When comparing demographics, elderly people, women, and subjects with a lower income level were more frequently observed among the excluded subjects (Table S2). The mean ± standard deviation age of participants was 52.2 ± 8.7 years; 60.9% were males, 39.3% had hypertension, 9.0% had diabetes mellitus, and 25.3% were current smokers. Approximately 13.1% and 24.1% of included subjects had periodontal disease and at least one tooth lost, respectively. Based on the self-reported surveys, 40.6% of the participants brushed their teeth ≥3 times/day. Approximately 23.8% of subjects had at least one professional teeth scaling per year (Table 1).
Table 1. Baseline characteristics of the study population.
|
Characteristics
|
Total
|
Number of subjects
|
150,774
|
Age (years)
|
52.2 ± 8.7
|
Male sex
|
91,855 (60.9)
|
Income levels
|
|
Fifth quintile (highest)
|
59,339 (39.4)
|
Fourth quintile
|
30,701 (20.4)
|
Third quintile
|
20,871 (13.8)
|
Second quintile
|
18,962 (12.6)
|
First quintile (lowest)
|
20,665 (13.7)
|
Covered by medical aid
|
236 (0.2)
|
Alcohol consumption
|
71,800 (47.6)
|
Smoking status
|
|
Never smoker
|
97,037 (64.4)
|
Former smoker
|
15,590 (10.3)
|
Current smoker
|
38,147 (25.3)
|
Regular physical activity
|
14,570 (9.7)
|
Anthropometric measurements
|
|
Body mass index (kg/m2)
|
23.9 ± 2.9
|
Systolic blood pressure (mmHg)
|
126.4 ± 17.2
|
Diastolic blood pressure (mmHg)
|
79.4 ± 11.2
|
Comorbidities
|
|
Hypertension
|
59,234 (39.3)
|
Diabetes mellitus
|
13,609 (9.0)
|
Dyslipidemia
|
24,027 (15.9)
|
Laboratory findings
|
|
Total cholesterol (mg/dL)
|
198.2 ± 36.4
|
Fasting blood sugar (mg/dL)
|
97.0 ± 29.0
|
Aspartate aminotransferase (U/L)
|
26.0 ± 16.0
|
Alanine aminotransferase (U/L)
|
25.4 ± 19.8
|
Gamma glutamyl transferase (U/L)
|
38.3 ± 53.0
|
Proteinuria (≥1+ in dipstick test)
|
4,495 (3.0)
|
Oral hygiene care
|
|
Frequency of tooth brushings (times/day)
|
|
0–1
|
22,111 (14.7)
|
2
|
67,502 (44.8)
|
≥3
|
61,161 (40.6)
|
Dental visits for any reason
|
63,506 (42.1)
|
Professional teeth scaling
|
35,859 (23.8)
|
Oral health status
|
|
Periodontal disease
|
19,861 (13.1)
|
Number of teeth lost
|
|
0
|
114,459 (75.9)
|
1–7
|
32,545 (21.6)
|
8–14
|
2,235 (1.5)
|
≥15
|
1,535 (1.0)
|
Data are expressed as the mean ± SD or n (%).
|
After a median 11.1 years of follow-up, 1,155 oral and pharyngeal cancers had occurred, which included oral cavity and oral cancer (73.8%), salivary gland cancer (6.2%), and tonsil and pharynx cancer (20.0%). The estimated 10-year event rate for oral and pharyngeal cancers was 0.76%. The cumulative incidence curves for oral and pharyngeal cancers are presented in Figure 2 based on frequency of tooth brushings, professional teeth scaling, dental visits for any reason, and number of teeth lost. The risk of oral and pharyngeal cancers was lower when a subject had better oral hygiene, for example, frequent tooth brushing, frequent dental visits, and professional teeth scaling. In contrast, poor oral health status, including a greater number of teeth lost, was associated with a higher risk of oral and pharyngeal cancers.
