Annals of Oncology 28: 985–995, 2017

doi:10.1093/annonc/mdx019
Published online 25 January 2017

REVIEW

Periodontal disease, edentulism, and pancreatic

cancer: a meta-analysis

P. Maisonneuve1*, S. Amar2,3 & A. B. Lowenfels4,5

1
Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy; Departments of 2Pharmacology; 3Microbiology and Immunology;
4
Surgery; 5Family Medicine, New York Medical College, Valhalla, USA

*Correspondence to: Dr Patrick Maisonneuve, Division of Epidemiology and Biostatistics, European Institute of Oncology, Via Adamello, 16, 20139 Milan, Italy.
Tel: þ39-0257489822; E-mail: patrick.maisonneuve@ieo.it

Background: Periodontal disease (PD), now our commonest infectious disorder leads to tooth loss, and has been linked to
various systemic diseases, including various types of cancer. The aim of this study is to provide a systematic review and a meta-
analysis of the relationship between PD, edentulism, and pancreatic cancer (PC).
Patients and methods: From an initial review of 327 references we selected eight studies concerning periodontitis or
edentulism with sufficient quantitative information to allow us to examine the risk of PC. We used relative risks (RRs), hazard
ratios, or odds ratios to measure the association between periodontitis, edentulism, and PC. We employed random effects
models to obtain summary risks, and we also provide measures of study differences and possible biases.
Results: The summary RR for periodontitis and PC was 1.74 [95% confidence interval (CI) 1.41–2.15] and 1.54 for edentulism
(95% CI 1.16–2.05). There was no evidence of heterogeneity for either variable, and no evidence of publication bias. The
studies included reports from three continents, suggesting that the association is generalizable. Most of the studies were
adjusted for variables thought to be associated with PC, such as gender, smoking, BMI, diabetes, and alcohol.
Conclusions: Using meta-analysis, both periodontitis and edentulism appear to be associated with PC, even after adjusting
for common risk factors. As yet, the mechanisms linking oral disease and PC are uncertain, but could be related to changes in
the oral microbiome—an area of current research.
Key words: periodontal disease, periodontitis, edentulism, pancreas cancer, meta-analysis

Introduction
Pancreatic cancer (PC) is relatively infrequent, but ranks as the
fourth most common cause of cancer death [1]. This is mainly
due to its poor outcome, to late diagnosis, and to the lack of pre-
ventative measures. Because it is age-related, and since popula-
tions in most countries are ageing, the absolute number of PC
cases is increasing; PC is anticipated to be the second leading
cause of cancer death in the United States by 2020 [2, 3].
PC has been extensively studied and many risk factors, includ-
ing tobacco smoking, heavy alcohol drinking, red meat, fruits
and vegetables consumption, obesity, diabetes mellitus, meta-
bolic syndrome, chronic pancreatitis, helicobacter pylori
infection, ABO blood group, or allergy, have been identified and
often confirmed by meta-analyses. Several of the identified risk
factors are interrelated, indicative of common underlying etiolo-
gical pathways such as insulin resistance [4], inflammation [5],
DNA damage, immunity, or genetic susceptibility [6]; altogether
they explain only a fraction of all PC cases [7]. Estimates of the
fraction of PC attributable to known preventable risk factors
range from 24% in China [8] or Japan [9] to 36% in the United
Kingdom [10].
Periodontal disease (PD) and alterations in the oral micro-
biome, which are responsible for its development, have been
linked to several forms of cancer including cancer of the oral cav-
ity, head and neck, and cancer of the pancreas [11–13].

