger evidence than observational studies; however, as BCC and SCC were not investigated separately in these studies, it is unclear whether these effects would apply equally to each type of cancer. Of note, in the intervention study by Jaax et al. (15), the low fat intervention also resulted in increased intakes of β-carotene, vitamin C, and fiber, which suggests an increase in fruit and vegetable consumption. This is important considering the evidence supporting a protective role for fruit and vegetable consumption and these nutrients in many types of cancer (8).

Although only one of the existing observational studies found a relationship between keratinocytic cancer and fat intakes, it is also important to consider that the level of fat intake applied in the intervention studies (20% of energy) would be considered very low in the general population (31). It is possible that the range of fat intakes among participants of the observational studies thus did not allow a corresponding effect to be identified and this may explain the contrasting results.

There have been three case-control studies (all hospital-based), two cohort studies, four nested case-control studies, and two intervention studies that have investigated the relationship between retinol (or vitamin A) and BCC or SCC (26, 28, 30, 32-39).

The results of studies investigating the relationship between retinol and keratinocytic cancer have been inconsistent. For BCC, an inverse association was shown with use of vitamin A supplements in the hospital-based case-control study by Wei et al. (39). No relationship was shown between either plasma retinol concentrations or intake in two case-control studies, two nested case-control studies (33), two cohort studies (28, 30), and two intervention studies (36, 37). In contrast, Breslow et al. (32) found that serum retinol levels were higher among patients with BCC compared with controls.

With respect to SCC, two intervention studies provided contradictory results with the study by Moon et al. (37) showing a protective effect of retinol, whereas the study by Levine et al. (36) found no protective effect. Both studies used a similar dose of retinol and included subjects with a previous history of skin cancer. The remaining observational studies (one hospital-based case-control study and two nested case-control studies) found no relationship with SCC (26, 32, 34).

Additionally, in one case-control study and one nested case-control study in which BCC and SCC were not investigated separately, there was an inverse association between serum retinol and keratinocytic cancer risk (35, 38).

There have been 15 studies investigating carotenoids and keratinocytic cancer, including 2 case-control studies (both hospital-based), 5 cohort studies, 5 nested case-control studies, and 3 intervention trials (28-30, 32-34, 40-45). The majority of these studies have investigated either serum/plasma levels or dietary intake of β-carotene only. Intakes of carotenoids other than β-carotene have been investigated in analyses of the Nurses' Health Study (46, 47) and in the cohort study by Dorgan et al. (45), and serum lycopene has been investigated in two nested case-control studies (32, 40).

There is little evidence for a protective effect of β-carotene in BCC or SCC. None of the studies investigating intake or plasma β-carotene concentrations found an association with BCC risk (one hospital-based case-control, three nested case-control, four cohort studies, and three intervention studies; refs. 28-30, 32, 34, 40-43, 45, 46). There have been fewer studies investigating β-carotene and SCC risk; however, no relationship was found in the two nested case-control studies (32, 34), two cohort studies (45, 47), and one intervention study (42) when either plasma β-carotene or intake was assessed. Only the hospital-based case-control study, which investigated BCC and SCC combined, found higher plasma β-carotene and a higher intake of β-carotene containing vegetables among controls compared with cases (35).

There is insufficient evidence to draw solid conclusions on the relationship between other carotenoids and BCC or SCC risk, as the evidence is limited to three cohort studies of α-carotene, β-cryptoxanthin, and lutein and/or zeaxanthin (46, 47) and two nested case-control studies of serum lycopene (32, 40). With respect to α-carotene, no relationship between was found with either BCC (two cohort studies) or SCC (two cohort studies) using either serum or dietary intake measurements (45-47). For β-cryptoxanthin and lutein and/or zeaxanthin, no relationship was identified in two cohort studies of BCC (45, 46), but for SCC the two cohort studies were inconsistent with one showing no effect (47), whereas a recent study using serum levels showed a positive relationship with SCC (45). Similarly, lycopene was found not to be associated with either BCC (one nested case-control study and one cohort study) or SCC (two nested case-control studies and one cohort study; refs. 32, 40, 45).

There have been 12 studies investigating vitamin E and the risk of keratinocytic cancer (28-30, 32-34, 39, 40, 45-48). Five of the studies investigated serum levels of vitamin E, whereas six of the studies investigated dietary intake of vitamin E and one study investigated intake of vitamin E supplements.

The evidence for a protective effect of vitamin E in BCC or SCC is weak. For BCC risk, no relationship was found between plasma and intake in six studies (one case-control, three cohort, and two nested case-control; refs. 28-30, 32, 40, 45). An inverse relationship was found between intake and BCC risk in two studies (one hospital-based case-control and one nested case-control; refs. 33, 39); in contrast, one cohort study showed a significant positive relationship between vitamin E intake and BCC risk (46). The four studies that investigated SCC showed no relationship with vitamin E (two nested case-control studies and one cohort study; refs. 32, 34, 45, 47). Similarly, the nested case-control study by Wald et al. (48), which did not distinguish between BCC and SCC, also found no significant association between serum vitamin E and keratinocytic cancer risk.

