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Keywords:

  • case-control study;
  • family history;
  • laryngeal cancer;
  • risk factors

Abstract

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Only limited data is available on the relationship between family history of laryngeal and other neoplasms and laryngeal cancer risk. We investigated the issue using data from a multicentre case-control study conducted in Italy and Switzerland between 1992 and 2009 including 852 cases with histologically confirmed laryngeal cancer and 1970 controls admitted to hospital for acute, non neoplastic conditions. Unconditional logistic regression models adjusted for age, sex, study center, education, tobacco smoking, alcohol drinking and number of siblings were used to estimate the odds ratios (ORs) of laryngeal cancer. The multivariate OR was 2.8 (95% confidence interval [CI], 1.5–5.3) in subjects reporting a first-degree relative with laryngeal cancer, as compared to subjects with no family history. The OR was higher when the relative was diagnosed before 60 years of age (OR = 3.5, 95% CI 1.4–8.8). As compared to subjects without family history, non-smokers, and moderate drinkers, the OR was 37.1 (95% CI 9.9–139.4) for current smokers, heavy drinkers, with family history of laryngeal cancer. Family history of colorectal (OR = 1.5, 95% CI 1.0–2.3) and kidney (OR = 3.8, 95% CI 1.2–12.1) cancer were also associated to an increased risk of laryngeal cancer, while no significant increase in risk was found for family history of cancer at all sites, excluding the larynx (OR = 1.1).

Alcohol and tobacco consumption are well-recognized risk factors for laryngeal cancer.1–3 A few epidemiologic studies have investigated the risk of laryngeal cancer in subjects with family history of cancer. In the Swedish Family-Cancer Database, only four cases had a family history of cancer at the same site.4 A study based on a Utah population database including 246 laryngeal cancer cases found a standardized incidence ratio of 8.0 (95% confidence interval [CI], 2.1–17.9) for subjects with family history of laryngeal cancer.5 A case-control study conducted in China on 288 cases found an odds ratio (OR) of 2.3 (95% CI, 1.2–4.5) in subjects with family history of any malignancy.6 The International Head and Neck Cancer Epidemiology Consortium (INHANCE) pooled data from 12 case-control studies, on a total of 2,357 laryngeal cancer cases, and showed an OR of 2.1 (95% CI, 1.6–2.7) in subjects reporting a first degree relative with a head and neck cancer.7

Scanty information is available on the variation of risk for family history in relation to age, alcohol drinking, tobacco smoking and type of affected relative, or on the association of family history of other than laryngeal neoplasms. Thus, we investigated the relationship between family history of laryngeal and other cancers and the risk of laryngeal cancer using data from a large case-control study conducted in Italy and Switzerland. Part of these data was included in the INHANCE study.7

Material and Methods

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

A case-control study of laryngeal cancer was conducted between 1992 and 2009 in the greater Milan area and the provinces of Pordenone in northern Italy, and in the Swiss Canton of Vaud.8 Data collection started and ended later in Milan. However, the same questionnaire and selection criteria were used in all centers.

Cases were 852 subjects (median age 62 years, range 21–80) admitted to major teaching and general hospitals in the study areas with incident, histologically confirmed carcinoma of the larynx diagnosed within 1 year before the interview. Controls were 1970 subjects (median age 61 years, range 27–80), selected among patients admitted to the same hospitals as cases for a wide spectrum of acute, non-neoplastic conditions, unrelated to known or potential risk factors for laryngeal cancer. Controls were frequency-matched with cases by 5-year age groups, sex and area of residence, with a control-to-case ratio of approximately 2 for men and 5 for women. A total of 21% of the controls were admitted for traumas, 24% for other orthopedic disorders, 31% for acute surgical conditions and 24% for miscellaneous other illnesses, including eye, nose, ear, skin or dental disorders. In Italy less than 5% of cases and controls contacted refused to participate; in Switzerland the proportion of refusals was <15%.

