Cancer is a major threat to population health and is currently the second leading cause of death in Canada and the United States.1, 2 Cancer researchers have attempted to describe a role for various biological, lifestyle, and environmental factors in cancer development, including a potentially important role for the immune system.3, 4, 5 The concept of immune surveillance, first proposed almost a century ago,6, 7 suggests that the immune system is continuously searching for and destroying tumor cells as they arise. Although historically controversial, recent scientific advancements have led to renewed interest in the immune surveillance theory.3, 7, 8, 9
It has been suggested that those with a history of allergy, in particular atopic disorders, may possess an enhanced capacity for immune surveillance.10, 11, 12, 13 Although it has been commonly assumed that the atopic immune response offers little benefit to individuals, recently, it has been argued that it may offer a valuable evolutionary advantage.14, 15 This immune response may also be related to cancer development.
Numerous epidemiological studies have evaluated some aspect of the association between a history of allergy and cancer occurrence. In this article, we provide an overview of the epidemiological evidence and discuss a number of methodological issues important in this area of study. A critical assessment of the literature in this area is important to clarify previous conflicting reports and to determine future research directions.
Literature searches were conducted using the MEDLINE database from 1966 through August 2005, using standard search procedures.16, 17, 18, 19 Articles that explored a personal history of allergic disorders as a risk factor for cancer were sought. The following MeSH headings and key words were used: allerg$, atop$, hypersensitivity, asthma, hay fever, rhinitis, eczema, dermatitis, hives, skin test$, cancer, tumor, tumour, malignancy, neoplasm, leukemia, leukaemia, lymphoma, myeloma, hodgkin, and glioma.
Study selection was restricted to human and papers written in English. Case reports and descriptive studies were excluded. Additional studies were identified through hand searching reference lists. For multiple publications, only the most relevant article was included. The studies were categorized by cancer site and study design, and the overall and subgroup results were examined while taking into account possible study limitations, including sample size, exposure measurement, confounding, and other methodological issues. Relative risks were rounded to one decimal place, and all standardized mortality ratios (SMR) and standardized incidence ratios (SIR) were converted to base one hundred for consistency.
A total of 148 epidemiological studies were identified that evaluated some aspect of the association between a history of allergy and cancer occurrence. The studies took place largely throughout North and South Americas, Asia, and Europe. This overview provides a brief historical perspective and a detailed discussion of the most relevant epidemiological studies published by cancer site.
A number of early case-control studies reported an inverse association between allergy and cancer all sites combined.20, 21, 22, 23, 24, 25, 26, 27 These early studies were hospital-based, and many of which involved small sample sizes20, 21, 24 and little control for potential confounders.20, 21, 22, 23, 24, 25, 26, 27 The results from early cohort studies were not consistent and also involve small numbers of cancer cases and have little or no control for possible confounders.12, 28, 29, 30, 31, 32
Several large cohort studies have recently examined this association. Results from large record linkage studies of asthmatics have reported conflicting results. In Sweden, a record linkage study of 64,346 people treated in hospital for asthma found a significant inverse association for all cancer mortality (standardized mortality ratio (SMR) = 66, 95% confidence interval (CI) = 64–68) and for site-specific cancer mortality.33 Another study linking 77,952 people on the Finnish Social Insurance Institution Register who had received reimbursement for asthma medication with the Finnish Cancer Registry reported a significant positive association for all cancer in men (standardized incidence ratio (SIR) = 112, 95% CI = 107–117) but not women (SIR = 103, 95% CI = 98–107).34 Both of these large record linkage studies were unable to control for individual level covariates in analysis. We recently analyzed data from the American Cancer Society (ACS) prospective cohort of nearly 1.2 million participants.35 A significant inverse association was reported for all cancer mortality in participants who reported a history of both asthma and hay fever (relative risk (RR) = 0.9, 95% CI = 0.8–0.9). The estimate attenuated slightly upon restriction to never smokers (RR = 0.9, 95% CI = 0.8–1.00). The remaining out of all cohort studies revealed few significant findings,36, 37, 38, 39, 40 including 3 studies using skin prick testing as an indicator of allergic status.11, 41, 42 Overall, the studies conducted to date provide little clear evidence that allergies are associated with cancer overall.