Three case-control studies (all hospital-based), four cohort studies, and one nested case-control study have investigated the dietary intake of vitamin C and one case-control study investigated the use of vitamin C supplements and risk of keratinocytic cancer (26, 28-30, 33, 35, 39).

With respect to vitamin C and BCC, the available evidence for a protective effect is weak. In analysis of the Nurses' Health Study cohort, Fung et al. (46) found a significant, but small, positive relationship between vitamin C intake and BCC, whereas the hospital-based case-control study by Wei et al. (39) showed an inverse association between BCC risk and use of vitamin C supplements. The four remaining studies (one hospital-based case-control study, two cohort studies, and one nested case-control study) found no relationship between vitamin C and BCC (28-30, 33).

There are fewer studies investigating vitamin C and SCC risk, with only one hospital-based case-control (26) and one cohort study (47); both found no relationship between vitamin C intake and SCC risk.

In addition, the hospital-based case-control study by Kune et al. (35) investigated BCC and SCC combined and found that a high intake of β-carotene and vitamin C containing foods was significantly related to reduced risk of keratinocytic cancer.

There have been two case-control studies (both hospital-based), three nested case-control studies, and one intervention trial investigating the relationship between selenium and keratinocytic cancer (29, 32-34, 49-51). Three of these studies investigated selenium exposure using serum/plasma measurements, whereas three studies investigated dietary intakes of selenium.

The evidence suggests that there is no protective effect of selenium in BCC or SCC. With respect to selenium and BCC, only one case-control study found an inverse relationship between plasma selenium and BCC (49), whereas no relationship with selenium intake or plasma concentrations was shown in the remaining studies (two case-control studies, two nested case-control studies, and one intervention study; ref. 50). Of the four studies investigating the relationship between selenium and SCC (one case-control study, two nested case-control studies, and one intervention study), none identified a significant relationship (32, 34, 49, 50).

This review has focused on evaluating the possible role of fats, retinol, carotenoids, vitamin E, vitamin C, and selenium in the development of cutaneous BCC and SCC. A total of 26 studies were critically reviewed according to study design and quality of the epidemiologic evidence. Overall, there is a possible positive relationship between fat intake and BCC and SCC, but for the remaining dietary factors the evidence is, at best, weak.

The potential mechanisms through which diet may influence the development of skin cancer, as summarized in Table 1, are well supported by the results of animal studies. Overall, the existing epidemiologic studies reviewed here have not provided strong evidence to support the role of dietary factors in skin cancer development. Dietary factors may not be of sufficient importance in keratinocytic cancer risk at a population level for an effect to be detected, and the effect of UV radiation may overwhelm any effects of diet. However, an ability to detect as association may also be hampered by limitations in the existing epidemiologic studies in key areas, including dietary exposure assessment, inclusion of subjects with previous skin cancers, and case ascertainment.

A potential explanation for the lack of effect of many of the dietary factors is that the relevant period of dietary exposure was not measured (28, 50, 52). It is acknowledged that BCCs have a long induction period and that the origins of disease may occur early in life (53). Serum/plasma biomarkers used in many of the studies are hypothesized to represent dietary exposure over the short term, and although the dietary intake measurements used have tended to represent a longer-term measurement of habitual intake (54), the appropriate exposure period may not have been investigated. Therefore, it is still possible that dietary factors may act at earlier stages of keratinocytic cancer development.

However, it has been shown that some dietary factors may act in the late stages of carcinogenesis. Synthetic retinoids have rapid effects on BCC risk and probably act in the late stages of carcinogenesis (28). This suggests that different dietary factors may act at different stages of the carcinogenic process, and the relevant exposure period may be different according the dietary factor under consideration.

Similarly, with respect to many of the interventions trials, it has been suggested that the treatment period may have been too short (50, 52). In reference to the potential effects of selenium, Clark et al. suggested that although an effect of selenium supplementation on total cancer mortality and lung, colorectal, and prostate cancer incidence could be detected the treatment period for BCC and SCC may have been to short (50). It was suggested that UV radiation increases the risk of BCC and SCC through a genetic mutation preventing apoptosis, which occurs early in the process of skin carcinogenesis, whereas in other types of cancer this mutation occurs late in the process. They proposed that if the primary protective action of selenium is the stimulation of cell death, prevention of SCC and BCC may require a longer treatment period than other cancers; otherwise, a significant number of cells already contain the mutation and selenium treatment cannot reverse the effects (50). With respect to trials of β-carotene supplementation, Manson et al. (52) also suggested that the treatment and follow-up periods of 5 years may have been too short. These authors also suggested that many of the skin cancers detected during the study period may have been present when the treatment began; therefore, β-carotene would not have had an effect unless it acted late in carcinogenesis. However, later studies with longer treatment periods also showed no effect, suggesting that this was not the reason for a lack of effect of β-carotene (41). An alternate explanation is that the cancer-protective action seen in observational dietary studies, which has been attributed to β-carotene, may not actually be due to β-carotene but due to some other dietary component that is closely associated with β-carotene (40, 55, 56). This has been suggested in the prevention of lung cancer where a large number of observational studies have supported the role of β-carotene, but large intervention trials have shown either no effect or an adverse effect (57).