C The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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Review
Periodontitis is an inflammation of the periodontium caused by
a microbial biofilm that adheres to the tooth’s surface. It is char-
acterized by a progressive loss of alveolar bone around the teeth,
and, if untreated can lead to tooth loss. PD is a common chronic
disease and a major health problem worldwide, affecting about
half of adult populations. Globally, severe periodontitis and
edentulism affect, respectively, 743 million and 158 million peo-
ple worldwide [14–16].
The purpose of this study is to review the literature and to em-
ploy meta-analytic techniques to quantify the association be-
tween periodontitis, edentulism, and PC risk.
Materials and methods
Search strategy, inclusion criteria, and data
abstraction
We carried out a systematic literature search using PubMed,
without language or other restrictions, looking for papers refer-
ring to PD and PC. Only reports fulfilling the following inclusion
criteria were included in the meta-analysis.
• Studies that contained the minimum information necessary to estimate
the relative risk (RR) of PC associated with any measure of PD (i.e. peri-
odontitis, tooth loss, gingivitis) and a corresponding measure of uncer-
tainty [i.e. 95% confidence interval (CI), standard error, variance, or P
value of the significance of the estimate].
• Case–control and cohort studies, published as original articles.
• Studies that were independent. In case of multiple reports on the same
population or subpopulation, we considered the estimates from the most
recent or most informative report.
When available, we used adjusted risk estimates and those
based on population-based controls.
Overall, 327 references published up to 31 January 2016 were
retrieved from the following Pubmed search query: (‘periodontal
diseases’[MeSH Terms] OR ‘gingival diseases’[MeSH Terms] OR
‘mouth diseases’[MeSH Terms] OR (‘periodontal’[All Fields] AND
‘diseases’[All Fields]) OR ‘periodontal diseases’[All Fields] OR
(‘gingival’[All Fields] AND ‘diseases’[All Fields]) OR ‘gingival
diseases’[All Fields] OR ‘gingivitis’[All Fields] OR ‘edentulous’[All
Fields] OR ‘tooth loss’[All Fields] OR ‘teeth loss’[All Fields] OR
‘porphyromonas’ [All Fields]) AND (‘pancreatic neoplasms’[MeSH
Terms] OR (‘pancreatic’[All Fields] AND ‘neoplasms’[All Fields])
OR ‘pancreatic neoplasms’[All Fields] OR (‘pancreatic’[All Fields]
AND ‘cancer’[All Fields]) OR ‘pancreatic cancer’[All Fields] OR
‘pancreas cancer’[All Fields]) and (1900/01:2016/10 [EDAT]).
Titles and abstracts available in PubMed of all identified art-
icles were screened to ascertain their relevance. The full text of 14
potentially relevant study reports were further evaluated. Full text
of eight additional study reports identified from other sources
(WEB of Science, Google scholar, and citations in reference lists of
identified relevant articles or reviews on the topic) were also eval-
uated for inclusion in the meta-analysis. Selected articles were re-
viewed and data were extracted and crosschecked independently
by two investigators (PM and ABL) and any disagreement was
resolved by consensus among both of them. In the event of dupli-
cate publications, the most recent or more complete publication
was used. Fourteen were excluded: five were reviews or comments
986 | Maisonneuve et al.
Annals of Oncology
and did not contained original data, five contained pertinent in-
formation but could not be used in the meta-analysis, three did
not provide measure of association between PD or tooth loss and
PC and one study contained data reported in another report. In
total eight studies satisfied the eligibility criteria and were
included in the quantitative synthesis (Figure 1). No attempt was
made to contact authors of the single report, out of the five which
contained pertinent data that could possibly hold sufficient data
to provide a risk estimate for our outcome of interest.
We carried out a second literature search in order to present
credible measures of the magnitude of the association between a
series of established potential confounders (tobacco smoking, al-
cohol drinking, overweight, diabetes mellitus, metabolic syn-
drome, or allergy) and PC, looking for recent meta-analyses,
pooled analyses or review on the topic.
Definitions of PD
The definition and assessment of periodontal status varied across
studies, being either self-reported, evaluated by dental examin-
ation or retrieved from health claim data. The conditions studied
in the various reports also varied including gingivitis, periodon-
titis, other periodontal diseases, dental plaque, edentulism, or
teeth number. In the meta-analysis, we summarized results for
the two most frequently studied periodontal conditions, namely
‘Periodontitis’ and ‘Edentulism’ (being toothless to at least some
degree). In the absence of specific risk estimates for ‘Periodontitis’
we used risk estimates reported for ‘any periodontal disease’, or
‘unacceptable dental plaque’ defined as a dental plaque covering
more than one-third of the teeth. In absence of specific risk esti-
mates for ‘Edentulism’ we used risk estimates reported for the
lower category of remaining teeth. Studies reporting on non-
sufficiently specific conditions (i.e. oral cavity disease) or related
conditions (i.e. oral bacterial infection), studies providing risk es-
timates using peculiar reference group (i.e. gingivitis) or studies
considering the effect of treatment of PD were used a supporting
material but could not be included in the meta-analysis.
Statistical analysis
RRs or hazard ratios (cohort studies) and odds ratios (case–con-
trol studies) were used as a measure of the association between
PD and PC. We used random effects models to estimate summary
