Article Type : Research Article
Authors : Chrysanthakopoulos NA
Keywords : Epidemiology; Cancer; Periodontal disease
Previous research has investigated the possible
role of periodontal disease (PD) as a risk factor for systemic diseases and
disorders such as diabetes mellitus, cardiovascular disease, arterial
hypertension, respiratory diseases, rheumatoid arthritis, endocrine disorders,
osteoporosis, and cancer. Recently, many investigators have focused on the
possible role of PD in carcinogenesis, using several PD indices, such as depth
of the periodontal pockets (PPD), clinical attachment loss (CAL), Community
Periodontal Index of Treatment Needs (CPITN), bleeding on probing (BOP), the
number of existing or lost teeth, gingivitis indices, whereas periodontal
tissue condition has also been assessed by radiographic examinations.
Associations have been observed between PD indices and an increased risk of
cancer development in organs such as tongue, oropharynx, breast, esophagus,
stomach, lung, kidney, pancreas, hematopoietic, colon, prostate and uterus.
However, those studies are characterized by differences in design and methods,
whereas possible influences caused by unknown confounders could lead to
secondary biases associations. The aim of the current review was to refer the
possible association between PD and various types of less common cancers in
organs such as breast, gall bladder, liver, prostate and
hematological/hematopoietic malignancies.
Several studies have investigated the possible role of
periodontal disease (PD) as a risk factor for systemic diseases and disorders
such as cardiovascular disease, arterial hypertension, diabetes mellitus,
respiratory diseases, rheumatoid arthritis, endocrine disorders, osteoporosis,
and cancer [1,2]. It has also recorded that the association between oral
cavities diseases with some systemic diseases are possible bi-directional as PD
is correlated with an intense local and systemic immune response [3].
Especially the association between PD and diabetes mellitus has been
investigated and is considered to be bi-directional [4].
Associations have been observed between PD indices and an
increased risk of cancer development in various organs and locations such as
tongue [5], oropharynx [6-9], breast [10], esophagus [11], stomach [11,12],
lung, kidney, pancreas, hematopoietic [13-15], colon, prostate and uterus
[14,16,17]. However, a few amounts of studies have explored the association
between PD and less common malignancies. The aim of the present review was to
examine the possible association between PD and various types of less common
cancers in organs such as breast, gall bladder, liver, prostate and hematological/hematopoietic
malignancies.
It has been shown that chronic inflammation is able to
promote tumor development and progression [18], and that tumors can arise from
infectious locations in human organs such as liver, colon, stomach, urinary
bladder, uterine cervix, ovaries and lung [19,20]. Host’s persistent infections
induce chronic inflammation, in which leukocytes and other immune cells are
responsible for DNA damage in proliferating cells due to secretion of reactive
oxygen species (ROS) and reactive nitrogen species (RNI). Those species are
normally produced by immune cells for the treatment of infection. ROS are
produced through a variety of intracellular and extracellular actions, as act
as signal mediators which are implicated in growth, differentiation,
progression, and death of the cell. RNI act as both positive and negative
regulators of cell death. Moreover, ROS
and RNI react and form peroxy-nitrate (PN), a mutagenic agent, and in case of a
repeated tissue damage in the presence of ROS and RNI high levels which are
released by inflammatory cells, leads to interactions with DNA in the
proliferating epithelium, and consequently to permanent genomic alterations
such as point mutations, chromosomal rearrangements or deletions [21]. The
mentioned mechanism is the endogenous mechanism in which those genetic
aberrations and alterations trigger tumor development, whereas the exogenous
one is the presence of a chronic inflammation which increases the risk of
carcinogenesis [20].
A chronic infection can stimulate epithelial malignancies
through an indirect mechanism implicating an inflammatory activation of
cellular environment, condition that can expose those epithelial cells to
mutagenic factors. Moreover, inflammatory cells, fibroblasts and epithelial
cells can be activated by bacteria and their products, and can produce and
release a wide variety of cytokines, chemokines, growth factors, and other
biological mediators which can cause damage to epithelial cells DNA. Chronic
inflammations can produce an inflammatory environment which is associated with
cell functions such as survival, proliferation, migration, angiogenesis, and
apoptosis. This environment can induce the epithelial cells to accumulate
mutations and lead those mutant cells to proliferation, migration and provide
growth benefits [10].
The possible association between PD as a chronic
inflammation and carcinogenesis was based on the observation that individuals
with chronic inflammatory conditions showed a higher incidence of cancer
development [22].
PD as a chronic inflammation increases the risk for
cancer development in various organs [13,16,22,26], is caused by the
colonization of Gram-negative bacteria mainly that stimulate an inflammatory
response, which in some individuals leads to destruction of the connective
tissue [27]. Moreover, that inflammatory response to periodontal infection
spreads beyond the oral tissues and leads to increased levels of circulating
inflammatory biomarkers [28]. This link, as has already been stated, is
supported by the higher incidence of cancer cases in individuals with chronic
inflammatory conditions [22] and the effectiveness of anti-inflammatory
medication in prevention of some cancers, such as colorectal cancer [29],
however this observation has not been confirmed in all surveys [30,31].
The appearance of a chronic and systemic inflammation due
to PD may lead to signaling pathways which increase the risk of cancer
development in various organs. Moreover, other mechanisms have been proposed
and concern the deflection of the immune system and the production of
carcinogenic products by the periodontal tissues pathogens [32].
