The ICARE study (Investigation of occupational and environmental CAuses of REspiratory cancers) is a multicentre population-based case–control study on lung and upper aerodigestive tract cancers carried out from 2001 to 2007 in 10 French administrative areas (“départements”) covered by a general cancer registry. This study was set up to explore the role of lifestyle, environmental and occupational risk factors in lung and UADT cancers. The study design has been described in details elsewhere 27 .

Briefly, all newly diagnosed primary oral cavity, pharynx, larynx, sinusal cavities, trachea and lung cancers were selected. Only histologically confirmed cases aged 75 or younger at interview, identified between 2001 and 2007, and residing in one of the 10 départements, were eligible. Clinical and anatomo-pathology reports were reviewed to determine topography and histological type of the tumours according to the International Classification of Diseases for Oncology 28 . All histological types were included.

Controls were selected from the general population by random digit dialling 29 . The controls were frequency-matched to the cases by age, gender and area of residence (“département”). Additional stratification ensured that controls were representative of the population of the “département” in terms of socio-economic status based on the last job held.

The present analysis included all ICARE controls and only the cases with oral cavity cancer (ICD-10 codes C01-C06).

Among the 1316 oral cavity cancer cases identified as eligible, 196 could not be reached, 81 were deceased and 71 were too sick to be interviewed. Of the 968 cases who were contacted, 176 refused to participate and 792 (81.8%) answered the questionnaire. We focused only on the cases with squamous cell carcinoma (772 subjects, 97.5% of all cases with oral cavity cancer).

Of 4673 eligible controls, 4411 were contacted, and 3555 (80.6%) agreed to participate.

Trained interviewers administered a detailed standardised questionnaire during face-to-face interviews. If the subject was too sick to be interviewed, a shortened version of the questionnaire was used to interview him or a next-of-kin. Among the 772 subjects with squamous cell carcinoma of the oral cavity, 689 (89.2%) filled a complete questionnaire and 83 (10.8%) a shortened questionnaire. Among controls, 3481 (97.9%) filled a complete questionnaire and 74 a shortened questionnaire (2.1%). As the shortened version of the questionnaire did not contain information about family history of cancer and medical conditions, the present analysis was based on 689 cases with squamous cell carcinoma and 3481 controls, all with a complete questionnaire.

The complete questionnaire consisted of the following items: socio-demographic characteristics (age, gender, birth country, education level, marital status), residential history, personal medical history, family history of cancer, detailed tobacco and alcohol consumption (quantity, duration, type of product, age at starting, time since cessation), non-alcoholic beverage consumption (coffee, tea), anthropometric variables (height, weight at interview, two years before and at age 30), detailed lifelong job history and occupational exposures.

To ascertain personal medical history, study participants were asked if, throughout their lives, they had ever had (“yes, no, or don’t know”) any of the following diseases: tuberculosis, chronic bronchitis, asthma, recurrent rhinitis, nasal polyps, recurrent nose bleeds, recurrent sinusitis, gastro-oesophageal reflux (heartburn or regurgitation), herpes, candidiasis, and warts. If the answer was “yes”, the subjects were asked to specify the age at first occurrence, the treatment and if the diagnosis was made by a doctor. Subjects reporting having ever had herpes, candidiasis or warts were asked to specify the location: lip and genitals for herpes, oral cavity and genitals for candidiasis, and hands, feet and head and neck for warts.

To ascertain the family history of cancer, subjects were first asked to give the year of birth of their biological mother and father, and of their full brothers or sisters (“brother or sister having the same mother and the same father than you”). Then, they were asked for each of these relatives if she/he had ever had a cancer (“yes, no or don’t know”). If the answer was “yes”, the subjects were asked to specify the age at cancer diagnosis and if possible the type of cancer. No verification of the cancer diagnosis in the relatives was performed.

We used unconditional logistic regression models to calculate odds ratios (OR) and their 95% confidence intervals (95% CI). All p-values were derived from two-sided statistical tests.

All logistic regression models controlled for age (≤ 50, 51–59, 60–69, ≥ 70 years), gender, area of residence, education level (primary or less, vocational secondary, general secondary and university), BMI two years before the interview (categorical, according to the classification of the World Health Organization 30 : < 18.5, 18.5-24.9, 25.0-29.9, ≥ 30 kg/m²). Previous analyses of our data showed that the variables that best characterize the association between tobacco and alcohol consumption and oral cancer risk were smoking status, smoking duration, daily quantity of tobacco smoked and daily quantity of alcohol drinking 31 . To control for smoking, we used smoking status (never, current, former), average daily quantity of tobacco smoked (1–19, 20–39, ≥ 40 grams), and duration of smoking (1–30, 31–40, > 40 years) 32 . Average daily quantity of alcohol drinking in quartiles (never, < 0.6, 0.6-2.0, 2.1-4.5, > 4.5 standard glasses) was included in the models to adjust for alcohol drinking. The quantity of pure alcohol contained in a standard glass (15 cl of wine, 30 cl of beer, 5 cl of spirits, 10 cl of aperitif, and 30 cl of cider) is the same for each type of alcoholic beverage.