RRs in order to account for heterogeneity of the risk estimates
and to provide more conservative risk estimates. Homogeneity of
effects across studies was assessed using the I2 statistic [17], which
represents the percentage of total variation across studies that is
attributable to heterogeneity rather than chance. Publication bias
was graphically evaluated by funnel plots [18] and quantified by
the test developed by Macaskill et al. [19] obtained by a regression
of log (RR) on the sample size, weighted by the inverse of the vari-
ance. Meta-analysis was carried out using Review Manager soft-
ware (RevMan) version 5.3.5 (Copenhagen: The Nordic
Cochrane Centre, The Cochrane Collaboration, 2014).
Results
Table 1 provides detailed information about the eight studies
(seven cohort studies and one case–control study) reporting risk
Volume 28 | Issue 5 | 2017
Annals of Oncology
Records identified through
PubMed searching
(n = 327)
Additional records identified
through other sources
(n = 8)
Full-text articles assessed for eligibility
(n = 22)
Studies included in quantitative synthesis
(meta-analysis)
(n = 8)
Figure 1. Flow diagram: Literature search of studies on periodontitis and pancreatic cancer.
estimates for the association between periodontitis (six studies)
and/or edentulism (four studies) and PC [20–28]. All risk esti-
mates were adjusted at least for age and sex. Further adjustment
for tobacco smoking was made in six studies [20, 21, 23, 25, 26,
28], for alcohol drinking in three studies [25–27], for diabetes in
three studies [23, 26, 27], or for body mass index (BMI) in four
studies [20, 23, 25, 26]. Information on dental status and PD
were obtained by dental examination in three studies [20, 22, 28],
were self-reported in four studies [21, 23, 25, 26], or were derived
from a health claim database in one study [27].
The summary RR (SRR) and 95% CI, using random effect
model for periodontitis and edentulism are, respectively, 1.74
(95% CI 1.41–2.15) and 1.54 (95% CI 1.16–2.05) with no evi-
dence of heterogeneity (I2 ¼ 0%) for either variables, or publica-
tion bias (Macaskill’s test P ¼ 0.30 and P ¼ 0.90, respectively)
(Figures 2 and 3).
Risk estimates from single studies ranged from 1.55 (95% CI
1.02–2.33) to 4.56 (95% CI 0.93–22.3) for periodontitis and from
1.30 (95% CI 0.70–2.30) to 1.90 (95% CI 0.95–3.81) for edentu-
lism. In two large cohort studies, the risk estimates for periodon-
titis were adjusted for all potential confounding factors
(including age, sex, tobacco smoking, diabetes, and BMI). The
risk estimate in these two studies: 1.64 (95% CI 1.19–2.26) in the
Male Health Professional Study [23] and 2.06 (95% CI 1.14–
3.75) in the Swedish Twin registry study [26] were very close to
the SRR estimated from the meta-analysis. In a subset analysis,
Michaud et al. [24] also confirmed the association between PD
and PC among never smokers (RR 1.57; 95% CI 0.98–2.50).
Apart from the four studies reporting risk estimates for edentu-
lism, Michaud et al. [23] reported risk estimate for tooth loss in
the past 4 years, excluding edentulous participants at baseline.
Although this risk estimate was not included in the meta-analysis
its magnitude (RR, 1.61; 95% CI 1.13–2.31) is similar to the SRR
estimated for edentulism.
Volume 28 | Issue 5 | 2017
Review
Records excluded after
initial screening
(n = 313)
Full-text articles excluded
with reasons
(n = 14)
Five other studies reported pertinent information on the associ-
ation between oral health, periodontitis or microbiome and PC
risk (Table 2) [29–33]. Ljung et al. [30] carried out a large nested
case–control study based on data from National Swedish registries
and found a modest but significant increased risk of PC (RR, 1.2;
95% CI 1.0–2.4) associated with disease of the oral cavity, which
includes but is not limited to PD. Michaud et al. [29] also carried
out a nested case–control study based on data from the European
Prospective Investigation into Cancer and Nutrition study (EPIC)
and found that individuals with high levels (>200 ng/ml) of anti-
bodies against P. gingivalis had a twofold increased risk (OR, 2.14;
95% CI 1.05–4.36) of PC compared with individuals with lower
levels. In a national cohort from Taiwan, Wen et al. [31] compared
cancer risk among patients with periodontitis and gingivitis. The
risk of PC was slightly higher (RR, 1.15; 95% CI 0.75–1.78) in the
periodontitis group than in the gingivitis group, but the associ-
ation was not statistically significant. A similar relation was found
by Hujoel et al. [22] in the NHANES I epidemiologic follow-up
study with higher risk of PC observed for periodontitis (RR, 1.77;
95% CI 0.85–3.67) than for gingivitis (RR, 1.44; 95% CI 0.67–
3.11), corresponding to a 20% excess risk for periodontitis com-
pared with gingivitis. In another cohort study from Taiwan,
Hwang et al. [32] compared cancer incidence in treated versus un-
treated periodontitis patients. PD with treatment was associated
with a significantly reduced risk of PC (HR, 0.55; 95% CI 0.35–
0.85). Finally, a recent nested case–control study based on longitu-
dinal data from two prospective cohort studies, the American
Cancer Society Cancer Prevention Study II and the National
Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer
Screening Trial revealed significant increased risk of PC with car-
riage of P. gingivalis (OR ¼ 1.60; 95% CI 1.15–2.22) and
Aggregatibacter actinomycetemcomitans (OR ¼ 2.20; 95% CI 1.16–
4.18) assessed from pre-diagnostic oral wash samples, using bac-
terial 16S ribosomal RNA (16S rRNA) gene sequencing [33].
doi:10.1093/annonc/mdx019 | 987
 Table 1. Characteristics of studies included in the meta-analysis
First author Study Study population Study Pancreas Controls Dental status Risk estimate Adjustments
design period cancers (95% CI)

