The current study indicated that a marker of atopic allergy, specific IgE to respiratory and food allergens, identifies a population with increased risk to SCC among persons with prior skin cancer. Furthermore, this increased risk is confined to individuals with fair skin, ie., those with a “burn” phenotype as determined by a dermatologist. Furthermore, IgE was found to be a highly stable biomarker over time and insensitive to diagnosis of cancer.
Allergy and allergic conditions are related to the etiology of several cancers, including pancreas, lymphoma, brain, and lung. While the skin is a primary target organ for allergic pathology [e.g
., atopic dermatitis (AD), eczema], little literature exists assessing the relationship of allergy and allergy biomarkers to skin cancers. The association of allergy to melanoma is equivocal: one study suggested marked reduction in melanoma in asthma patients in a health registry dataset (4
), another cohort study indicated an increased melanoma risk in male hayfever patients (8
), and a case-control study found a marked reduction in risk (5
). Non-melanoma skin cancers were examined far less, possibly due to their lack of capture in most central cancer registries; results have been mixed. A twin study suggested an increased risk of skin cancer with atopic eczema, but was non-significant due to low power (13
). A large cohort study found no relationship between non-melanoma skin cancer and allergy (6
), while a case control study saw a slight inverse relationship (7
). An inverse association also was observed in a study assessing potential effects of AD treatment on nonmelanoma skin cancer risk, using controls that had other types of dermatitis besides AD (14
). Two recent large cohort studies demonstrated clear age-dependent increased risk of non-melanoma skin cancer with atopic dermatitis (9
). These cohorts may suffer from surveillance bias as atopic dermatitis patients will be subjected to frequent cutaneous examination by their physicians or their increased cancer risk could be confounded by immunosuppressive therapies for dermatitis (for example, glucocorticoid or light therapy) rather than dermatitis pathology itself (9
). Our current study may suffer less from detection bias as all participants were actively screened for subsequent cancer on an annual basis. However, as individuals in the highest quartile of IgEs are most likely to be those participants who are under treatment for allergies there may have been some treatment bias. In support of a true association is that the increased risk was largely confined to fair-skinned individuals, and skin type should not affect intention to obtain treatments for allergy. Additional studies on immunologic conditions that may affect skin cancer risk should incorporate biological markers to help clarify relationships as we have done here.
While total IgE is a good indicator of an atopic individual, the Phadia-designed specific allergen panels are diagnostics for clinically-relevant allergies. Our current results indicate that these specific allergies more closely define the “allergic immune phenotype” that impacts risk of skin cancer. Risk ratios were larger and associated with dose-related trends in risk with the specific panels (respiratory and food). In our prior studies on brain cancer, total IgE was a predictor of risk but self-reported respiratory and food allergies, as well as the numbers of reported allergies, were more consistently and strongly inversely associated with risk than total IgE (12
It is likely that the specific allergy pathologies themselves underlie risk rather than simply the presence of IgE. For skin cancer, this result is consistent with the theory that increased inflammation induced by allergic dermatitis, caused by specific allergens that induce disease pathology, may promote skin cancer occurrence. Type I hypersensitivity reactions are associated with increased oxygen radicals, recruitment of granulocytes with inflammatory mediators, and subsequent tissue damage and tissue remodeling. This pathology could promote skin cancer, much the way that allergic asthma promotes lung cancer [fourteen studies reviewed in (17
)]. Our study population already had skin cancer, indicating that immune immunosurveillance systems had already failed once. It is not surprising that immunosurveillance mechanisms have failed a second time in these individuals (11
). Whether such effects occur among those without a prior history of skin cancer remains to be elucidated.
The effect of elevated serum IgE on risk of skin cancer clearly differed by skin type – those who sunburn easily exhibited an increased risk related to higher IgE, whereas those with a tendency to tan demonstrated a reduced risk but not statistically significantly so ( and ). There are known pathophysiologic and etiologic skin cancer differences between tan and burn skin type individuals in populations worldwide (18
). Darker skinned individuals, who exhibit the tan skin phenotype, are more likely to have an etiology of SCC involving burn scars or chronic infection, and a more aggressive phenotype (19
). This suggests that some of the difference in associations with IgE and subsequent risk of skin cancer by skin type may be accounted for by differences in the disease phenotypes, with solar-associated skin cancer being more susceptible to the impact of allergy/IgE. Whether allergy and IgE levels might be related to skin type is more difficult to discern. Skin color is associated with several physical parameters of skin, including lipid content, permeability, and the number of cell layers (20
), however, it is unclear if these differences affect allergies. Many allergy studies have found significant effects of socioeconomic and environmental factors on allergy separately from skin type, such as income, gender, house pets, and family history of atopic disease. Skin type may be confounded with one or more of these factors in the current study as well as many other allergy studies. Thus, while we accounted for some of the major risk factors for SCC occurrence, we cannot completely rule out the possibility of residual confounding.
While IgE is an immunoglobulin with a very short half-life in serum (about 48 hours), an IgE-related allergen reaction from a specific acute challenge (eg
., bee venom) can result in an elevated level of IgE for several years (21
). Our current data indicate that an IgE phenotype may be highly stable in individuals irrespective of allergen challenge – total IgE and perhaps more significantly, specific allergen IgEs are extremely stable for several years and over repeat measurements in different seasons, and insensitive to change in the presence of a new cancer. Very little information on longitudinal testing of IgE exists. Thus, the current result provides strong rationale for considering IgE as a stable biomarker of immune response in longitudinal studies rather than simply a transient and environmentally/seasonally labile marker. IgE as a marker could be effectively utilized in skin cancer case-control studies in which blood samples are collected after diagnosis.
In conclusion, allergy and allergy-associated IgE may impact risk of subsequent skin cancer among persons who have had a prior skin cancer. Respiratory allergy-related IgE is associated with a nearly 4-fold increased risk of skin cancer among persons with a sun sensitive skin type. Our findings raise the possibility that efforts to control allergy and IgE levels may be a new avenue of skin cancer prevention in susceptible populations.