High while a positive association has been demonstrated

High activation of immune system may
lead to lower risk of several diseases. It had been shown that history of atopic
allergic conditions (Allergy) such as asthma, hay fever,
eczema and food allergies could be related with several types of cancer,
although the evidence is not entirely conclusive.  The aim of current review is to summarize the
current knowledge about association betw­­een allergy and the risk of cancers with
particular emphasis on case-controls and cohort studies to estimate of the cancer risk in
case with allergy.

 

 

 

 

 

 

 

Key
words: Allergy, Atopy, Asthma, Cancer, Tumor , Rhinitis

 

 

 

 

Introduction:

Allergic disorders (Allergy)
such as asthma, eczema, hay fever, allergic rhinitis and food allergies are common
health problems around the world and as a result of immune system response to innocuous
environmental antigens which is mainly mediated by TH2 response. In contrast to
TH2 cells, TH1 cells produce pro inflammatory cytokines and are the major
player in immunity against infections, eliminating cancerous cells as well as
autoimmune disorders (1). Imbalance of
these Th1/Th2 pathways is responsible for multiple immunological disorders
including allergies, autoimmune disorders and hypersensitivity reactions, consequently
manipulating and deviation one pathway toward the other is a promising strategy
for management of many immune-associated disorders, although there are some
controversies (1-4).

As the TH1 and TH2
cells down regulate each other, over activation of one system, may exacerbate or
relieve symptoms. In this regard inverse relationship between atopic dermatitis
(AD) and insulin-dependent diabetes mellitus as well as  different cancers reported (5). At the moment
there is controversy about the relationship between allergy and cancers. Some evidences
supported the protective role of Allergy against glioma (GM) (6), pancreatic
cancer (PC) (7), and
hematological malignancies (8), while a positive
association has been demonstrated between Allergy and lung cancer (LC) risk (9) and for Allergy
and gastrointestinal  (GI) cancers the
results has been inconclusive (10).

Two hypotheses suggest
the plausible mechanism for allergic conditions and tumor: immune surveillance
and the antigenic stimulation. The immune surveillance theory is frequently
used to demonstrate the inverse relationships between atopic diseases and many tumors
(8,
11, 12). It has been shown that T helper
Type 2 (Th2) cytokines, which participate in the pathophysiology of atopic disorders,
may contribute in antitumor immunity(13) by attracting
and activating eosinophils, macrophages, natural killer (NK) cells, and Type 2
CD8+ T cells. IgE as the essential player of
allergic reactions has the pivotal role in response to allergens and up-grading
allergic symptoms but recently researchers have concerned on its anti-cancer
properties and several studies demonstrated high tumoricidic effects of IgE (14,
15).

On the other hand, the
antigenic induction hypothesis suggests that overactive immune conditions stimulate
chronic cellular inflammation, causing DNA mutation in dividing cells and consequently
tumor initiation and propagation (16). In addition,
cytokines originated from Th2 cells such as interleukin 4 (IL-4), and IL-13 mediate
some biological effects, such as tumor proliferation, cell adhesion, cell
survival and lymph node-metastasis (17,
18).

Studies published
before 1985 provided evidences for reduced risk of cancer in allergic diseases (19). Finding of
epidemiological studies since 1980s are more complicated, implicating that the
association might rely on both particular Allergy and specific organs.
In
this review, we discuss the existing data on the association between Allergy and
different type of cancers. A critical evaluation of the literature in this matter
is essential to clarify previous controversial findings and to determine future
research directions.

Hematological
malignancies

Allergy has been
assessed as protective factors for several cancers including childhood leukemia. Evaluation
of 1842 children with acute lymphoblastic leukemia (ALL) disclosed that a
history of eczema correlated with a significant reduced risk for cancer (odds
ratio (OR)=0.7, 95% CI:0.5 to 0.9) in a case–control study in the USA(20). Also, history
of AD was related with significantly 50% lower risk for ALL and not-significantly
20% decrement in the risk of acute myeloid leukemia (AML) (21). Controversy, a
study including 180 childhood ALL patients in Taiwan demonstrated no
significant association of childhood ALL with history of eczema (OR 1.1, 95% CI:0.6
to 2.0) (22). Studies evaluating
association in adult leukemia have mixed results. A non-significant risk of chronic
lymphocytic leukemia (CLL) in adults with a history of eczema was announced in
USA population (23). A case-control
record and population-based study reported that any allergy and asthma was
related with an greater odds of childhood ALL (24).
Specifically,
in a meta-analysis performed in 2010 on childhood/adolescent ALL, the risks of
atopy/allergies, asthma, hay fever and eczema were 0.7, 0.8, 0.5, and 0.7 (95%
CI: 0.5 to 0. 9; 95% CI: 0.6 to 1.0; 95% CI:0.4 to 0.5; and 95% CI:0.6 to 0.9)
respectively (8). Recently, a
cohort population- based study in UK revealed that atopy is linked with a 50 %
lower risk of CLL (relative risk (RR)=0.5, 95 % CI: 0.3 to 0.8)(25).