Stolzenberg- Cohort Alpha-Tocopherol, Beta- 1985 174 cases 29,104 male smokers Self-reported 1.00 Age, number of years of smok-
Review

Solomon, 2003 [21] Carotene Cancer 1997 Missing teeth 1.23 (0.82–1.85) ing, education, urban living,
Prevention Study cohort, 0–10 1.63 (1.09–2.46)a and height (by quintile trend
Finland 11–31 variable

988 | Maisonneuve et al.

Edentulous
Hujoel, 2003 [22] Cohort NHANES I Epidemiologic 1971 12 cases with 11,328 persons Dental examination 1.00 Age, gender
Follow-up Study, USA 1975 periodontitis, Periodontal statusb 1.44 (0.67–3.11)
F-up 11 gingivitis, Healthy 1.77 (0.85–3.67)c
1992 21 edentulism Periodontium 1.90 (0.95–3.81)a
Gingivitis
Periodontitis
Edentulism
Michaud, 2007 Cohort Male health professionals 1986 216 cases 48,375men19,933 Self-reported 1.00 Age, smoking history (pack-
and 2016 [23, 24] study, USA Follow-up 141 cases never smokers Periodontal disease 1.64 (1.19–2.26)c years, time since quit), pro-
2002 No 1.00 fession, race, geographic lo-
1986 Yes 1.57 (0.98–2.50) cation, physical activity,
Follow-up Periodontal disease diabetes, BMI, height, chole-
2012 No cystectomy, NSAID use,
Yes multivitamin use, baseline
teeth number, dietary fac-
tors, total calories
Hiraki, 2008 [25] Case– Aichi Cancer Center, Japan 2001–2005 178 cases 10,480 controls Self-reported 1.00 Adjusted for age, sex, smoking
control Remaining teeth 1.33 (0.86–2.07) and drinking status (never,
21 0.60 (0.32–1.14) former, current), vegetable
9–20 1.33 (0.57–3.10)a and fruit intake, BMI, and
1–8 regular exercise
0
Arora, 2010 [26] Cohort Swedish Twin Registry, 1963 142 cases 15,333 Swedish twins Self-reported 1.00 Sex, age, education, employ-
Sweden F-up Periodontal disease 2.06 (1.14–3.75)c ment, number of siblings,
2004 No smoking status, smoking sta-
Yes tus of partner, alcohol status,
diabetes, and BMI.
Ahn, 2012 [20] Cohort NHANES III National Health 1988–1994 18 deaths 12,605 persons Dental examination 1.00 Age, sex, smoking, education,
and Nutrition Examination F-up Periodontal disease 4.56 (0.93–22.3)c race/ethnicity and BMI
Survey III, USA 2006 No
Yes
Chang, 2015 [27] Cohort National Health Insurance 1998–2005 107 cases 214,890 persons Health claim data 1.00 Age, sex, diabetes, hyperlipid-
Research Database, Taiwan Periodontal disease 1.67 (1.05–2.66) aemia, allergies, viral hepa-
No 1.42 (0.87–2.30) titis, peptic ulcer,
Gingivitis or periodontitis 1.55 (1.02–2.33)c

Continued

Volume 28 | Issue 5 | 2017

Annals of Oncology
Annals of Oncology Review
Discussion

pancreatitis, COPD, and alco-

Age, sex and attained calendar

period, tobacco use, alcohol
consumption, and area of
We carried out a review of the literature and identified eight

hol-related conditions
studies reporting on the association between PD or edentulism,
a consequence of PD, and PC risk. In a meta-analysis, both con-
ditions were associated with a significant increase risk of de-
Adjustments

veloping PC (respectively, þ74% and þ54% for PD and

residence
edentulism), with no evidence of heterogeneity across studies
and no evidence of publication bias. Seven of the reports were
based on either cohort studies, National health survey or
National registry data which should be less subject to bias than
Risk estimate

case–control studies. Three studies were conducted in North

1.3 (0.7–2.3)a

2.1 (1.0–4.7)c
1.2 (0.7–2.0)