Several case-control studies that did not control for smoking found significant inverse associations between lung cancer and a history of allergies, atopy, or asthma.43, 44, 45, 46, 47 Since smoking is a major risk factor for lung cancer, adequate control for smoking is critical. Recently, a meta analysis estimated a combined odds ratio (OR) of 1.8 (95% CI = 1.3–2.3) from previous case-control studies that evaluated lung cancer risk in never smokers with asthma versus those without asthma.48 A RR of 1.7 (95% CI = 1.3–2.2) was found when combining the results for all case-control and cohort studies that controlled for smoking history in the analysis. It was concluded that asthmatics are at increased risk of lung cancer; however, potential misclassification and differential recall bias in previous studies are still of concern. The potential positive association between asthma and lung cancer may be due to various mechanisms, including: (i) elevated levels of free radicals and reduced levels of antioxidants in the respiratory tract,49, 50 (ii) continual stimulation of cell regeneration to repair inflammatory lung damage,49, 51 and/or (iii) an increased sensitivity to carcinogens.34
Population-based case-control studies and cohort studies have generally reported no association between a history of asthma and pancreatic cancer.10, 34, 52, 53, 54 Previous studies that evaluated hay fever in relation to pancreatic cancer risk all reported an inverse association with point estimates ranging from 20–70% reductions in risk with some findings significant.10, 53, 54, 55 Recently, a meta-analysis reported a significant inverse association between a history of any allergy (RR = 0.8, 95% CI = 0.7–0.99), respiratory allergy (RR = 0.6, 95% CI = 0.5–0.8), and atopy (RR = 0.71, 95% CI = 0.6–0.8) and pancreatic cancer risk.56 No association was found with a history of asthma. The most recent case-control study, which did not use any proxy data, reported numerous inverse associations for pancreatic cancer in relation to various allergies, allergic conditions, and symptoms.57 A significant exposure-response relationship was also found with risk decreasing with increasing number of allergies and severity of symptoms. In our recent analysis, we also recently reported a significant inverse association for pancreatic cancer mortality in the overall ACS cohort among participants with a history of hay fever (RR = 0.85, 95% CI=0.77–0.95) but not asthma.35 Similar results were found among never smokers (RR hay fever = 0.84, 95% CI = 0.71–1.0).
Neoplasms of lymphatic and hematopoietic tissue
Non-Hodgkin's lymphoma (NHL)
Although case-control studies have generally reported inverse associations of NHL with a history of asthma or hay fever, conflicting results for other indicators of allergic status (specific allergies or eczema) have been reported58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 and few prospective studies exist. Unstable risk estimates were reported in 3 prospective studies with few cases.11, 12, 39 Of the remaining cohort studies, one large record linkage study reported a decreased risk of fatal NHL in asthmatics (SMR = 61, 95% CI = 51–74),33 with no significant findings reported in the others.34, 35, 70 Notably, one case-control study that evaluated risk for NHL in HIV positive men found a significant inverse association with an allergy to grass, hay, leaves, plants, and pollen.64 It was suggested that this inverse association may be due to the continual capacity for differentiation of B-cells.64
Hodgkin's disease (HD)
There is no convincing evidence to support an association between a history of allergy and HD. All cohort studies involve very small numbers of cases.11, 28, 32, 33 Virtually all case-control studies, with the exception of those by Vineis et al.69 and McKinney et al.,66 reported no significant relationships.68, 71, 72, 73 Vineis et al.69 reported that a reduced risk of HD was significantly associated with a history of hay fever (OR = 0.5, 95% CI = 0.3–0.8), but not with eczema (OR = 0.7, 95% CI = 0.4–1.3) or allergies (OR = 0.9, 95% CI = 0.5–1.4). McKinney et al.66 reported HD to be positively associated with a history of eczema (OR = 1.9, 95% CI = 1.2–3.0), but reported no association with a history of allergies.