Cases and controls were interviewed during their hospital stay, using a structured questionnaire that included information on sociodemographic characteristics, anthropometric measures, lifestyle habits (including tobacco smoking and alcohol drinking), usual diet and personal medical history. The subjects were specifically asked how many sisters and brothers they had, and whether their parents, siblings, children, grandparents or spouse had ever had any cancer (excluding nonmelanoma skin cancer). For each relative with a history of cancer, the subject was asked to report the vital status at the time of interview, his/her current age or the age at death, the site of the neoplasm and the age at cancer diagnosis. In our analysis, we considered the history of cancer in first-degree relatives only, i.e., parents, siblings and children. On account of recall and classification difficulties, some sites were combined (i.e., the whole intestinal tract, Hodgkin and non-Hodgkin lymphomas as well as cervix and corpus uteri). No verification of the cancer diagnoses in the relatives was performed. Informed consent was obtained before the interview from the patients and from the hospitals, with respect to the legislation in force.

We estimated the OR and the corresponding 95% CI of laryngeal cancer according to history of cancer at selected sites using unconditional multiple logistic regression models,9 including terms for age, sex and study center. Alternative models were further adjusted for education, tobacco smoking, alcohol drinking and number of brothers and sisters.

Results

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Table 1 presents the distribution of 852 cases and 1970 controls according to center, sex, age and selected other covariates. By design, there was a high predominance of male cases, while cases and controls had similar distribution by center and age. Cases had a lower level of education and were more frequently and heavily exposed to tobacco smoking and alcohol drinking.

Table 1. Distribution of 852 cases of laryngeal cancer and 1970 controls according to center, sex, age and other selected variables. Italy and Switzerland, 1992–2009
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Table 2 shows the ORs of laryngeal cancer according to selected aspects of family history of laryngeal cancer in first-degree relatives. Overall, 29 cases (3.4%) vs. 27 controls (1.4%) reported a family history of laryngeal cancer. One case and three controls reported more than one first-degree relative with laryngeal cancer. The OR in subjects reporting at least one first-degree relative with laryngeal cancer was 2.5 (95% CI, 1.5–4.4), as compared to subjects with no family history, and did not materially change after allowance for education, smoking, alcohol and number of brothers and sisters (OR = 2.8, 95% CI, 1.5–5.3). No meaningful difference was found according to the type of relative affected. The OR was 3.5 (95% CI, 1.4–8.8) when the relative was diagnosed before 60 years of age, and 1.7 (95% CI, 0.7–4.2) when diagnosed at older age.

Table 2. OR of 852 cases of laryngeal cancer and 1970 controls and corresponding 95% CI according to family history of laryngeal cancer in first degree relatives. Italy and Switzerland, 1992–2009
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Table 3 gives the distribution of cases and controls according to family history of laryngeal cancer in strata of age, tobacco and alcohol consumption and the corresponding ORs. The ORs were somewhat higher in younger probands, current smokers and in heavy drinkers, although the tests of heterogeneity were not significant.

Table 3. OR of 852 cases of laryngeal cancer and 1970 controls and corresponding 95% CI according to family history of laryngeal cancer in first degree relatives in strata of selected covariates. Italy and Switzerland, 1992–2009
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The combined effect of tobacco, alcohol and family history of laryngeal cancer is shown in Figure 1. As compared to the lowest risk category, i.e., non-smokers, drinkers of less than 28 drinks per week, without family history, the risk was increased in those with one or more factors in the highest risk category: the OR was 1.4 (95% CI, 0.3–6.2) for nonsmokers and moderate drinkers with family history of laryngeal cancer, 18.2 (95% CI, 13.7–24.2) for current smokers and heavy drinkers without family history and 37.1 (95% CI, 9.9–139.4) for smokers and heavy drinkers who also reported a first degree relative with laryngeal cancer.

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Figure 1. OR (adjusted for age, sex, study center, education and number of brothers and sisters) and 95% CI for laryngeal cancer according to alcohol drinking, tobacco smoking and family history of laryngeal cancer in first-degree relatives. Abbreviations: OR, odds ratios; Cl, confidence intervals.

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Table 4 shows the distribution of cases and controls according to history of other selected cancers in first-degree relatives, and the corresponding ORs. A significant increase in laryngeal cancer was observed for family history of colorectal (OR = 1.5; 95% CI, 1.0–2.3) and kidney (OR = 3.8; 95% CI, 1.2–12.1) cancer. Family history of cancer at other sites showed no significant association. The OR was 1.3 (95% CI, 1.0–1.6) for family history of cancer at all sites combined, and 1.1 (95% CI, 0.9–1.4) for family history at all sites except the larynx.