1.8 (0.9–3.6)
America, three in Northern Europe and two in Asia, providing a
(95% CI)

good geographical representation and further supporting the

generalizability of the association. All studies provided risk esti-
1.0

1.0

mates adjusted at least for age and sex. In six studies risk esti-
mates were also adjusted for tobacco smoking, in four for BMI,
in four for alcohol consumption, in three for diabetes, which
Dental examination
Teeth at baseline

represent potential confounding factors.

Dental plaque

Unacceptabled
Dental status

PC and PD share many common risk factors including tobacco

Acceptable

smoking, heavy alcohol drinking, obesity, the metabolic syn-

Other PD
Any PD

21–32
11–20

drome, diabetes, and allergy (Table 3). In a large meta-analysis of

0–10

No

47 case–control studies and 35 cohort studies, Iodice et al. [34]

estimated that PC risk was increased by 74% (RR, 1.74; 95% CI
1.61–1.87) in current cigarette smokers compared with never
smokers. Using data from the National Health and Nutrition
19,924 persons

Examination Survey (NHANES) 2009–2012, Vogtmann et al.

[35] found a very similar risk between current cigarette smoking
Controls

and PD (RR, 1.70; 95% CI 1.57–1.86). Heavy alcohol intake (30

grams/day or >3 drinks/day) has also been consistently associ-
ated with a modest increase risk of PC in pooled analyses of indi-
RR retained in the meta-analysis for periodontal condition (gingivitis, dental plaque, periodontitis).

vidual data from cohort studies (RR, 1.22; 95% CI 1.03–1.45)

Pancreas

126 cases

[36] and similarly from case–control studies (RR, 1.22; 95% CI

cancers

1.01–1.48) [37]. Da Silva Furtado Amaral et al. [38] carried out a

systematic review of studies on alcohol drinking and PD; due to
Unacceptable defined as a dental plaque covering more than one-third of the teeth.

heterogeneity a meta-analysis could not be carried out. However,

1973–1974

the authors concluded that alcohol consumption can be con-

period
Study

sidered a ‘risk indicator’ for periodontitis. Obesity represents an-

2012
F-up

other common risk factor for PC and PD: In a pooled analysis of

RR retained in the meta-analysis for edentulism (or severe teeth loss).

individual data from 14 cohort studies, Genkinger et al. [39]

population-based prevalence

found that obese people had a 47% increased risk (95% CI 1.23–
1.75) of developing PC compared with individuals of normal
weight, a risk similar to that reported by Chaffee et al. [40] for PD
Study population

study, Sweden

(RR, 1.35; 95% CI 1.23–1.47) in a meta-analysis of 28 observa-

tional studies.
Assessed using the Russell periodontal index.

The association between diabetes and PC, whether as a risk fac-

tor or an early manifestation or a consequence of the cancer, has
also been reviewed. In a huge pooled analysis of data from 97 pro-
spective studies, the emerging risk factors collaborative group
[41] estimated that diabetes was associated with a 51% (95% CI
design

Cohort
Study

1.24–1.83) excess risk of PC. In a meta-analysis, Ben et al. [42]

found that long-term diabetes (more than 5 years) leads to an
83% increase risk of PC (95% CI 1.38–2.43). In other meta-
analyses, Khader et al. [43] and Chavarry et al. [44] found that
Table 1. Continued

Huang, 2016 [28]

type 2 diabetes mellitus could also be considered a risk factor for

First author

PD and that diabetics had significantly higher severity of PD. The

metabolic syndrome, which embraces a series of conditions
including obesity, diabetes, dyslipidaemia, and hypertension, has
b

d
a

also been associated with PC (RR, 1.55; 95% CI 1.19–2.01) and

Volume 28 | Issue 5 | 2017 doi:10.1093/annonc/mdx019 | 989

Review Annals of Oncology
Study RR (95% CI) Relative risk (95% CI) Funnel plot
Hujoel, 2003 1.77 (0.85-3.67)
Michaud, 2007 1.64 (1.19-2.26)
0.0 SE(log[RR])
Arora, 2010 2.06 (1.14-3.75)
0.2
Ahn, 2012 4.56 (0.93-22.3)
Chang, 2015 1.55 (1.02-2.33) 0.4
Huang, 2016 2.10 (1.00-4.70) 0.6
0.8
Summary risk 1.74 (1.41-2.15) 1.0
–3 –2 –1 0 1 2 3
Heterogeneity I2=0%
0.5 1 2 5 10

Figure 2. Forest and Funnel plots of studies reporting association between periodontal disease and pancreatic cancer.