This review included six case-control studies; however, case-control studies (and in particular, hospital-based case-control studies) provide the weakest evidence of a relationship between an exposure and disease compared with other study designs (24). Prospective study designs, such as nested case-control and cohort studies, avoid concerns over recall bias and clearly define the temporal relationship between exposure and onset of disease. This is particularly important when considering serum/plasma biomarkers as measures of dietary exposure (58). Contrasting results have been shown in studies using plasma biomarkers depending on the timing of the plasma biomarkers. In a case-control study of plasma selenium, there were significant inverse relations with BCC (49); however, in a study based on prospectively collected data, there was no association between keratinocytic cancer and selenium (32). Similar discrepancies were identified in the study by Wald et al. (38) in which mean serum retinol levels were significantly lower among cases compared with controls but only when patients with <1 year between collection of the blood sample and diagnosis of cancer were investigated. These results highlight the importance of using prospectively collected blood samples.

Many of the studies of BCC and SCC included participants that had had a previous BCC. These subjects are at a higher risk of subsequent skin cancers (59). It is unclear from the existing literature whether dietary factors act differently in the development of a first skin cancer or in subsequent skin cancers. The inclusion of participants with a previous history of skin cancer may only affect the findings if dietary factors act in the early stage of keratinocytic skin cancer. As described above, some dietary factors, such as retinol, have been shown to act in the later stages of carcinogenesis; however, early stage effects have not been completely dismissed.

A further limitation of several studies relates to the methods used for ascertaining cases of keratinocytic cancer. Firstly, several studies relied on health records and cancer registries, which increase the potential for misclassification with respect to skin cancer outcome (32, 33, 38, 40, 44, 48). Secondly, several studies only used self-report of keratinocytic cancer (28, 30, 46, 47). The validity of the self-report measures was assessed in analyses of the Nurses' Health Study and the Health Professionals' Follow-up Study (28, 30, 46), although in the former study it was conducted among a small number of subjects.

A few studies did not distinguish between the two types of keratinocytic cancer; that is, they combined BCC and SCC in the analysis (15, 25, 35, 38, 44, 48). Despite this, these studies were retained in the review as they included two intervention studies, which are considered to provide strong epidemiologic evidence. However, it is unclear whether the effects of diet would apply equally to each type of skin cancer and it is possible that combining the outcomes in the analysis may attenuate any effects of diet.

Another important limitation of the existing published literature is that in many of the earlier studies there is inadequate investigation and control for potential confounders (26). Many of the case-control studies match cases and controls for major factors, such as age and sex (29), but the potential confounding effects of other skin cancer risk factors are overlooked. This is important as there is clustering of healthy lifestyle behaviors (60, 61); for example, intakes of fruits and vegetables are higher in nonsmokers compared with smokers (62). These relationships may also exist between healthy eating behaviors and a variety of sun protection behaviors and other skin cancer risk factors.

Overall, the studies suggest that there may be a possible positive relationship between fat intake and BCC and SCC, whereas the results for retinol are inconsistent with both positive and negative relationships with both BCC and SCC observed. There is little evidence for a role for β-carotene in BCC or SCC development, whereas there is insufficient evidence on which to make a judgment for other carotenoids for either BCC or SCC. The evidence for associations between vitamin E, vitamin C, and selenium and BCC or SCC is weak.

Many of the studies of diet and keratinocytic cancer to date have limitations. The most common problems relate to limitations in the dietary exposure assessment, reliance on health records and cancer registries for cases ascertainment, combined analysis of BCC and SCC, small numbers of BCC or SCC cases, a lack of adjustment for potential confounding factors, and a lack of population-based studies. High-quality epidemiologic studies with adequate diagnosis of skin cancer, sufficient power, and adjustment for important confounding factors are required to clarify the role of many dietary factors in the development of skin cancer.

In addition, there remain several dietary factors that may have anticancer potential that have not been substantially investigated with respect to skin cancer, including flavonoids and other polyphenols, folate, vitamin D, Allium compounds, coumarins, riboflavin, and zinc (8). Further investigation into these dietary factors that may be involved in BCC and SCC development is required.