The
last decades the association between PD, gingivitis and mainly periodontitis,
and cancer risk has been explored, leading in most cases in conflicting
outcomes. PD as a chronic inflammatory disease has been associated with diverse
systemic diseases and disorders [55-58]. A great amount of research studies has
investigated the association between oral health status and various types of
cancers. Most reported that periodontitis or the number of missing teeth were
associated with an increased risk of several cancers in diverse populations
[13,17,59-64]. However, those associations have little practical significance
as prevention indices [15], even though useful aspects have been provided on
the role of PD treatment in decreasing the risk of different types of cancers
[65]. The current report showed that conventional risk factors for CHL
development, such as age, SES, educational level, cigarette smoking, and
presence of auto-immune diseases were not significantly associated with and
increased risk for CHL appearance. Those observations were not in agreement
with the outcomes of previous researches, in which adolescents and young adults
[2,3,66], low SES and educational level [2,3,67], cigarette smoking [2,3,68],
and presence of diseases such as RA, SLE, sarcoidosis, and ITP [51,69-74], were
at a higher risk of CHL. Moreover, epidemiological parameters such as age, SES,
educational level, and smoking have been considered as confounders. Presence of
a CHL family history and history of previous EBV infection were found to be
statistically significantly associated with the risk of CHL development among
the indices investigated, findings which were in accordance with those from
previous reports [1,2,66]. The outcomes also showed that deep periodontal
pockets, expressed by PPD and moderate/severe attachment loss, expressed by CAL
were significantly associated with risk of developing CHL, findings that were
not confirmed by previous studies, as the available ones have investigated the
mentioned possible association for hematopoietic malignancies such as Acute
Myeloid (AM) and Lymphoblastic Leukemia (ALL), the Chronic ones (CML, CLL),
their diverse variants, and NHL. PPD is used for estimating PD severity [75],
as is a current disease inflammation status indicator [76], and CAL is a
critical index for estimating cumulative periodontal tissue destruction,
including previous PD attacks. The mentioned indices concern the chronic
inflammation long-term stages including the chronic inflammatory response
destructive signs [77]. Gingival inflammation, as expressed by GI and number of
missing teeth were also not statistically associated with risk of CHL
development, in the current study. Similarly, no previous studies have examined
the mentioned possible associations. GI reflects gingival inflammation
severity, nevertheless that index is not used regularly in epidemiological
studies regardless of that estimates the gingival tissues inflammatory load. A
specific role has been suggested for gingival inflammation as a risk factor for
diverse cancer types [78], whereas other researchers observed no relationships
[79,80]. Tooth loss is the advanced periodontitis final outcome. Previous
prospective studies have recorded an association between number of missing
teeth and the cancer risk in various locations [18, 80, 81]. Similarly,
case-control surveys, have recorded powerful links between tooth loss and
pancreatic [15], upper gastrointestinal [82], lung [83], gastric [84],
esophageal [85], oral [83], and ovarian [62] cancers.
The
mechanism which is implicated in cancer development in PD patients is still
remain unclear. An hypothesized role of immune-inflammatory mechanisms and
inflammation in both periodontitis and cancer has been suggested [18]. The
periopathogenic bacteria and their by-products associated with chronic
periodontitis can lead to chronic systemic inflammation [86,87] not only at the
oral tissue but even at distant locations [88]. That periodontal bacteria
accumulation has been detected at local or distant locations, are able to
infiltrate through infected periodontal tissues into the systemic circulation
and reach those distant locations [87], such as various organs and tissues,
lymph nodes [35], arteries [36,89] etc. At the target location, periodontal
pathogens may create an appropriate micro-environment which is able to
contribute to cancer progression [14,37,41]. Inflammation is a cancer hallmark
[90], and PD is an infectious process that induces chronic low?grade
inflammation and, persistent low?grade inflammation has been associated with
cancer initiation [19,91,92]. Inflammatory response can generate Reactive
Oxygen Species (ROS) and active intermediates producing oxidative/ nitrosative
stress, which may lead to DNA mutations, or they may affect the DNA repair
mechanisms [93]. The inflammatory cells may further contribute to the cells
damage by producing ROS, cytokines, chemokines, and arachidonic acid
metabolites. Those products recruit various inflammatory cells and maintain a
vicious cycle [93]. Periopathogenic bacteria such as Porphyromonas gingival is
and Aggregatibacter actinomycetemcomitans are anaerobic, gram?negative bacteria
which colonize sub gingival biofilms in periodontitis patients [94]. Those
bacteria produce and release enzymes which deconstruct the extra-cellular
matrix ingredients including collagen, process that leads to substrates
production which increase tissue invasion [95]. The released bacterial
endotoxins, enzymes, and metabolic by-products are toxic to tissues, may cause
direct damage to neighboring epithelial cells DNA, and they can induce
mutations in proto-oncogenes and tumor suppressor genes, or alterations in
molecular signaling pathways involved in cell survival, differentiation or
proliferation [96]. Oral bacteria may also induce carcinogenesis by
constitutively activating toll?like receptors (TLRs), such as TLR5 [95]. TLR5s
are present on the innate immune system cells surfaces, have been associated
with epithelial and cancer cells [97] and are implicated in proliferation,
inflammation, invasion, and anti-tumor immune responses evasion [98,99].