Study RR (95% CI) Relative risk (95% CI) Funnel plot

Stolzenberg- 0.0 SE(log[RR])
Solomon, 2003 1.63 (1.09-2.46)
0.2
Hujoel, 2003 1.90 (0.95-3.81)
0.4
Hiraki, 2008 1.33 (0.57-3.10)
Huang, 2016 1.30 (0.70-2.30) 0.6
0.8
Summary risk 1.54 (1.16-2.05) 1.0
–3 –2 –1 0 1 2 3
Heterogeneity I2=0% 0.5 1 2 5 10

Figure 3. Forest and funnel plots of studies reporting association between edentulism (or severe teeth loss) and pancreatic cancer.

PD (RR, 1.71; 95% CI 1.44–2.03) in two meta-analyses from
Rosato et al. [45] and Nibali et al. [46], respectively.
Finally allergy has been consistently associated with a reduced
risk of PC and in many reports protective against PD. In a meta-
analysis of 10 case–control studies and four cohort studies,
Gandini et al. [47] reported a 20% risk reduction of PC in aller-
gic individuals (RR, 0.82; 95% CI 0.68–0.99). The inverse asso-
ciation was even stronger with atopic allergy (RR, 0.71; 95% CI
0.64–0.80). The same results were found in a more recent
pooled analysis of individual data from 10 cases-control studies
[48]. Arbes and Matsui [49] found an inverse association be-
tween allergy and oral pathogens or PD. Furthermore, allergy
was associated with a risk reduction of PD ranging from 23% in
a study by Grossi et al. [50] to about 50% in a study by Friedrich
et al. [51].
Because the association between PD and PC could be subject to
residual confounding from common risk factors, it is important
to rely primarily on properly adjusted risk estimates. In several of
the reports included in our meta-analysis, risk estimates were ad-
justed for most of these confounders: Michaud et al. [23] adjusted
risk estimates for age, smoking history, diabetes, BMI in addition
to a series of other variables. In an updated analysis of data from
the same cohort but limited to never smokers, Michaud et al. [24]
reported a risk of 1.57 (95% CI 0.98–2.50) for PD, which is simi-
lar to the risk reported for the whole cohort (RR, 1.64; 95% CI
1.19–2.26), but not subject to residual confounding by tobacco
smoking. In the study by Arora et al. [26], the risk estimate for
PD (RR, 2.06; 95% CI 1.14–3.75) was fully adjusted for sex, age,
education, employment, number of siblings, smoking status,
smoking status of partner, alcohol status, diabetes, and BMI and
was again similar to the summary risk estimates obtained from
our meta-analysis.
Since we observed no evidence of heterogeneity across studies,
a thorough sensitivity analysis was not necessary. However, a sub-
group analysis limited to studies in which dental status was as-
sessed by clinical examination [20, 22, 28] showed similar results
(SRR for PD 2.11; 95% CI 1.28–3.49; SRR for edentulism 1.51;
95% CI 0.96–2.37) than for studies in which dental status was
self-reported or obtained from health claim databases (SRR for
PD 1.67; 95% CI 1.32–2.10; SRR for edentulism 1.57; 95% CI
1.09–2.27). Limiting analysis to cohort studies, or excluding atyp-
ical studies such as the one by Chang which relied on health claim
data [27] does not significantly change the results and conclu-
sions (data not shown).
Our results are based on a relatively limited number of pub-
lished reports but are supported by additional studies showing a
significant increased risk of PC associated with carriage of known
periodontopathic pathogens and with plasma level of
Porphyromonas gingivalis (P. gingivalis) [33, 52, 29].
Porphyromonas gingivalis, a Gram-negative bacterium of the phy-
lum Bacteroidetes has been implicated in the pathogenesis of
human periodontitis. One investigation reported a threefold
increased risk of orodigestive cancer, including PC, in relation to
high levels of P. gingivalis antibodies, even in individuals without
overtly expressed symptoms of PD [20]. Therefore, the role of the
oral microbiota may not necessarily depend on oral disease.
Although P. gingivalis is a well-described periodontal pathogen, it
is also a normal inhabitant of the oral microflora, making it un-
clear whether the observed associations with this bacterium re-
flect proxy associations with other oral bacteria or perhaps a
distinctly dysbiotic oral microbiota [53]. Either direct or indirect
competitive exclusion of pathogens, indigenous and commensal
oral bacteria may play a significant role in the risk of pancreatic
oncogenesis [29]. An increasing number of studies have revealed