Hodgkin lymphoma (HL) ,
malignancy of B-cell, is one of the most prevalent cancers in younger adults (26). It has been proposed
that Allergy might be related with an increased risk of HL, particularly in
younger cases (27). It has reported
that history of allergic rhinitis was correlated with a non-significantly lower
risk of HL (OR = 0.8, 95 % CI: 0.6 to 1.0; P = 0.09)(28). Similarly, self-reported
of hay fever, was associated with a 14% lower risk of non-Hodgkin (NHL) in a
large population-based study (29).

Breast cancer

Breast cancer (BC) is
the second most frequent cause of cancer related mortality among women
worldwide. In 1985s, a study reported no association between BC risk and hay
fever, but the risk of BC was rather decreased in women with history of hives
or other allergies (19). But in other
study, a history of allergies or hay fever was related with a 20% lower risk of
BC (95 % CI: 0.7 to 0.9) (30). Also, among young
American women, an allergic condition was associated with a low risk of BC (31). Other several
studies of allergies and BC risk represented no association, although may not
have had enough power to evaluate this association (32-34). Case control studies evaluating relationships
of allergy and BCs was shown in table1.

Petridou and collogues found serum
IgE level positively associated with BC in Greek population(35). Moreover, there was positive relationship
between history of allergy and serological test. In a meta-analysis conducted
in 2009, there was no association between IgE and BC (36). Recently, it
has been shown that serum IgE levels were significantly lower in BC patients than
healthy subjects (37). Conflicting results which
discussed above might be as a result of interfere effect of many varied
allergic factors.

In Canadian individuals,
asthma was not related with BC risk overall; but, a significant decrement in BC
risk was observed only in premenopausal women (30). The reason may
be explained by difference in pattern of asthma among pre- and postmenopausal women,
as allergic asthma is usually occur earlier compared to non-allergic asthma (38,
39) which affects
older people (40-43).

Pancreatic
cancer

Pancreatic cancer (PC) as
a fourth cause of cancer related mortality worldwide has extremely poor
prognosis. A meta-analysis of 14 PC studies showed the 30% and 45% lower risk
in subjects with history of any allergies and nasal allergies, respectively (44). Other review exploring
11 published studies reported reduced risk of PC in respiratory allergy
conditions such as allergies to plants or pollen or hay fever (45). In PanGenEU study
conducted on 1297 pancreatic ductal adenocarcinoma (PDAC) cases and 1024 normal
controls above 18 years old revealed that asthma was related with 40 % reduced
risk of PDAC (95% CI:0.5-0.9) which consist with a result of meta-analysis of
10 case–control studies (OR=0.7, 95% CI:0.6- 0.9). Nasal allergies and associated
symptoms were protective factor for PDAC (OR=0.7, 95% CI: 0.5 to 0.8 and OR= 0.6,
95% CI: 0.5 to 0.8, respectively) which confirmed by a meta-analysis of nasal
allergy studies (OR=0.6, 95% CI: 0.5 to 0.7) (46).

Controversy, cohort
studies performed in different countries (34,
47, 48) reported no association between PC
risk and serum Ig E levels, history of Allergy, or skin prick tests. These
inconclusive results may be attributed to young studied population and short follow
up, resulting to only a small number of cases; Furthermore, data were not
adjust for potentially confounding factors.

The underlying mechanisms
of association between Allergy and PDAC risk are unclear. It has been proposed
that hyperactive immune system involved in subjects with Allergy(10). Furthermore,
susceptibility and severity of asthma and allergies are known to be affected by
genetic factors and interactions between gene and environment (49-51). Further researches are needed to
clarify the role of genetics in these relationships. In addition, it has been found
that cromolyn as an anti-allergic agent can suppress proliferation and propagation
of human PC cells invitro and invivo (52).