Porphyromonas gingival is and Fusobacterium nucleatum can promote tumor
progression by activating TLRs on oral epithelial cells to up-regulate the
IL-6/STAT3 signaling pathway [100]. PD may also increase cancer risk through
the chronic release of inflammatory mediators or immune system dysregulation
[19, 101-103], or may affect carcinogenesis through the increased exposure to
carcinogenic nitrosamines [104]. Oral bacteria and nitrosamines generation is increased
in oral cavity in individuals with poor oral hygiene and PD [62]. Consequently,
anti-inflammation therapy in PD individuals reduces the systemic inflammation
biomarkers and may decrease subsequent cancer risk. On the contrary, Hwang, et
al. [65] recorded that anti-inflammation treatment did not reduce the lymphatic
and hematopoietic cancers risk. Tooth loss was found to be positively
associated with risk of certain cancers such as head and neck, esophageal, and
lung cancers [62], as mentioned. Moreover, a dose response meta-analysis
reported that each ten-tooth loss was associated with a 3% increase of risk of
hematopoietic cancer [105]. Periodontal bacteria may contribute to
carcinogenesis by influencing cell proliferation and activation of nuclear
factor NF-?B and inhibiting apoptosis [106]. PD plaque is in many cases not
under reasonable control, driving periodontal bacteria to disseminate and
accumulate in some locations of the human organism through the digestive or
respiratory tract, or endocrine system, contributing to cancer development
[107-109]. Oral bacteria in the blood circulation, particularly their
lipopolysaccharide component (LPS), can induce systemic inflammatory responses
[110]. Inflammatory mediators released from chronic PD, such as Il-6, tumor
necrosis factor-alpha (TNF-?), and prostaglandin E2 (PGE2), can escape through
damaged periodontal tissue pockets and produce systemic effects in the whole
organism [111]. Recent epidemiological studies have investigated the risk of
hematopoietic and lymphatic cancers in individuals with periodontitis
[18,30,112-115]. However, these studies resulted in contradictory outcomes.
Chronic periodontitis could lead to increased risks of hematological cancers
[112], and severe PD was associated with a two-fold higher risk of
hematological cancers, including leukemia and other hematological cancers
[113]. Michaud, et al. [18] confirmed such an association even after
controlling for smoking and other risk factors, as was observed that PD was
found to be statistically significant-ly associated with an increased risk of
hematopoietic cancers, whereas among never smokers, PD was associated with
statistically significantly increases in hematopoietic cancers. Similar
researches revealed no association between PD and hematopoietic malignancies,
such as leukemia’s and lymphatic cancers [30,114,115]. As shown, few previous
and recent reports have observed an increased risk of AML, ALL and other
hematopoietic malignancies development among individuals with PD however,
considerable limitations of those included inadequate sample sizes and
adjustment for potential confounders. The strengths and limitations of the
current research should be taken into account in interpretation of the observed
outcomes. Strengths of the study are the completeness of follow-up, the
well-characterized cohort which it was possible to examine both confounding and
interaction by known risk factors, in order to avoid secondary biased
associations. Another critical aspect is PD definition by oral clinical
examination and not by self-report, therefore no potential misclassification of
exposure to PD exists that may result in the underestimation of the association
examined. Another limitation is the possibility of confounding in estimates of
risk caused by additional unknown confounders.