Table 4. OR of 852 cases of laryngeal cancer and 1970 controls and corresponding 95% CI according to family history of selected cancers in first degree relatives. Italy and Switzerland, 1992–2009
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Discussion

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Our study confirms that family history of laryngeal cancer in first degree relatives increases the risk of laryngeal cancer, and provides further evidence that the risk is higher when the affected relative is younger than 60 years. Moreover, it shows that the risk is independent from that of tobacco smoking and alcohol drinking. Family history of kidney and colorectal cancer is also directly associated with laryngeal cancer.

An elevated risk of laryngeal cancer in subjects with a history of cancer at the same site has been reported in a few other studies.5–7 The point estimates vary widely across studies, the ORs ranging between 2.1 and 8.0, but this is not surprising, as only a small proportion of subjects had a family history of laryngeal cancer, and estimates were based on small numbers. Moreover, our findings are in broad agreement with other reports on cancers of the head and neck combined.7, 10–13

Familial aggregation may indicate that inheritable genetic factors play a role in laryngeal cancer risk, but may also reflect a tendency of relatives to have similar alcohol and tobacco habits. Genetic polymorphisms in genes involved in the metabolism of carcinogens have been associated to head and neck cancer risk,14–16 although the data were limited for laryngeal cancer alone. A locus (15q25) including nicotinic acetylcholine receptor genes has been associated to lung cancer risk, but not to head and neck cancer.17 A better characterization of genetic pathways in head and neck cancers is still necessary. Given that differential ability to metabolize carcinogens matters only if exposure occurs, it is possible that the familial risk reflects both a higher genetic susceptibility to head and neck cancer and an aggregation of exposures. However, we found no increased risk for family history of oral cavity, esophageal, or lung cancer, i.e., other cancers caused by tobacco and/or alcohol. Moreover, the association with family history did not materially change after allowance for consumption of alcohol and tobacco.

With reference to possible sources of bias, the use of hospital controls has long been debated.9 We included in the comparison group only subjects admitted for a wide spectrum of acute, non-neoplastic conditions, unrelated to the major risk factors for laryngeal cancer. Moreover, hospital admission for controls is unlikely to be related to the same genetic or familial aspects as familial laryngeal cancer. The practically complete participation and the comparable catchment area of cases and controls contribute to the strength of our study.

Information on family history was self reported and it was not possible to validate the cancers reported in relatives using pathology/medical records. It is possible that cases tend to recall family history of cancer more accurately than controls. However, the accuracy and completeness of reporting family history in relatives was found to be satisfactory and comparable in cases and controls, particularly for first-degree relatives.18 Therefore, we only considered first-degree relatives in our analysis. In our population, reproducibility of family history of cancer was satisfactory (K = 0.70 for all cancers).19, 20 Furthermore, the observation that family history of all cancer sites excluding the larynx was not associated with an increased risk of laryngeal cancer indicates that no major recall bias affects our results. With reference to confounding, we allowed for age, sex, study center, education, as a social class indicator, tobacco smoking, alcohol drinking, and number of brothers and sisters, and none of these factors meaningfully modified our risk estimates, suggesting that residual confounding is unlikely.

The direct associations with family history of kidney and colorectal cancer should be interpreted with caution, in the absence of confirmatory findings from other studies, and may be attributed to chance findings owing to multiple testing. Still, these associations should be verified on other datasets.

The analysis of the joint effect with alcohol and tobacco showed that the effect of family history of laryngeal cancer is stronger in smokers and heavy drinkers. The ORs of family history in the low exposure category of smoking and drinking was 1.4, whereas the OR for high exposure to tobacco and alcohol in subjects without family history was 18.2. Thus, the OR of those with family history and high exposure to alcohol and tobacco predicted would be 19 by assuming an additive effect and 25 by assuming a multiplicative model. Our point estimate is 37, suggesting, if anything, a multiplicative or a supra-multiplicative effect. The best way to avoid laryngeal cancer is thus to avoid tobacco smoking and alcohol drinking, particularly in subjects with a family history of the disease.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The authors thank Ms. I. Garimoldi for editorial assistance.

References

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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