990 | Maisonneuve et al. Volume 28 | Issue 5 | 2017

 Table 2. Studies with pertinent information to the review but not included in the quantitative synthesis
First author Study Study Study Number of patients Condition Risk estimate Adjustments
Annals of Oncology

design population period (95% CI)

Volume 28 | Issue 5 | 2017

Ljung, 2011 [30] Nested case– Sweden 1973–2008 29,218 pancreas cancer cases/ Oral cavity disease 1.2 (1.0–1.4) Age, sex, alcohol, chronic obstruct-
control 99,992 controls ICD-8/9 codes 520–529 ive pulmonary disease, obesity,
ulcer disease, diabetes, and
pancreatitis
Michaud, 2013 [29] Nested case– Europe, 1992–2000 405 pancreas cancer cases/416 Plasma 2.14 (1.05–4.36) Centre, sex, follow-up time, age at
control EPIC cohort controls P. gingivalis 0.55 (0.39–0.83) blood collection, date and time
High antibody titres against of blood collection, fasting sta-
commensal (non- tus and use of exogenous hor-
pathogenic) mones among women, BMI
oral bacteria (continuous) and smoking status
(never, past, current).centre, sex,
follow-up time, age at blood
collection, date and time of
blood
Wen, 2014 [31] Cohort Taiwan 1997–2010 57191 patients with periodontitis Periodontitis vs Gingivitis 1.15 (0.75–1.78) Sex, age and the presence of
and comorbidities
96375 with gingivitis
Hwang, 2014 [32] Cohort Taiwan 1997–2010 38 902 treated and 77804 untreated Treated vs Untreated 0.55 (0.35–0.85) Age, sex, occupation, type 2 dia-
periodontitis patients betes mellitus, hypertension and
hyperlipidaemia
Fan, 2016 [33] Nested case– USA, CPSII 1992–2008 4361 pancreas cancer cases/371 Presence vs absence 1.60 (1.15–2.22)2.20 Random effect of cohorts as well
control and PLCO 1993–2010 controls Porphyromonas gingivalis (1.16–4.18) as age, race, sex, BMI, smoking
cohorts Aggregatibacter status, alcohol consumption sta-
actinomycetemcomitans tus and history of diabetes.

EPIC, European Prospective Investigation into Cancer and Nutrition study; CPSII, American Cancer Society Cancer Prevention Study II; PLCO, National Cancer Institute Prostate, Lung, Colorectal and Ovarian
Cancer Screening Trial.

doi:10.1093/annonc/mdx019 | 991
Review
Review Annals of Oncology
Table 3. Common risk factors for pancreatic cancer (PC) and periodontal diseases (PD) (estimates from selected studies)
Exposure Pancreatic cancer Periodontal disease

Tobacco smoking Iodice, 2008 [35] Vogtmann, 2016 [36]

Meta-analysis of 47 case–control studies and 35 cohort Prevalence of PD within categories of cigarette and tobacco
studies use in the USA population aged 30 years and older,
(24,726 PC cases) NHANES 2009–2012.
Current smokers 1.74 (1.61–1.87) Current smokers 1.70 (1.57–1.86)
Alcohol drinking Genkinger, 2009 [37] da Silva Furtado Amaral, 2009 [39]
Pooled analysis of data from 14 cohort studies (2,187 PC Systematic review: due to heterogeneity, no meta-analysis
cases) was carried out.
30 grams/day 1.22 (1.03–1.45) Alcohol consumption can be considered a risk indica-
Lucenteforte, 2012 [38] tor for periodontitis
Pooled-analysis of data from 10 case–control studies
(5,585 PC cases)
4–5 drinks/day 1.22 (1.01–1.48)
6 drinks/day 1.46 (1.16–1.83)
9 drinks/day 1.60 (1.16–1.22)
Overweight obesity Genkinger, 2011 [40] Chaffee, 2010 [41]
Pooled analysis of 14 cohort studies Meta-analysis of 28 studies
(2,135 PC cases) Obesity 1.35 (1.23–1.47)
Obesity 1.47 (1.23–1.75)
Diabetes mellitus (DM) Emerging Risk Factors Collab, 2011 [42] Khader, 2006 [44]
Pooled analysis of data from 97 prospective studies meta-analysis
(2,189 PC deaths) Diabetics had a signi˚cantly higher severity but the
Diabetes 1.51 (1.24–1.83) same extent of PD than non-diabetics
Ben, 2011 [43] Chavarry, 2009 [45]
Meta-analysis of 35 cohort studies meta-analysis
(20,410 PC cases) Type 2 DM can be considered a
Diabetes 1.94 (1.66–2.27) risk factor for periodontitis
Diabetes >5 yr 1.83 (1.38–2.43)
Metabolic syndrome Rosato, 2011 [46] Nibali, 2013 [47]Meta-analysis of 20 observational studies
Meta-analysis of 1 case–control and 4 cohort studies METs 1.71 (1.44–2.03)
(1,352 PC cases)
METs 1.55 (1.19–2.01)
Allergy Gandini, 2005 [48] Grossi, 1994 [51]
Meta-analysis of 10 case–control studies and 4 cohort stud- Allergy 0.77 (0.58–1.00)
ies (3,040 PC cases) Friedrich, 2006 [52]
Any allergy 0.82 (0.68–0.99) Hay fever 0.53 (0.3–0.9)
Atopic allergy 0.71 (0.64–0.80) Mite allergy 0.39 (0.2–0.9)
Olson, 2013 [49] Asthma 0.48 (0.2–1.0)
Pooled analysis of data from Many negative reports, see review by Arbes et al. [50]
10 case–control studies (3,567 PC cases)
Any allergy 0.79 (0.62–1.00)
Hay fever 0.74 (0.56–0.96)
Animal allergy 0.62 (0.41–0.94)

