eczema (OR 1.1, 95% CI:0.6–2.0)
(23).
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 (24).
A case-control study in Taiwan reported that any allergy and asthma was related
with an greater odds of childhood ALL (25).
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: 0.5–0. 9; 95% CI: 0.6–1.0; 95% CI:0.4–0.5; and 95% CI:0.6–0.9) 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:0.3–0.8)(26).

Hodgkin lymphoma (HL) ,
malignancy of B-cell, is one of the most prevalent cancers in younger adults (27).
It has been proposed that Allergy might be related with an increased risk of
HL, particularly in younger cases (28).
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 ,1.0;P = 0.09)(29).
The results with a lower incidence of self-reported Allergy in HL patients are compatible
to observations in studies of Non-Hodgkin lymphoma (NHL)         ??? ?? ??? ?????? ?? ????? ?? ????? ??? . ???? ????? ????
????? ???? ???)(30).

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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 (20).
But in other study, a history of allergies or hay fever was related with a low risk
of BC (OR = 0.8, 95 % (CI): 0.7–0.9) (31).
Also, among young American women, an allergic condition was associated with a
low risk of BC (32).
In a linkage study, contact allergy has been associated with decreased BC risk (33).
Other several studies of allergies and BC risk represented no association, although
may not have had enough power to evaluate this association (34-36). Case control studies evaluating relationships
of allergy and BCs was shown in table1.

In Canadian individuals,
asthma was not related with BC risk overall; but, a significant decrement in BC
risk was observed only in premenopausal women (31).
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 (37, 38) which affects older people (39-42).

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 (43).
Also, several studies have confirmed their finding, but only one study
estimated a non-significant decreased risk???? ???? (7, 44-47). 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 (48).
Regarding skin allergies, two studies announced negative association but only
one reached statistical significance(46, 47).

In a study conducted on
1297 PDAC cases and 1024 normal controls revealed that asthma was related with
reduced risk of PDAC (OR=0.6, 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: 0.5-0.8 and OR= 0.6,
95% CI: 0.5-0.8, respectively) which confirmed by a meta-analysis of nasal
allergy studies (OR=0.6, 95% (CI):0.5- 0.7) (49).

Controversy, cohort
studies performed in different countries (36, 50, 51) 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 (52, 53). A study investigating SNP in 56
allergy-associated candidate genes revealed that genetic variants may be related
with a fewer PC risk (54).
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
(55).

Colorectal Cancer

Colorectal cancer (CRC)
is another most common malignancies regarding to incidence and mortality (56).
 Studies reporting the association
of Allergy and digestive tract tumors have had different results (10).
Allergy
were described to be protective factors in a case–control studies on  CRC patients in Australia and Italy (57, 58). 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. Another cohort
study in California reported (RR=1; 95% CI: 0.7–1.3) for colon cancer and (RR=0.9;
95% CI: 0.5–1.4) for colon and rectum cancer (35, 59). Cohort studies investigating
association between AAC and CRCs was presented in table2.

A meta-analysis of 16
studies in 2009 found no association between Allergy and CRC risk (60).
A study among colon and rectum cancer patients in Taiwan reported an inverse relationship
between allergic rhinitis and only rectum cancer (61).
The Iowa Women’s Health study highlighted history of two or more atopic
conditions correlated with a 42% decrement in CRC risk (62).
More recent cohort study among different iethnic population explained that Allergy
were a protective effect against CRC among both men and women (RR = 0. 9, 95%
CI: 0.8-0. 9) in all populations except Latinos. Also, Allergy cases had a 20% fewer
CRC-related mortality(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 inhance 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 (62, 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 (59, 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). Two case–control and three cohort
studies highlighted the protective effect of Allergy against GM (Table1)(22, 79, 80). It has been presented a lower
risk of GM among people with a history of allergy (OR=0.5; 95% CI: 0.2–1.0) in Swedish
twins cohort and (HR=0.5; 95% CI: 0.1–1.9) for high-grade GM in hospital
discharges cohort (22).
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: 0.6–0.9), acoustic neuroma (OR = 0.6, 95 % CI:0.5–0.8)
, and meningioma (OR = 0.8, 95 % CI: 0.6–0.9), but not parotid gland tumors (OR
= 1.2, 95 % CI: 0.7–2.0) (81). There
are few reports about acoustic neuroma. Brenner et al. in a case–control
study of 96 cases and 799 controls reported a significant positive association
between a history of hay fever and acoustic neuroma (OR = 2.4, 95 % CI 1.4–4.0),
which was stronger with an older age at diagnosis or shorter disease duration (80).
Two studies in adults noted an inverse relationship between prediagnostic IgE
levels and GM risk (73, 82).