Alternatively, underlying genetic factors may increase
the sensitivity or susceptibility to both diseases or may alter the
relationship of known environmental risk factors, such as smoking, with PD and
cancer. However, the accurate role of the common genetic risk factors between
both conditions remains unknown, whereas it is not clear whether systemic
inflammation, pathogenic invasion in blood circulation or immune response to PD
could affect the overall risk of cancer development at various locations [33].
A
previous case-control study by Hiraki et al. [34], in which PD status was assessed by
numbers of loss and remaining teeth, after matched for age and gender, no
association was recorded between PD and risk of liver cancer. Similarly, no
association was identified in another study between PD, which was based on
self-reported data and liver cancer risk in a female study sample [35]. On the contrary, other researchers
in a prospective study observed a higher risk of liver cancer in individuals
who had lost many permanent teeth or were completely edentulous when compared
with those reporting a lower number of teeth loss [36]. However, after adjusting for Helicobacter pylori infection and known
risk factors of liver cancer, such as hepatitis B, and hepatitis C, the risk
insisted but was not significant. A recent register-based Swedish cohort report
showed that the loss of many teeth did not lead to an increased risk of liver cancer
mortality [37].
In another Japanese cohort survey was found that the risk of death from liver
cancer was almost significance [38].
Only one survey has examined the possible association between PD and gall
bladder risk cancer, and showed a significantly higher risk of gall bladder
cancer among females with a history of PD compared with those with no history
of PD. However, after limitation to never?smokers only, the association reduced
significantly [35].
A
few amounts of studies have investigated the possible association between PD
and breast cancer development, and in some cases the outcomes were
inconsistent. A previous study by Hiraki et al. [34] in which tooth loss was used as a PD
index showed no associations between both diseases. Similar results were
observed in another survey by Arora et al. [17]. Mai X et al. [39] used radiographic analyses of
alveolar crestal height for assessing PD status and found that the risk of
breast cancer was not associated to either mild/moderate or severe PD after adjusting
for age and smoking. Moreover, the sample size for breast cancer cases was
small and thus, the outcomes could not be reliable. Similarly, Michaud et al. [40] in a recent study observed that
breast cancer risk was not associated with varying clinical measures of severe
periodontitis when restricted to never?smokers.
On
the contrary, a Swedish study showed that more breast cancer cases were
observed among females who had PD accompanied by missing molars compared with
those with PD and remaining molars [10].
However, that study had some endogenous limitations as many participants did
not undergo a clinical examination. The NHANES (National Health and Nutrition
Examination Survey) survey recorded an increased risk of breast cancer
mortality among those with periodontitis, however that risk was not
statistically significant [23].
A larger research to date was carried out by Freudenheim et al. [41]. Self?reported PD history was found
to be associated with an increased risk of breast cancer after adjustment for
known breast cancer risk factors, such as body mass index (BMI), age at
menarche, parity, age at first birth, and age at menopause. However, that risk
was substantially reduced after additional adjustment for smoking status and
pack years. It is possible that residual confounding from smoking may have
played a role in the positive associations observed. Chung et al. [42], in one retrospective cohort study
with equal numbers of cases and matched controls was observed that the rate of
breast cancer was significantly higher among females with chronic periodontitis
than those without periodontitis, despite the fact that known risk factors for
breast cancer and smoking status were not controlled for, in logistic
regression analyses. In another study in Turkey, individuals with
moderate/severe periodontitis had a greater than 2?fold increase in breast
cancer comparative to the expected risk for a similar age?matched group [43]. Limitations of that study was the
small sample size of breast cancer cases and the fact that smoking and other
important risk factors were not adjusted for, leading to unreliable outcomes. A
recent case-control study in Brazil used four different case definitions for
periodontitis and found that the odds of having breast cancer in all cases
varied from 2? to 3?fold based on the case definition carried out [44]. In case of a possible association
between PD and breast cancer risk, smoking status, and other factors, may play
a contributory role.
Lee
et al. [45]
examined the association between PD and prostate cancer risk over a 12?year
period, in Korean adults aged over than 40 years. PD was determined by clinical
and radiographic findings. The outcomes showed an increased risk of prostate
cancer among those with PD after adjustment for known confounders, smoking,
alcohol, and sociodemographic factors.
Similarly,
Arora et al. [17]
reported a 47% higher risk of prostate cancer among individuals with PD, in
which tooth mobility was used as PD index, compared with those with no evidence
of PD. On the contrary Michaud et al. [40]
found no association between severe periodontitis with risk of prostate cancer.
Similarly, in a previous study in male health professionals Michaud et al. [13] examined history of PD in relation to
risk of advanced prostate cancer and observed a negative association after
adjustment for relevant factors such as smoking. In another more recent study,
the outcomes when restricted to never?smokers revealed no association between
both diseases [46].
Similarly, Hiraki
et al. [34] examined that association using categories of tooth
loss, as a PD index and found no association between that index and
prostate cancer risk.
Few surveys have
examined the possible association between PD with increased risks of
hematological cancers [42] and of lymphoid/hematopoietic malignancies in
never?smokers [35] and have recorded such associations. Michaud et al. [13] in a prospective e
cohort study revealed increased risks with hematopoietic malignancies, whereas
in a recent one [40] observed that PD was not associated with hematopoietic and lymphatic
cancers. Similar surveys have shown an association between PD and non?Hodgkin
lymphomas [47], but not lymphomas in general [34] or leukemias [35].