We analysed the risk of oral cavity cancer related to the personal medical history using two variables: all medical conditions self-reported by the subjects and medical conditions reportedly diagnosed by a doctor. The date of interview was used as the date of reference for both cases and controls. This date was close to the date of diagnosis of the cases since cases were interviewed on average within three months of diagnosis.

The family history of cancer was evaluated separately for mothers, fathers, brothers and sisters, and then among all first-degree relatives taken together. We analysed the risk of oral cavity cancer related to the cancer site among relatives: all sites together, head and neck (including oral cavity, pharynx, larynx, nasal cavity and sinuses) and non-head and neck cancers. Because a high number of cancers in family members were reported non-specifically as “cancer of the head and neck”, we chose to group the locations of head and neck cancers to reduce potential inaccurate reporting of cancer subsites. We nevertheless performed some analyses for family history of specific head and neck cancer sites among all first-degree relatives.

We also conducted analyses stratified by tobacco and alcohol consumption. We also performed the same analyses using a more restricted definition of the oral cavity excluding base of tongue (C01), lingual tonsils (C02.4), soft palate (C05.1) and uvula (C05.2), since these subsites are often included in the oropharynx. In addition, seven subsites (base of the tongue, mobile tongue, floor of the mouth, gums, soft palate, hard palate, and other parts of the oral cavity) were compared for family history of cancer and personal history of other medical conditions using unconditional polytomous logistic regression.

Statistical analyses were conducted using STATA software version 10.0 (StataCorp, Texas, USA).

Statistical analysis showed significant positive associations between the risk of oral cavity cancer (C01-C06) and chronic bronchitis (OR 1.7, 95% CI 1.2-2.4) (Table 2). Histories of tuberculosis and candidiasis overall were associated with an increased risk of oral cavity cancer (ORs 1.6), but the results did not reach statistical significance. Among candidiasis locations, oral candidiasis was associated with an increased risk of oral cavity cancer (OR 5.0, 95% CI 2.1-12.1). Significant inverse relations were observed between the risk of oral cavity cancer and recurrent rhinitis (OR 0.6, 95% CI 0.4-0.9), nasal polyps (OR 0.3, 95% CI 0.1-0.9), and gastro-oesophageal reflux (OR 0.5, 95% CI 0.4-0.7). Herpetic lesions were not related to the risk of oral cavity cancer, regardless of the location of the herpes. The risks associated with a history of skin warts were reduced, but the results did not reach statistical significance.

^*OR adjusted for age, gender, area of residence, education level, tobacco smoking (duration, quantity and status), alcohol drinking (quantity) and BMI two years before the interview.

^‡Location of herpetic lesions and candidiasis not reported by 24 subjects and 17 subjects, respectively.

^§Multiple locations reported by 83 subjects.

Because high prevalence of oropharyngeal candidiasis has been described in subjects with head and neck cancer undergoing radio/chemotherapy 33 34 , we also conducted analysis after excluding subjects declaring candidiasis at the time of interview or at the time of diagnosis of another cancer; the association between oral cavity cancer risk and oral candidiasis remained practically unchanged (OR 6.0, 95% CI 2.2-16.4). Oral candidiasis may also constitute an early manifestation of the cancerous disease. When we excluded all subjects reporting a history of oral candidiasis near the current cancer (up to two years before the cancer diagnosis), the association between oral cavity cancer and oral candidiasis remained significant (OR 3.7, CI 95% 1.3-10.1).

We calculated the ORs for oral candidiasis in strata of tobacco and alcohol consumption. The OR was slightly higher in ever smokers (OR 5.6, 95% CI 2.0-15.2) than in never smokers (OR 4.3, 95% CI 0.5-41.7), but the interaction between tobacco smoking and oral candidiasis was not significant (p-value for interaction = 0.14). Oral candidiasis was associated with an elevated risk of oral cavity cancer in drinkers of more than 2 glasses/day (OR 3.9, 95% CI 1.0-14.8) but not in drinkers of 2 glasses/day or less (OR 1.1, 95% CI 0.2-23.8), although the ORs were not statistically different (p-value for interaction = 0.50).

When the analysis was restricted to medical conditions that the subjects reported as diagnosed by a doctor, similar results were observed, except for the association between bronchitis and oral cavity cancer which became weaker and non-significant (OR 1.2, 95% CI 0.9-1.6) (data not shown).

The associations between family history of cancer and risk of oral cavity cancer are presented in Table 3.

^†OR adjusted for age, gender, area of residence, education level, tobacco smoking (duration, quantity and status), alcohol drinking (quantity) and BMI two years before the interview.

^‡OR adjusted, in addition to the variables of the first model, for the number of brothers, sisters or siblings, respectively.

History of cancer in general, and of head and neck cancer in particular, among fathers, were associated with a slightly elevated risk of oral cavity cancer, but the results were not statistically significant (OR 1.3, 95% CI 0.9-1.6, and 1.5, 95% CI 0.9-2.4, respectively).

