Tobacco-related carcinogenesis in head and neck cancer



Head and neck cancer (head and neck squamous cell carcinoma (HNSCC)) is a devastating disease. Patients require intensive treatment that is often disfiguring and debilitating. Those who survive are often left with poor speech articulation, difficulties in chewing and swallowing, and cosmetic disfigurement, as well as loss of taste. Furthermore, given that HNSCC survivors are frequently disabled and unable to return to work, the economic and societal costs associated with HNSCC are massive. HNSCC is one of many cancers that are strongly associated with tobacco use. The risk for HNSCC in smokers is approximately ten times higher than that of never smokers, and 70–80% of new HNSCC diagnoses are associated with tobacco and alcohol use. Tobacco products have been used for centuries; however, it is just within the last 60–70 years that we have developed an understanding of their damaging effects. This relatively recent understanding has created a pathway towards educational and regulatory efforts aimed at reducing tobacco use. Understanding the carcinogenic components of tobacco products and how they lead to HNSCC is critical to regulatory and harm reduction measures. To date, nitrosamines and other carcinogenic agents present in tobacco products have been associated with cancer development. The disruption of DNA structure through DNA adduct formation is felt to be a common mutagenic pathway of many carcinogens. Intense work pertaining to tobacco product constituents, tobacco use, and tobacco regulation has resulted in decreased use in some parts of the world. Still, much work remains as tobacco continues to impart significant harm and contribute to HNSCC development worldwide.


Head and neck squamous cell carcinoma Tobacco products Tobacco carcinogenesis Tobacco regulation History of tobacco 