Gastrointestinal
(GI) cancers

Studies reporting the
association of Allergy and GI cancers have had different results (10).
Allergy
were described to be protective factors in a case–control studies on CRC patients
(53,
54). Although, these
studies used self-reported history of atopy and did not differ between different
types of allergies; so, it may be lead to misclassification. In contrast,
cohort studies did not advocate the protective effect of atopy against CRC (33,
55). A prospective data
analysis of first National Health and Nutrition Examination Survey (NHANES I) showed
non-significant higher risk  (RR=1.7, 95%
CI: 0.9 to 3.1) among 45 CRC patients regarding to any type of allergy(34). The Busselton cohort
study noted that Allergy is a protective factor, although non-significant for
CRC (33). Cohort
studies investigating association between Allergy and CRCs was presented in
table 2.

A meta-analysis of 16
studies in 2009 found no association between Allergy and CRC risk (36). A study among
colon and rectum cancer patients in Taiwan reported an inverse relationship
between allergic rhinitis and only rectum cancer (56). The Iowa
Women’s Health study highlighted history of two or more atopic conditions correlated
with a 42% decrement in CRC risk (57). More recent
cohort study among different ethnic population explained that Allergy were a
protective effect against CRC among both men and women (RR = 0. 9, 95% CI: 0.8
to 0.9) in all populations except Latinos. Also, Allergy cases had a 20% fewer
CRC-related mortality (58).

Ye et al.
reported that higher risk of esophageal and gastric cancers in asthmatic
patients which may be due to the more gastro-esophageal reflux in these
patients (59). Several case-control
studies have reported inverse relationships between esophageal tumor and history
of allergy (60-62). Kallen et al. reported a
50% lower risk of stomach cancer mortality among asthmatics; but, cohort
studies reported no significant relationships(63).

The biological mechanism
for the correlation of Allergy with CRC is not understood but could be as a
result of antitumor functions of type I Ig E-mediated immune activity. This
effect leads to migration of immune cells such as eosinophils and mast cells to
intestinal mucosa. Allergens can enter the body through respiratory system and
the digestive system, where mast cells and eosinophils are widespread (64). This can result
to type I Ig E-mediated hypersensitivity reactions, due to the high activation
of eosinophils and mast cells and over response of T-helper cell type II. Complexes
of Ig E and cancer cell can degranulate mast cells which release factors to enhance
permeability and inflammation (65). Eosinophil
levels are speculated to have cytotoxic effects and antitumor activity on
precancerous cells that drive from high proliferating tissues, such as the gut
lining (57,
66, 67). Due to the high presence of
eosinophils and degranulation of mast cell in the respiratory mucosal lining of
asthmatic cases, leukocytes in the gut of subjects with atopic conditions is
more (68). Another theory,
termed the prophylaxis hypothesis proposed that immune responses and
inflammation in mucosal layer can cause to further rapid clearance of mutagenic
stimulators (10).

Brain cancer

Since early 1990s, many
studies reported that Allergy may be related with a lower risk of brain tumors (55,
69-73).

In a case–control study
in Boston displayed an inverse association of glioblastoma with medications for
any kind of allergies (RR= 0.6, 95% CI: 0.4–1.0) (74). In a multicenter
international case–control research recruited data among 1178 patients history
of allergy was a protective factor (OR=0.4, 95% CI: 0.5–0. 7) for GM. (75-78). Several case–control and cohort studies
highlighted the protective effect of Allergy against GM (Table1)(21,
79, 80). It has been presented a lower
risk of GM among people with a history of allergy in Swedish twins cohort and hospital
discharges cohort (21). A
meta-analysis published in 2009 disclosed that meningioma (a low-grade tumor)
did not display inverse relationship with Allergy in adults (70).

INTERPHONE is a large
population based case–control study performed among 13 country included 2103
patients with different type of brain tumor, as well as  2520 normal controls. Finding of this study
indicated an significant inverse association between a history of any allergy
and GM (OR = 0.7, 95 % CI: 0.6 to 0.9), acoustic neuroma (OR = 0.6, 95 % CI:0.5
to 0.8) , and meningioma (OR = 0.8, 95 % CI: 0.6 to 0.9), but not parotid gland
tumors (OR = 1.2, 95 % CI: 0.7 to 2.0) (81). Brenner
et al. in a multicenter hospital-based study among adults reported a 2.4-fold
increased risk of having a history of hay fever for acoustic neuroma (95 % CI
1.4 to 4.0)(80). Also, it has
been shown that  an inverse relationship
between prediagnostic IgE levels and GM risk (73,
82). In another
population-based case–control study (CEFALO), among children and adolescents was
not observed any relationship between Allergy and all type of brain tumor (OR=1.0;
95% CI: 0.7 to 1.3)(83). Recently, Porcelli et al in a cross sectional study
investigated allergic condition may protect against pediatric brain tumors
(PBT) development in individuals with Neurofibromatosis type 1 (NF1). Non-significant inverse
relationships between asthma and PBTs were reported. Although, this association was
strongly more in the younger than in the older age group (84).