Another
population-based case–control study (CEFALO), among children and adolescents in Denmark,
Norway, Sweden, and Switzerland. There was no relationship between Allergy and all
type of brain tumor (OR=1.0; 95% CI: 0.7–1.3). The risk of Allergy at present
and in the past were 0.8 and 1.2 (95% CI 0.5–1.1; 95% CI: 0.9–1.7) respectively.
Similarly, these results were repeated for GM (83). In contrast,
results of two case–control studies among children with brain tumor was
compatible with the results of studies of adults (84, 85). They reported greater declines risk
for PNET/medulloblastoma than pilocytic astrocytoma or GM (84, 85).The older age-range of
participants in CEFALO
study (7–19 years) compared with 0–14 years in the two other reports might
explain some of controversies, as the distribution of brain cancer subtypes vary
between these studies. Moreover, the distribution of GM subtypes greatly
differs from adults. The main type of adult GM is stage 4, and the rest are
stage 3 or 2, but main GMs in children are stage 1 (pilocytic astrocytoma).
This may explain the discrepancy between findings of studies with different age
range.

Lung cancer (LC)

Almost all
epidemiological studies indicated that people with a history of allergic
disease have a greater risk of LC. Five case–control studies among never-smoker
reported risks of LC associated with asthma to be 1.1–2.7 (86-89). Santillan and colleagues analyzed
results of five case–control studies and estimated (RR=1.8, 95% CI: 1.3– 2.3)(90).
The analysis of the data from studies, which controlled for smoking history
gave a pooled estimate of 1.7 (95% CI:1.3–2.2) (90).
History of asthma among nonsmokers and smokers cases were 1.6 and 1.7 respectively
(86).
Another study expressed a strong association between asthma and with higher
risk of LC only among men (91).
Another population-based case–control study among Missouri woman found the asthma
was a non-significant risk factor (OR=1.2, 95% CI: 0.8–2.1) in smokers and
significant risk factor (OR=2.7, 95% CI: 1.4–5.4) in non-smokers (87).
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: 1.1–2.5) for
history of asthma (88).
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 (92).
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)
(89).

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: 1.0–4.1)(93).
In two studies in USA were not observed any association between history of
asthma and LC after adjusting age and smoking history (94, 95). 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 (96).
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 (97).
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 (98).
In Swedish patients which hospitalized for asthma (99),
the SIR was 1.6 (95% CI: 1.5–1.7) during 8.5-years follow up.

Esophageal and gastric
cancer

Inconclusive results were
obtained from studies exploring esophageal and gastric cancer risk factors. 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 (100).
Several case-control studies have reported inverse relationships between
esophageal tumor and history of allergy (101-103). Kallen et al. reported a
50% lower risk of stomach cancer mortality among asthmatics; but, cohort
studies reported no significant relationships(104).

Medullary
thyroid carcinoma (MTC)

The association between
a history of allergies and
medullary
thyroid carcinoma (MTC) investigated in pooled analysis of 14 case-control
studies. Results of 48 cancer patients and 240 controls showed a two-fold risk
for MTC in allergic disease. However, the positive association may as a result
of the release of vasoactive agents by the tumor leading allergic-like symptoms(105).

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 (106).
Other case-control studies have demonstrated positive relationships of having
history of asthma and either urothelial tumor (107)
or BlC (108).
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 (108).
In cohort studies was reported no significant associations (59)
or advanced risk for BlC in asthmatics patients only among men (98).

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: 0.4–0.9) (109).

Prostate cancer

Prostate cancer (PrC)
is one of most frequent malignancy in men and remains a main public health
problem(110).
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 (111).
Also, it has been found that increased white blood cell count, as a marker of
systemic inflammation, was significantly associated with advance PrC risk(112).
Results from large-scale cohort study including 16,934 men which performed by Severi
and coworker revealed a small increment in prostate cancer risk in asthmatic
patients compared to controls (HR: 1.2; 95% CI: 1.05– 1.5) (113).
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 (110).
In contrast, Zhao et al reported 86 of 1552 asthmatics were diagnosed PrC
during follow-up (35).
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 (114).
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 prostate cancer (OR= 2.4; 95% CI: 1.2–4.6; P = 0.011) and its independent
risk factors were age and hypertension (115).

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: 0.6–0.9) (116).
In contrast, cohort studies showed that higher serum IgE levels were related
with an higher risk of HNC (117).
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:1.0–1.8) (26).

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(118).

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:0.8–3.9) (119).
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 (120).
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 (121).
Similarly, a higher risk of SCC was reported in asthmatics subjects compared
with non-asthmatics subjects (Table2) (122).
Other studies presented positive (122),
negative (20, 61, 104, 123), and null association between BCC
and SCC and allergic condition (20, 123, 124). 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 (125).
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 (126). 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(127).

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 gastrointestinal 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 (128),
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.

 

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