Oral Health, Periodontal Pathogens and Carcinogenesis by Dr Kishan Sheth

New Evidence to Support the Oral–Systemic Link

(The second in a two-part series)

by Dr Kishan Sheth

The purpose of this second article is to carefully analyse the research findings to date regarding a potential link between periodontitis and oral carcinogenesis; to evaluate, critically review and explore the variety of potential study confounders and study criteria differences that suppress the accuracy and validity of the relationship claims being made; to gain an appreciation of the biological plausibility of mechanisms that could underpin the relationship between the two diseases; and to conclude whether the current level, findings and quality of research is accurate in supporting the existence of the periodontitis–cancer link.

Introduction
The international burden of cancer has risen every year, a trend that has been paralleled by the increase in periodontitis cases. Research undertaken by GLOBOCAN (2012) states there were 7.6 million global cancer cases in 2008, and in 2012 there were 14.1 million global cancer cases, an increase of 84%.

Although there is a lack of recent statistical data related to periodontitis cases, between the years 1997 and 2005 there was an increase of 27% of adults aged between 35 and 44 who had periodontal pocket depths greater or equal to 4 millimetres (Dye, 2012).

Periodontal diseases are a wide range of mostly plaque-induced disease types, and each type is distinguished from the others by the 1999 Gary Armitage classification.

The two major types of periodontal diseases are:

• Gingivitis: Reversible inflammation confined to gingival tissues.
• Periodontitis: Inflammation spreading further to the periodontal ligament and underlying alveolar bone, causing irreversible destruction of these vital structures (Zeng et al., 2013, Levine, 2013, Armitage, 1999).

This project will focus on the link between periodontitis and cancer types, because some degree of gingivitis occurs in most members of the population,as a natural reaction against plaque accumulation and deposition within the gingival sulcus.

Pihlstrom (2005) states that periodontitis involves a complex plaque/host relationship that is still not fully understood, and that it has long been known to have an association with many systemic diseases, including cardiovascular disease, renal infections and both type 1 (insulin-dependent) and type?2 (insulin-independent) diabetes mellitus.

However, the latest research that examines the relationship between periodontitis and several cancer types suggests there is a link between the diseases, because both involve inflammation occurring and spreading within the body, and a potential underlying scientific mechanism creating the association between the two diseases could be an inflammatory process.

Whilst there is a substantial level of research evidence to support the existence of a periodontitis/cancer relationship, it is of vital importance that one appreciates that the causal basis is simply being assumed and has not, at this moment in time, been proven.

To effectively analyse the potential link between periodontitis and cancer, a project must ensure the critical evaluation of scientific studies and the exploration of confounding variables that may not have been considered but have potential to influence the accuracy and validity of the research conclusions.

The growing evidence of a link between periodontitis and many cancer types means that dentists have great reason to take periodontitis’ effects on the entire body very seriously, and to consider referring patients with developed periodontitis to medical professionals for MRI scans or other forms of cancer detection in an effort to reduce the development of cancerous tumours by intervening as soon as possible (Zeng et al., 2013).

Epidemiological evidence of a periodontitis/oral cancer link
Warnakulasuriya (2010) and Ferlay et al. (2002) believe that oral cancer has its highest incidence and mortality rates in Brazil, India and Hungary, and is the sixth-most prevalent form of cancer on a global scale according to Wen et al. (2013).

Oral cancer is characterised by a progressive growth of a tumour within the oral cavity, leading to the rise of abnormal lumps, leukoplakia or erythroplakia patches, stated by Marshall et al. (1992). Seoane et al. (2006) argue that oral cancer is able to impersonate the cellular appearance of developed periodontitis, demonstrating almost identical clinical signs—in particular, bone loss giving rise to loose dentition and excessive bleeding when brushing occurs (Yao et al., 2014).

Solomon et al. (1975) report that cases of oral tumours looking very similar to developed periodontitis have been noted and reported by dental professionals. Such similarities between oral cancer and periodontitis progression are a key indication of both diseases sharing a similar scientific system and mechanism of development and progression.

Oral squamous cell carcinoma (OSCC) is thought and estimated to account for more than 90% of all oral tumours around the world, according to Meyer et al. (2008). Marshall et al. (1992) conducted the first case control study on a possible relationship between periodontitis and OSCC in the years 1975–1983, comparing 290 OSCC sufferers with 290 noncancer, age, residing location and gender matching controls.

The study’s conclusion was that after the loss of the 11th tooth to periodontitis, there was a 2.7-fold increased risk of developing OSCC (95% C.I. 1.1–6.5), adjusted for smoking and alcohol consumption, and a 12.8-fold increased risk when smoking and alcohol consumption were also taking place.

One cohort study, conducted from 1988 to 1994 by Tezal et al. (2005), examined 131 oral tumours and 323 oral premalignant lesions out of a total cohort of 13,798 nonsmoking participants. The outcome was a 5.25-fold increased risk of oral cancer development when a subject’s clinical attachment loss was greater than 1.5mm (95% C.I. 2.25–9.30), a statistically accepted link.