Lung cancer (LC)

Almost all scientific
findings indicated that history of allergic disease related with greater risk
of LC. Multiple case–control studies among never-smoker reported risks of LC
associated with asthma to be 1.1–2.7 (85-88). A population-based case–control
study among Missouri woman found the asthma was a non-significant risk factor (OR=1.2,
95% CI: 0.8 to 2.1) in smokers and significant risk factor (OR=2.7, 95% CI: 1.4
to 5.4) in non-smokers (86). This finding
is compatible with finding of study conducted among never-smoking women in five
city areas of the USA with risk of 1.7 (95% CI: 1.1 to 2.5) for history of
asthma (87). A study in 98
female cases of small cell lung cancer (SCLC) and 204 controls reported history
of asthma related with statistically significant increased risk of LC after
adjustments (89). A study in
China reported the increased risk of asthma (OR=2.0, 95% CI: 0.9 to 4.2) among nonsmokers
even adjusting for smoking history (OR=2.1, 95% CI: 1.5 to 3.0) (88).

In a case–control study
including 437 nonsmoking cases and 437 controls was revealed no significant association
among nonsmokers, however a higher risk was found after adjusting for smoking
history (OR=2.1, 95% CI: 1.0 to 4.1)(90). In two studies
in USA were not observed any association between history of asthma and LC after
adjusting age and smoking history (91,
92). It have been
shown a %50 reduced risk for LC among 217 case–control pairs women with asthma
or hay fever from the Californian nested case–control study (93). Similarly, prospective
cohort studies displayed a higher risk of LC among asthmatic patients. In a
prospective study on a Finnish twin cohort, the risk of LC-mortality was higher
in men with asthma (94). In a large ancient
study covering 78000 participants, the risk of LC was increased (Standardized
Incidence Ratio (SIR) = 1.3 in men and SIR = 1.7 in women) among asthmatic patients
(95). In Swedish
patients which hospitalized for asthma (96), the SIR was
1.6 (95% CI: 1.5–1.7) during 8.5-years follow up.

Bladder cancer
(BlC)

An early case-control
study expressed that a history of atopic condition was associated to higher
risk of BlC in men, but with a lower risk in women (97). Other case-control
studies have demonstrated positive relationships of having history of asthma
and either urothelial tumor (98) or BlC (99). Interestingly,
risk of BlC increased in asthmatics with the glutathione S-transferase (GSTM1)
or glutathione S-transferase (GSTT1) null genotypes. This finding was speculated
to be as a result of a lack of the detoxification of reactive asthma medication
intermediates by a deficiency of these enzymes (99). In cohort
studies was reported no significant associations (55) or advanced
risk for BlC in asthmatics patients only among men (95).

Rhabdomyosarcoma

 

Rhabdomyosarcoma (RMS)
is a scarce and high malignant cancer of developing skeletal muscle which can happen
anywhere in the body. Lupo et al in a case-control study of 322 RMS
cases and 322 controls found that allergies and hives were negatively related
with childhood RMS (OR = 0.6, 95% CI: 0.4 to 0.9) (100).

Prostate cancer

Prostate cancer (PrC)
is one of most frequent malignancy in men and remains a main public health
problem(101). There are several
studies exploring possible effect of systemic inflammation conditions on
prostate carcinogenesis. In a study was assessed single-nucleotide
polymorphisms (SNP) between patients with PrC and normal controls revealed that
4 genes (TLR1, TLR6, OAS1, and OAS2) participate in innate inflammation
pathways were associated to higher risk of Prc (102). Also, it has
been found that increased white blood cell count, as a marker of systemic
inflammation, was significantly associated with advance PrC risk (103). Results from large-scale
cohort study including 16,934 men which performed by Severi and coworker revealed
a small increment in PrC risk in asthmatic patients compared to controls (HR:
1.2, 95% CI: 1.05 to 1.5) (104). Furthermore,
the risk was further elevated in cases allocating antiasthma medications such
as inhaled glucocorticoids, systemic glucocorticoids, and bronchodilators.

In a prospective questionnaire-based
cohort study reported that men with a history of asthma had a 30% low risk of
lethal PrC (101). In contrast, Zhao
et al reported 86 of 1552 asthmatics were diagnosed PrC during follow-up (33). In the large nationwide
study, asthma was an independent risk factor for PrC and was associated to a
136% higher risk after adjustment for possible confounding variables. Also, there
was no direct relationship between history of glucocorticoids consumption and PrC
diagnosis. Glucocorticoids joined with mutated androgen receptors which may lead
to development and progression of androgen-independent PrC (105). Although,
there is inadequate document to establish this theory associated to prostate
carcinogenesis.