Based on multivariable regression, frequent tooth brushing (three or more times per day) was significantly associated with a lower risk of oral and pharyngeal cancers (HR: 0.75, 95% CI: 0.64–0.89, p=0.001, p for trend <0.001 in model 1; HR: 0.76, 95% CI: 0.64–0.90, p=0.002, p for trend=0.001 in model 2; HR: 0.79, 95% CI: 0.66–0.94, p=0.007, p for trend=0.005 in model 3) (Table 2 and Table S3). An increased number of teeth lost was positively related to the occurrence of oral and pharyngeal cancers based on multivariable analysis (p<0.001 in models 1, 2, and 3). Interaction effect between number of teeth lost and age, smoking, alcohol consumption, and periodontal disease was not shown (p value=0.467, 0.872, 0.136, and 0.502, respectively). Having lost more than 15 teeth was positively associated with increased risk of oral and pharyngeal cancers (HR: 1.71, 95% CI: 1.26–2.31, p=0.001 in model 1; HR: 1.68, 95% CI: 1.24–2.28, p<0.001 in model 2; HR: 1.66, 95% CI: 1.22–2.25, p=0.001 in model 3) (Table 2 and Table S3). However, adjusting for confounding factors, the statistical significance of the relationship between professional teeth scaling and dental visits for any reason and risk of future occurrence of oral and pharyngeal cancers was diminished in models 1–3 (Table 2 and Table S3). Paradoxically, the presence of periodontal disease insignificantly decreased the occurrence of oral and pharyngeal cancers (HR: 0.79, 95% CI: 0.65–1.02, p=0.069 in model 1; HR: 0.79, 95% CI: 0.66–1.03, p=0.066 in model 2; HR: 0.80, 95% CI: 0.65–1.03, p=0.063 in model 3) (Table 2).
In sensitivity analyses, the association of frequent tooth brushing and number of teeth lost with the risk of occurrence of oral and pharyngeal cancers was consistently noted in non-smokers and subjects with no alcohol consumption (Table S4-S8). In subgroup analysis, the relationship between frequent tooth brushing and number of teeth lost and the risk of occurrence of oral and pharyngeal cancers was consistently noted in oral cavity and oral cancer (Table S9 and S10). The number of teeth lost (≥15) and dental visits for any reason were associated with future risk of the occurrence of salivary gland cancer (Table S11). In contrast, periodontal disease and parameters of oral health were not related to the occurrence of tonsil and pharynx cancer (Table S12).
Table 2. Risk of oral and pharyngeal cancers based on periodontal disease and parameters of oral health.
|
Number of subjects
|
Number of events
|
Follow-up duration (person-years)
|
Age-adjusted incidence rate
(per 1,000 person-yrs, (95% CI))
|
Unadjusted model
|
Age, sex-adjusted model
|
Multivariable model 1
|
Multivariable model 2
|
Multivariable
model 3
|
|
HR
(95% CI)
|
p
value
|
HR
(95% CI)
|
p
value
|
HR
(95% CI)
|
p value
|
HR
(95% CI)
|
p value
|
HR
(95% CI)
|
p
value
|
Periodontal disease
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
No
|
130913
|
1036
|
1499100
|
0.52
(0.49, 0.56)
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
Yes
|
19861
|
119
|
225247
|
0.39
(0.33, 0.47)
|
0.76
(0.63, 0.92)
|
0.004
|
0.78
(0.65, 0.94)
|
0.011
|
0.79
(0.65, 1.02)
|
0.069
|
0.79
(0.66, 1.03)
|
0.066
|
0.80
(0.65, 1.03)
|
0.063
|
Frequency of tooth
brushings (times/day)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