In adults, it remains unclear whether a history of allergy is associated with leukemia. The majority of case-control studies are relatively small in size, few are population-based, and few consistent or significant results have been reported.60, 66, 74, 75, 76, 77, 78 Two case-control studies did note inverse relationships between specific forms of leukemia and number of allergies or allergic conditions.76, 77 Few cohort studies have evaluated leukemia as an outcome. Two cohort studies were based on very small numbers of cases.11, 12 Both Mills et al.39 and Söderberg et al.70 reported nonsignificant results for leukemia in relation to a variety of indicators of allergic status. Two large record linkage studies both reported inverse associations for incident and fatal leukemia with a 14–45% decrease in risk in asthmatics.33, 34 We also reported a significant inverse association of leukemia mortality with asthma (RR = 0.8, 95% CI = 0.6–0.98) in the ACS cohort but not with any other indicator of allergic status.35
Some inverse associations were reported in studies of childhood leukemia. Wen et al.79 found that acute lymphatic leukemia (ALL) in children was inversely related to a variety of allergic conditions, as well as an inverse relationship between ALL and number of allergies. Nishi and Miyake80 reported a significant inverse association for childhood ALL of the non T cell type in relation to a history of atopy (OR = 0.3, 95% CI = 0.1–0.8). A 60% reduction in risk for childhood leukemia was associated with a history of previous hospitalization for allergic disease.81 A large case-control study of childhood leukemia in Germany also reported significant inverse associations of ALL in children with a history of allergies and atopic conditions.82 Spector et al.,83 however, reported a 2-fold increase in risk for ALL among children with a medical record of atopy or hives.
Overall, little evidence exists for a relationship between allergy and multiple myeloma, with the majority of studies reporting no association.33, 34, 35, 39, 60, 69, 70, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 Williams et al.95 restricted cases to light chain myeloma and found no association with a history of allergy. A large case-control study by Lewis et al.92 evaluated risk of a multiple myeloma by immunoglobulin (Ig) subtype. Although no overall association was found, a significant positive association was reported between IgG myeloma in whites and a history of eczema (OR = 2.1, 95% CI = 1.1–4.2) or any allergic condition (OR = 1.6, 95% CI = 1.1–2.3). Another study examining risk factors for multiple myeloma by Ig subtype reported no association with a history of allergy.90 An increasing risk for multiple myeloma with increasing number of allergies was reported by Bourguet and Logue85; the results, however, were nonsignificant and based on a very small number of cases.
Case-control studies have consistently reported inverse associations between a history of allergy and the occurrence of glioma96, 97, 98; however, few prospective studies exist with which to confirm an association and limitations such as the use of proxy respondents and the potential for reporting biases in cases remain a concern. A large international case-control study examined various potential risk factors for brain cancer among adults in 8 centers.97 Upon pooling of the data, inverse associations were found between glioma and a history of any allergic disease (OR = 0.6, 95% CI = 0.5–0.7), asthma (OR = 0.8, 95% CI = 0.6–1.0) and eczema (OR = 0.6, 95% CI = 0.5–0.9). Brenner et al.96 reported significant inverse associations between glioma and various allergy measures, including a history of any allergy (OR = 0.7, 95% CI = 0.5–0.9), asthma (OR = 0.6, 95% CI = 0.4–0.9) and a chemical allergy (OR = 0.2, 95% CI = 0.1–0.9), but not hay fever (OR = 1.0, 95% CI = 0.7–1.4). Wiemels et al.98 reported a significant 50% reduction in risk for glioma in relation to a history of any allergy, with other significant findings noted for specific allergies and allergic symptoms. A significant trend in risk was also noted, with risk decreasing as the number of allergies increased. Recently, Wiemels et al.99 in another case-control study measured IgE levels in glioma cases and controls as a biomarker of allergic status. An OR of glioma risk in those with elevated IgE levels compared to normal levels of 0.3 (95% CI = 0.2–0.6) was reported. IgE levels were, however, not found to be strongly related with self-reported allergy. A small prospective study based on the Swedish Twin Registry reported an inverse association between allergies and glioma in a cohort of same gender twins born between 1886 and 1925 (hazard ratio (HR) = 0.4, 95% CI = 0.2–1.1).100 Allergies were associated with a reduced risk for high grade (HR = 0.4, 95% CI = 0.1–1.9) but not low-grade glioma (HR = 2.6, 95% CI = 0.9–7.8) in a cohort of same gender twins born between 1926 and 1958. It has been suggested that those with an allergic history may be better able to mount a successful immunological antiglioma response.98, 101
No significant association was reported between meningioma and a history of allergy in previous case-control studies.96, 97, 102 The Swedish Twin Registry study reported a doubling in risk for meningioma among those with any allergic condition.100 Brenner et al.96 reported that acoustic neuroma was significantly and positively associated with hay fever (OR = 2.4, 95% CI = 1.4–4.0), allergy to food (OR = 3.0, 95% CI = 1.1–8.5) and allergy to other substances (OR = 3.8, 95% CI = 1.4–10.0). In the ACS cohort, we found no association between a history of any asthma or hay fever and brain cancer mortality.35
The association between a history of allergy and reproductive cancers has received less attention. Although certain inverse associations have been reported, particularly among the record linkage studies, in general, results have been inconsistent, and no clear evidence exists.