Even more evidence for this link was provided by Moergel et al. (2013) in a case control study in 2013 that measured bone loss by a series of radiographic examinations in patients diagnosed with oral cancer.

The study patients’ bone loss was compared with a control group who did not suffer from oral cancer. The results showed a significant 1.4mm difference between the mean bone loss of the study and control groups. The study concluded that the presence of periodontitis increased a person’s risk of developing oral cancer by twofold.

However, the failure to provide confidence interval data suggests that the conclusion was not statistically acceptable. A major flaw of the study is that it did not account for the effects of oral cancer; bone loss may be one of these effects. Instead, it assumes that it is only periodontal disease that is capable of causing bone loss, which may not be the case.

Biological plausibility for a relationship between periodontitis and cancer
A more understood picture for the basis of a link between periodontitis and oral cancer has recently started to emerge, and many ideas have been proposed for the biological explanation for a link between periodontitis and cancer; however, none has yet been established.

Abnet et al. (2001) believe that the periodontitis pathogens may be directly triggering the carcinogenic process and that this triggering process is the most relevant mechanism.

Historical cases have seen bacteria species cause malignancies. Helicobacter pylorus is associated with malignant gastrointestinal cancers, Salmonella typhi with hepatic cancer, and Streptococcus bovis with many forms of cancerous tumours (Homann, 2000, Coussens and Werb, 2002, Lax and Thomas, 2002, Lazcano-Ponce et al., 2001, Al-Jashamy et al., 2010).

Conclusion and clinical considerations
A large amount of research has focused on the relationship between periodontitis and lung, oral and oesophageal cancers. In relation to other cancer types, such as prostate and breast cancer, the amount is research conducted is smaller.

The results of many of these studies do show the possibility of a periodontitis/cancer association. The strongest-seen link exists between:

• Periodontitis and oral cancer. All three of the studies reviewed demonstrate a statistical link: Marshall et al., 1992, Tezal et al., 2005, Moergel et al., 2013.
• Periodontitis and pancreatic cancer. Again, three studies show a clear link: Hujoel et al., 2003, Michaud, 2007, Stolzenberg-Solomon et al., 2003.

In comparison, the link of periodontitis with oesophageal cancer may be very weak; only one study out of three showed a potential link (Guha et al., 2007).

One out of three studies on lung cancer showed a small link after the effect of smoking is adjusted for, and a much larger relationship in smokers (Michaud et al., 2008). Michaud et al. (2008) does show a link between periodontitis and non-Hodgkin lymphoma; however, when periodontitis and both myelomas and leukemia are considered, no statistical correlation or relationship presents.

In relation to prostate cancer, only one study out of the three found a statistical link between prostate cancer and periodontitis (Hujoel et al., 2003). Remarkably, both other studies found that inverse relationships existed, and there is a call for more evidence to be put forward to identify a potential link (Hiraki et al., 2008, Michaud et al., 2008). Only one out of two studies on a breast cancer link showed an association (Hujoel et al., 2003).

In terms of the periodontitis link with total cancer cases, a link is statistically present in the studies conducted by Hujoel et al. (2003) and Michaud et al. (2008). However, these associations are opposed by the results of the studies conducted by Cabrera et al. (2005) and Tu et al. (2007), which both show no statistical correlation between total cancer cases and periodontitis.

This project expresses the latest study findings, and even though some degree of relationship can be seen between periodontitis and certain cancer types, more robust and controlled research needs to be conducted in an attempt to confirm this potential link.

In this robust future research:

• Participants should be never-before smokers to eliminate confounding by the smoking effect.
• Diet, exercise, age, gender and ethnicity should be carefully controlled, because all can change an individual’s susceptibility to cancer development.
• A standardised measure of periodontitis should be implemented; this should be the AAP/CDC classification case definition system, so studies can be easily compared with each other.
• The studies should be done on many different populations to prevent ethnicity acting as a confounder, and to allow results to be applicable to an international population.

Once, and if, this potential periodontitis/cancer link is statistically verified, the scientific world can then concentrate its efforts on unveiling the biological processes and mechanisms that are responsible for the link.

The statistical relationship between periodontitis and cancer creates clinical considerations for the dental profession. Dental professionals must appreciate that periodontitis poses a potential risk factor in cancer tumour development. Patients who suffer from periodontitis or cancer should be asked to come in to the dental office for regular recalls more often in an attempt to keep levels of disease low.

The importance of good, effective oral hygiene should also be stressed, because poor levels of oral hygiene pose a potential risk factor for the onset of both periodontitis and oral cancers. Patients with periodontitis should be referred for screenings to try to detect cancerous growth in its earliest stages.

In addition to the previously mentioned, it is important for dental professionals to promote the adoption of good health-related behaviours by their patients, such as getting regular exercise, quitting smoking and alcohol abuse, and sticking to a good dietary regime.

This project serves as a testament that dentistry is a very holistic subject, because poor oral health—in this case, the presence of periodontitis—has the ability to potentially influence an individual’s general health and the onset of disease processes.