In a large,
population-based case-cohort study including 4124 cases with asthma and
8248 full-matched healthy control subjects, asthma was significantly associated
with PrC (OR= 2.4, 95% CI: 1.2 to 4.6) and its independent risk factors were
age and hypertension (106).

Head and neck
cancer (HNC)

Head and neck cancer
(HNC) (tumors of the oral cavity, larynx oropharynx, and hypopharynx) is the
fifth most frequent cancer worldwide. A meta-analysis of 14 studies showed an protective
effect of allergy symptoms for HNC (OR=0.8, 95 % CI: 0.6 to 0.9) (107). In contrast,
cohort studies showed that higher serum IgE levels were related with an higher
risk of HNC (108). In a cohort study
with 14,849 participants subjects with positive tests for serum specific IgE for
inhalant allergens had higher risk of HNC (OR=1.7, 95 % CI: 1.0–3.1). In other
cohort including 37747 subjects, high IgE levels was linked with an higher risk
of oral and pharyngeal cancer (OR=1.4, 95 % CI:1.0 to 1.8) (25).

Recently, Liao et al
reported that elevated serum total IgE levels was related with a significantly 1.7-fold
higher HNC. Symptomatic allergy was related with a significantly 40% decrement
of HNC risk. Notably, asymptomatic atopic cases had a higher risk of HNC than
subjects with normal serum IgE level and no allergy symptoms(109).

Squamous cell carcinoma (SCC) and early
onset basal cell carcinoma (BCC)

There are limited data
about the contribution of atopic and allergic conditions in the etiology of
keratinocyte tumors. In 2003, Twin Cohort study reported that females with a
history of AD prone to be more likely to affect a basal cell carcinoma (BCC), but
it was non-significant (OR=1.8, 95% CI:0.8 to 3.9) (110). A Danish
nationwide cohort study reported that increased risk of both squamous cell
carcinoma (SCC) and BCC among subjects who had a history of AD (111). Results from a
nested case–control study of skin cancer patients demonstrated that cases who
developed a new primary cutaneous SCC had higher prediagnostic IgE levels than
controls who did not (112). Similarly, a
higher risk of SCC was reported in asthmatics subjects compared with non-asthmatics
subjects (Table2) (113). Other studies
presented positive (113), negative (19,
56, 63, 114), and null association between BCC
and SCC and allergic condition (19,
114, 115). In a population-based
case–control study including 375 early onset BCC patients and 251 controls, as
well as 254 SCC patients and 432 controls, an overall inverse association was
reported between an allergic conditions and risks of early onset BCC but not
SCC. Interestingly, reduced risks of either early onset BCC or SCC related to
atopic history was noticed only in women (116). Although,
almost all studies was discussed above had limited data about possible
modifying factors, for instance age at onset, type of allergy and its severity,
as well type of medications.

Cervical Cancer
(CC)

Cervical
cancer (CC) is a malignant cancer of the cervix with nearly 277,000 new
diagnosed cases and 266,000 deaths annually (117). A case-control study among USA individuals reported
that an odds of history of any allergy was 0.7 (95 % CI: 0.6 to 0.9) for
squamous cell SCC. Also, they estimated the risk of CC related with SNPs in the
chromosome 5 cytokine cluster genes(118).

Discussion

Despite the hesitant
results, the currently available data from case-control and cohort studies indicate
that Allergy is related with a lower risk of cancer. Further research should
focus on a more carefully defined atopy status and manifestation of different
atopic diseases, to advance our understanding of the role that allergies might
play in the risk of developing cancer.  Prophylaxis hypothesis may be the more probably
explain the inverse association between Allergy and certain cancers. Actually,
relationship between cancer risk and allergy symptoms was more commonly
highlighted in malignancies of tissues or organs which interface the external
environment such as GI cancers than others such as breast and prostate tumors.

Many of previous
reports above collected data of allergy symptoms retrospectively; so recall
bias is plausible. Also, study participants may mistake non-allergic symptoms
and over-estimated the allergy symptoms. Additionally, an ongoing chemoradiotherapy
may influence the manifestation of Allergy (119), which could
affect recall when subjects declaring history of atopic diseases.
 The involvements of
allergic inflammatory pathways in growth and development of cancer provide an
opportunity for further evaluation and consideration. Moreover, establishment
of the genetic mechanisms behind the association between Allergy and cancers
might allow a novel insight to development of primary prevention and promising
approach for effective treatments for cancer patients.