Mills et al.39 reported an 87% reduction in the risk of ovarian cancer in relation to a history of reaction to poisonous plants, as well as a significant inverse relationship with a number of allergies. No other significant associations were found with other allergy measures in this study. Except for the study by&#130;Kallen et al.,33 all other studies have reported no significant association between ovarian cancer and atopy, asthma or hay fever.27, 34, 35
Previous case-control studies have reported no association between a history of allergy, asthma, or hay fever and uterus cancer.27, 103 Previous record linkage studies in asthmatics reported inverse associations ranging from 24–64%.33, 34 Mills et al.,39 however, reported inconsistent results for risk of endometrial cancer in those with asthma or hay fever in the Seventh-Day Adventist cohort. We noted a nonsignificant inverse association between mortality of cancer of the corpus and uteus, not otherwise specified and a history of asthma and hay fever in the ACS cohort (RR = 0.6, 95% CI = 0.3–1.1); however, the results were based on only 12 cases with both disorders.35
A case-control study reported a significant inverse association between cervical cancer and a history of hives (OR = 0.6), but not asthma or hay fever.27 Recently, a tripling in risk for cervical cancer was reported among those with eczema, although this was considered to be likely of the nonatopic type.104 The same study also reported no association between a history of hay fever and cervical cancer.
A reduction in the risk of breast cancer by nearly half was reported among asthmatics in a case-control study of women in Montreal.105 Kallen et al.33 reported a reduction in risk of a similar magnitude for breast cancer mortality among individuals diagnosed with asthma in Swedish hospitals. Although inverse associations were also reported in several other case-control studies,103, 106 all remaining studies, including several prospective studies, reported no significant association between a variety of indicators of allergic status and breast cancer.12, 27, 34, 35, 39, 107
A 5-year cohort study in Japan reported an elevated risk of prostate cancer among those with asthma (RR = 22.8, 95% CI = 5.5–94.7).108 The results were based on only 10 cases and were subject to potential biases related to screening or hospital-based recruitment. A larger population-based cohort study also reported a positive association between prostate cancer and asthma (HR = 1.9, 95% CI 1.0–3.6), but no association with hay fever (HR = 1.1, 95% CI 0.6–2.0).107 A sub-cohort of participants in this study who were also skin-prick-tested demonstrated a significantly increased risk of prostate cancer among those with allergy to house dust mites (HR = 2.9, 95% CI = 1.3–6.7). The remaining cohort studies12, 34, 35, 39 reported no significant association, with the exception of the study by Kallen et al.33 who reported a SMR of 72 (95% CI = 67–78).