that the properties of the overall microbial community is the
driver of health and disease [54, 55].
One small case–control study using 16S rRNA amplicon-based
sequencing comparing salivary microbiota of PC patients with
healthy patients revealed significant differences between the two
groups [56]. However, since this study used saliva samples har-
vested after the onset of PC, it remains unclear whether observed
characteristics of the microbiome preceded and contributed to
carcinogenesis, or if they developed as a result of the cancer.
More informative, the recently reported prospective CPS-II and
PLCO cohort studies provides supportive evidence that oral
microbiota may play a role in the etiology of PC, in particular
since the association remained after exclusion of cases that de-
veloped within 2 years of sample collection [33].
There is also good evidence that the oral microbiome and PD
are associated with other forms of cancer in particular oral [57],
esophageal [58], gastric [58], and colorectal cancer [59].
The mechanism by which the oral microbiota might contribute
to the development of PC is still evolving. The oral cavity is an ob-
vious gateway for microbes, which could then enter the

992 | Maisonneuve et al. Volume 28 | Issue 5 | 2017

Annals of Oncology
gastrointestinal system or the bloodstream and affect distant
organs [60–63]. For example, Helicobacter pylori, one bacteria
identifiable in the mouth, has been possibly associated with
chronic pancreatitis as well as PC [64, 66]. Oral bacteria may play
a role in triggering pancreatitis [67, 68]. The systemic dissemin-
ation of oral microbes and their toxins may also trigger systemic
inflammatory and immune responses that could contribute to
the risk of PC [61, 68–72]. Cancer, and more specifically, PC, is
linked to chronic inflammatory states [72, 73]. Meanwhile, oral
bacteria are increasingly being implicated in chronic,
inflammatory-based systemic diseases [62, 74–76], that may de-
generate in tumor development. For example, microbial activa-
tion of innate immune signaling via Toll-like receptors was found
to inhibit apoptosis and stimulate tumor growth [53, 77, 78].
Oral bacteria play a role in producing carcinogenic metabolic
byproducts from oral exposures. Both N-nitroso and acetalde-
hyde compounds are etiological exposures for PC [69, 79–81].
Oral bacteria convert ethanol to the carcinogen acetaldehyde;
they also activate carcinogenic N-nitroso compounds present in
tobacco smoke and some foods, and catalyse their endogenous
formation from these and other sources [12, 69, 81–87]. Oral
nitrate-reducing bacteria play a key role in the formation of car-
cinogenic N-nitroso compounds in the stomach: oral nitrate re-
duction is responsible for nearly 80% of one’s total nitrite
exposure, and oral nitrate reduction and is directly correlated
with urinary N-nitroso compound levels [83]. The endogenous
formation of nitrosamines has been found to be substantially
higher among individuals with poor oral hygiene than among
those with good oral hygiene [88].
Major strengths of this meta-analysis are lack of heterogeneity
of risk estimates across studies, the absence of evidence of publi-
cation bias and the presence studies supporting the role of micro-
biota in PC development. The main limitations include the
relatively small number of published studies and use of different
study designs and definitions of periodontal outcomes across
studies.
In summary, available evidence points to an association be-
tween PD and subsequent tooth loss with PC. The potential link
between oral disease and PC is unclear, but could be related to al-
terations in the oral microbiome.
Funding
None declared.
Disclosure
The authors have declared no conflicts of interest.
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