History of head and neck cancer among mothers was significantly associated with an elevated risk of oral cavity cancer (OR 5.2, 95% CI 1.2-23.9). This OR was higher than that observed for fathers. When cancer history among siblings was analysed, after adjustment for the number of sisters and brothers, we observed a significant association between the risk of oral cavity cancer and history of cancer of any type (OR 1.4, 95% CI 1.1-1.9). History of head and neck cancer among siblings was associated with an increased risk of oral cavity cancer (OR 2.3, 95% CI 1.2-4.2). Analysis by type of sibling showed a significantly increased risk only among subjects having brothers with a history of head and neck cancer (OR 2.6, 95% CI 1.2-5.8); history of head and neck cancer among sisters was not significantly associated with an increased risk of oral cavity cancer (OR 1.7, 95% CI 0.6-4.2).

When we analysed the relationship between cancer history among all first-degree relatives and oral cavity cancer risk, we observed significant association for history of head and neck cancer (OR 1.9, 95% CI 1.2-2.8). A family history of any type of cancer slightly increased the risk of oral cavity cancer, but the results were not statistically significant (OR 1.2, 95% CI 0.9-1.5). The risk associated with first-degree relatives’ history of cancer (any type and head and neck) increased with the number of affected relatives.

Analysis by type of head and neck cancer in first-degree relatives showed significantly increased risks of oral cavity cancer in subjects with family history of oral cavity cancer (OR 3.5, 95% CI 1.1-11.2) and of “head and neck cancer” (not specified) (OR 1.8, 95% CI 1.1-2.9). A family history of pharyngeal, laryngeal, and sinonasal cancer was associated with non-significantly elevated risks of oral cavity cancer (OR 4.6, 95% CI 0.5-44.8 for history of pharyngeal cancer; 1.6, 95% CI 0.6-4.4 for history of laryngeal cancer; and 1.7, 95% CI 0.3-8.8 for history of sinonasal cancer). However, few subjects reported a specific location of head and neck cancer in first degree relatives (26 oral cavity, 5 pharynx, 35 larynx, and 11 nasal cavity/sinuses cancer).

Analysis stratified by gender of first-degree relatives showed that history of head and neck cancer among female relatives (mothers and sisters) was not significantly associated with the risk of oral cavity cancer (OR 2.3, 95% CI 0.9-5.4), although the result was borderline significant. Conversely, history of head and neck cancer in male relatives (fathers and brothers) was significantly associated with the risk of oral cavity cancer (OR 1.9, 95% CI 1.2-3.3). However, these ORs did not differ significantly (p-value of test of comparison of ORs = 0.91).

We found a stronger association between the risk of oral cavity cancer and family history of head and neck cancer in subjects aged 45 or more (OR 2.3, 95% CI 1.5-3.4) compared to subjects aged less than 45 (OR 1.3, 95% CI 0.3-6.7), although the ORs were not statistically different (p-value for interaction = 0.46).

Analysis by cancer site among first-degree relatives (Table 4) showed elevated ORs among subjects having a family history of lung, oesophagus, cervix and corpus uteri, brain and nervous system cancer, but the results were not statistically significant (OR 1.4, 95% CI 0.9-1.9; 1.5, 95% CI 0.7-3.3; 1.7, 95% CI 0.9-3.1; 2.0, 95% CI 0.9-4.8 respectively).

^†ORs adjusted for age, gender, area of residence, education level, tobacco smoking (duration, quantity and status), alcohol drinking (quantity) and BMI two years before the interview.

When we stratified by tobacco smoking and/or alcohol drinking (Table 5), significantly increased risks of oral cavity cancer related to family history of any type of cancer were observed only in smokers and/or moderate to heavy drinkers. Significantly elevated risks of oral cavity cancer associated with family history of head and neck cancer were seen for both never and ever smokers and for light and moderate to heavy drinkers. However, the increase in risk was small and not significant for never smokers who were also light drinkers.

^†OR adjusted for age, gender, area of residence, education level, tobacco smoking (duration, quantity and status), alcohol drinking (quantity) and BMI two years before the interview.

NS = never smoking; ES = ever smoking; D = drinking.

^‡Reference category: no history of cancer (any site) in first-degree relatives.

^§Reference category: no history of head and neck cancer in first-degree relatives.

When the analyses were limited to intraoral cavity (C02.0-C02.3, C02.8, C02.9, C03, C04, C05.0, C05.8, C05.9, C06), the results were similar to that observed for oral cavity globally (C01-C06). Thus, family history of UADT cancer among first-degree relatives was associated with an OR of 1.7 (95% CI 1.1-2.7), personal history of oral candidiasis with an OR of 4.9 (95% CI 1.8-13.3), gastro-oesophageal reflux with an OR of 0.6 (95% CI 0.4-0.8), recurrent rhinitis with an OR of 0.6 (95% CI 0.4-0.9), and nasal polyps with an OR of 0.3 (95% CI 0.1-0.9).

We assessed the risk of oral cavity cancer by anatomical site of the oral cavity (base of tongue, mobile tongue, gum, floor of mouth, hard and soft palate, and other parts of oral cavity) for personal medical conditions and for family history of cancer using a polytomous regression. We did not find any difference between subsites for any variable of interest (tests of comparison of odds ratios non-significant) (data not shown).