Swerdlow et al.109 reported increased risks for testicular cancer in relation with a history of atopy (OR = 1.8, 95% CI = 1.1–3.1), hay fever (OR = 2.6, 95% CI = 1.2–5.6), eczema (OR = 3.1, 95% CI = 1.0–10.0) and asthma (OR = 1.7, 95% CI = 0.8–3.6). All remaining studies that examined the association between testicular cancer and allergy, again with the exception of Kallen et al.,33 reported no association.110, 111
Results from previous case-control and cohort studies have not been entirely consistent27, 39, 112; however, some inverse nonsignificant107, 113, 114 and significant findings have been observed.33, 34, 35 A nonsignificant inverse association between colorectal cancer and a history of allergies was reported in large case-control studies by Negri et al.114 and Kune et al.113 A prospective study by Talbot-Smith et al.107 recently reported a reduced risk of colorectal cancer in association with a history of asthma or hay fever, although none were significant. We reported a significant inverse association between a history of both asthma and hay fever and colorectal cancer mortality (RR = 0.8, 95% CI = 0.6–0.9) in the overall ACS cohort, and a similar finding in never smokers (RR = 0.8, 95% CI = 0.6–1.0).35 Kallen et al.33 also reported a significant inverse association for colon and rectal cancer mortality in asthmatics; however, Vesterinen et al.34 reported a significantly increased risk for rectal cancer in relation to asthma in women (SIR = 142, 95% CI = 117–169).
Esophageal and stomach cancer
Inconsistent results were reported in studies of esophageal and stomach cancer risk. Elevated risks were reported for esophageal and gastric cardia adenocarcinomas in asthma patients by Ye et al.,115 which were attributed to excess gastro-esophageal reflux in that population. Several, mostly small, case-control studies have reported inverse associations between esophageal cancer and a history of allergy.103, 116, 117 Kallen et al.33 reported a 50% reduction in risk for stomach cancer mortality in asthmatics; however, remaining cohort studies reported no significant relationsips.34, 39
Medullary thyroid carcinoma
The association between a history of allergies and medullary thyroid carcinoma was evaluated in a pooled analysis of 14 international case-control studies.118 Upon analysis of 48 cases and 240 controls, a doubling in risk was found for medullary thyroid carcinoma in those with a history of allergies. The authors suggested, however, that the positive association observed may be due to the release of vasoactive compounds by the tumor causing allergic-like symptoms to be reported in cases.
An early hospital-based case-control study noted that a history of allergy was associated with an increased risk of bladder cancer in men (OR = 1.7), but a reduced risk in women (OR = 0.3).119 More recent case-control studies have reported positive associations between a history of asthma and both urothelial cancer (OR = 3.1, 95% CI = 1.4–6.8)120 and bladder cancer (OR = 4.2, 95% CI = 1.6–10.8)121 with risk increasing for bladder cancer in asthmatics with the glutathione S-transferase-[mu] (GSTM1) (OR = 9.2, 95% CI = 2.3–37.8) or glutathione S-transferase-[theta] (GSTT1) (OR = 19.2, 95% CI = 2.3–160.1) null genotypes. This finding was suggested to be due to a deficiency in the detoxification of reactive asthma medication intermediates through a lack of these enzymes.121 Among cohort studies, Mills et al.39 reported no significant findings, while Vesterinen et al.34 reported a significantly increased risk for bladder cancer in asthma patients among men (SIR = 125, 95% CI = 103–149) but not women (SIR = 90, 95% CI = 60–128).
Conclusions and future directions
A history of allergy has been inversely associated with risk for cancer at a number of sites; however, it is difficult to draw conclusions at many sites because of inconsistent findings and limitations of previous studies. For many cancer sites, few large prospective studies evaluating cancer incidence exist, and few have been able to adjust for potential cancer site-specific confounders, in particular cigarette smoking. Further study is needed in the validation of indicators of allergic status for use in large epidemiological studies, including biomarkers to reduce potential misclassification of allergic status and to confirm the results of previous studies based on self-report. The use of skin-prick testing and IgE levels were examined in few studies. More importantly, in advance of additional expenditure in epidemiological studies of this type, there is a need for further basic research to clarify the mechanisms behind an association, should one exist. Although great advances have been made, the role of the immune system in cancer development as well as relevant differences between allergic and nonallergic individuals require further clarification. Laboratory studies of gene knock out mice may help to determine individual genes that are involved in the allergy and cancer processes and delineate if they are related. Gene chip microarray studies may also help to determine specific animal gene targets and whether such targets can be extrapolated to human homologues that would then be applicable to population health studies.