0–1
|
22111
|
240
|
248224
|
0.59
(0.52, 0.68)
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
2
|
67502
|
587
|
774302
|
0.55
(0.50, 0.60)
|
0.80
(0.69, 0.93)
|
0.004
|
0.90
(0.78, 1.05)
|
0.185
|
0.91
(0.78, 1.06)
|
0.240
|
0.92
(0.79, 1.07)
|
0.263
|
0.94
(0.80, 1.09)
|
0.397
|
≥3
|
61161
|
328
|
701821
|
0.43
(0.38, 0.48)
|
0.49
(0.42, 0.58)
|
<.001
|
0.72
(0.61, 0.85)
|
0.001
|
0.75
(0.64, 0.89)
|
0.001
|
0.76
(0.64, 0.90)
|
0.002
|
0.79
(0.66, 0.94)
|
0.007
|
P for trend*
|
|
|
|
|
<.001
|
|
<.001
|
|
<.001
|
|
0.001
|
|
0.005
|
|
Dental visits for any reason
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
No
|
87268
|
703
|
995817
|
0.52
(0.48, 0.57)
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
Yes
|
63506
|
452
|
728530
|
0.49
(0.44, 0.54)
|
0.88
(0.79, 0.99)
|
0.040
|
0.98
(0.87, 1.10)
|
0.681
|
0.99
(0.88, 1.12)
|
0.928
|
1.00
(0.89, 1.12)
|
0.949
|
1.06
(0.93, 1.21)
|
0.377
|
Professional teeth scaling
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
No
|
114915
|
960
|
1311583
|
0.53
(0.49, 0.57)
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
Yes
|
35859
|
195
|
412764
|
0.44
(0.38, 0.50)
|
0.65
(0.56, 0.76)
|
<.001
|
0.86
(0.73, 1.00)
|
0.050
|
0.89
(0.76, 1.04)
|
0.133
|
0.89
(0.76, 1.04)
|
0.144
|
0.91
(0.77, 1.08)
|
0.295
|
Number of teeth lost
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
0
|
114459
|
749
|
1314108
|
0.47
(0.43, 0.51)
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
1
(Reference)
|
|
1–7
|
32545
|
313
|
370227
|
0.61
(0.54, 0.69)
|
1.47
(1.29, 1.68)
|
<.001
|
1.34
(1.17, 1.53)
|
<.001
|
1.30
(1.14, 1.48)
|
0.001
|
1.30
(1.13, 1.48)
|
<.001
|
1.29
(1.12, 1.47)
|
<.001
|
8–14
|
2235
|
44
|
24295
|
0.75
(0.55, 1.01)
|
3.02
(2.23, 4.10)
|
<.001
|
1.56
(1.15, 2.13)
|
0.005
|
1.51
(1.11, 2.06)
|
0.009
|
1.49
(1.10, 2.04)
|
0.011
|
1.47
(1.08, 2.01)
|
0.015
|
≥15
|
1535
|
49
|
15717
|
0.88
(0.65, 1.19)
|
4.93
(3.69, 6.59)
|
<.001
|
1.73
(1.28, 2.34)
|
<.001
|
1.71
(1.26, 2.31)
|
0.001
|
1.68
(1.24, 2.28)
|
<.001
|
1.66
(1.22, 2.25)
|
0.001
|
P for trend*
|
|
|
|
|
<.001
|
|
<.001
|
|
<.001
|
|
<.001
|
|
<.001
|
|
Number of events was the occurrence of oral and pharyngeal cancers, which was defined as the presence of one of the relevant ICD-10 codes at least once in the medical treatment database in 11.1 years of follow-up.
Event rates were reported as 11.1-year event rates (%).
Multivariable model 1 was adjusted for age, sex, income level, alcohol consumption, smoking status, regular exercise, body mass index (kg/m2), hypertension, diabetes mellitus, and dyslipidemia.
Multivariable model 2 was adjusted for the variables in model 1 as well as systolic blood pressure, total cholesterol, fasting blood sugar, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, and proteinuria.
Multivariable model 3 was adjusted for the variables in model 2 as well as periodontal disease, frequency of tooth brushings, dental visits for any reason, professional teeth scaling, and number of teeth lost except regarding the independent variable.
CI, confidence interval; HR, hazard ratio.
*: The trend test for hazard ratios
Multivariable analysis was performed by using the regression methods of Fine and Gray for competing risk data, (death is a competing event for oral and pharyngeal cancers).