  1. 1.
    Argiris, A., Karamouzis, M. V., Raben, D., & Ferris, R. L. (2008). Head and neck cancer. Lancet, 371(9625), 1695–1709. doi:10.1016/s0140-6736(08)60728-x.CrossRefPubMedGoogle Scholar
  2. 2.
  3. 3.
    Global Burden of Disease Cancer, C, Fitzmaurice, C., Allen, C., Barber, R. M., Barregard, L., Bhutta, Z. A., et al. (2017). Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncology, 3(4), 524–548. doi:10.1001/jamaoncol.2016.5688.CrossRefGoogle Scholar
  4. 4.
    Tobacco smoke and involuntary smoking (2004). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 83, 1–1438.Google Scholar
  5. 5.
    Borio, G. (2004). Tobacco timeline.
  6. 6.
    Doll, R., & Hill, A. B. (1950). Smoking and carcinoma of the lung; preliminary report. British Medical Journal, 2(4682), 739–748.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Doll, R., & Hill, A. B. (1952). A study of the aetiology of carcinoma of the lung. British Medical Journal, 2(4797), 1271–1286.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Doll, R., & Hill, A. B. (1954). The mortality of doctors in relation to their smoking habits; a preliminary report. British Medical Journal, 1(4877), 1451–1455.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hammond, E. C., & Horn, D. (1954). The relationship between human smoking habits and death rates: a follow-up study of 187,766 men. Journal of the American Medical Association, 155(15), 1316–1328.CrossRefPubMedGoogle Scholar
  10. 10.
    The 1964 report on smoking and health. Accessed 24 Jan 2017.
  11. 11.
    Office on Smoking and Health, N. C. f. C. D. P. a. H. P. History of the surgeon generals reports on smoking and health. Accessed 24 Jan 2017.
  12. 12.
    Medicine, T. I. o (2007). Ending the tobacco problem: a blueprint for the nation. The National Academic Press.Google Scholar
  13. 13.
    Office on Smoking and Health, N. C. f. C. D. P. a. H. P. Current cigarette smoking among adults in the United States.
  14. 14.
    Data, G. H. O Prevalance of tobacco smoking. Accessed 24 Jan 2017.Google Scholar
  15. 15.
    Organization, W. H (2006). Tobacco: deadly in any form or disguise. World Health Organization.Google Scholar
  16. 16.
    Franck, C., Budlovsky, T., Windle, S. B., Filion, K. B., & Eisenberg, M. J. (2014). Electronic cigarettes in North America: history, use, and implications for smoking cessation. Circulation, 129(19), 1945–1952. doi:10.1161/circulationaha.113.006416.CrossRefPubMedGoogle Scholar
  17. 17.
    Rigotti, N. A. (2015). e-cigarette use and subsequent tobacco use by adolescents: new evidence about a potential risk of e-cigarettes. JAMA, 314(7), 673–674. doi:10.1001/jama.2015.8382.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhou, J., Michaud, D. S., Langevin, S. M., McClean, M. D., Eliot, M., & Kelsey, K. T. (2013). Smokeless tobacco and risk of head and neck cancer: evidence from a case-control study in New England. International Journal of Cancer, 132(8), 1911–1917. doi:10.1002/ijc.27839.CrossRefPubMedGoogle Scholar
  19. 19.
    Ng, M., Freeman, M. K., Fleming, T. D., Robinson, M., Dwyer-Lindgren, L., Thomson, B., et al. (2014). Smoking prevalence and cigarette consumption in 187 countries, 1980–2012. JAMA, 311(2), 183–192. doi:10.1001/jama.2013.284692.CrossRefPubMedGoogle Scholar
  20. 20.
    Smokeless tobacco and public health: a global perspective (2014). (NIH Publication No. 14-7983): U.S. Department of Health and Human Services. Centers for Disease Control and Prevention and National Institutes of Health.Google Scholar
  21. 21.
    Siddiqi, K., Shah, S., Abbas, S. M., Vidyasagaran, A., Jawad, M., Dogar, O., et al. (2015). Global burden of disease due to smokeless tobacco consumption in adults: analysis of data from 113 countries. BMC Medicine, 13, 194. doi:10.1186/s12916-015-0424-2.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Coelho, K. R. (2012). Challenges of the oral cancer burden in India. J Cancer Epidemiol, 2012, 701932. doi:10.1155/2012/701932.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Hashibe, M., Brennan, P., Benhamou, S., Castellsague, X., Chen, C., Curado, M. P., et al. (2007). Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Journal of the National Cancer Institute, 99(10), 777–789. doi:10.1093/jnci/djk179.CrossRefPubMedGoogle Scholar
  24. 24.
    Khariwala, S. S., Carmella, S. G., Stepanov, I., Fernandes, P., Lassig, A. A., Yueh, B., et al. (2013). Elevated levels of 1-hydroxypyrene and N′-nitrosonornicotine in smokers with head and neck cancer: a matched control study. Head & Neck, 35(8), 1096–1100. doi:10.1002/hed.23085.CrossRefGoogle Scholar
  25. 25.
    Winn, D. M., Lee, Y. C., Hashibe, M., & Boffetta, P. (2015). The INHANCE consortium: toward a better understanding of the causes and mechanisms of head and neck cancer. Oral Diseases, 21(6), 685–693. doi:10.1111/odi.12342.CrossRefPubMedGoogle Scholar
  26. 26.
    Wyss, A., Hashibe, M., Chuang, S. C., Lee, Y. C., Zhang, Z. F., Yu, G. P., et al. (2013). Cigarette, cigar, and pipe smoking and the risk of head and neck cancers: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. American Journal of Epidemiology, 178(5), 679–690. doi:10.1093/aje/kwt029.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wyss, A. B., Hashibe, M., Lee, Y. A., Chuang, S. C., Muscat, J., Chen, C., et al. (2016). Smokeless tobacco use and the risk of head and neck cancer: pooled analysis of US studies in the INHANCE Consortium. American Journal of Epidemiology. doi:10.1093/aje/kww075.
  28. 28.
    Hashibe, M., Hunt, J., Wei, M., Buys, S., Gren, L., & Lee, Y. C. (2013). Tobacco, alcohol, body mass index, physical activity, and the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian (PLCO) cohort. Head & Neck, 35(7), 914–922. doi:10.1002/hed.23052.CrossRefGoogle Scholar
  29. 29.
    Hashibe, M., Brennan, P., Chuang, S. C., Boccia, S., Castellsague, X., Chen, C., et al. (2009). Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiology, Biomarkers & Prevention, 18(2), 541–550. doi:10.1158/1055-9965.epi-08-0347.CrossRefGoogle Scholar
  30. 30.
    Dal Maso, L., Torelli, N., Biancotto, E., Di Maso, M., Gini, A., Franchin, G., et al. (2016). Combined effect of tobacco smoking and alcohol drinking in the risk of head and neck cancers: a re-analysis of case-control studies using bi-dimensional spline models. European Journal of Epidemiology, 31(4), 385–393. doi:10.1007/s10654-015-0028-3.CrossRefPubMedGoogle Scholar
  31. 31.
    Khariwala, S. S., Hatsukami, D., & Hecht, S. S. (2012). Tobacco carcinogen metabolites and DNA adducts as biomarkers in head and neck cancer: potential screening tools and prognostic indicators. Head & Neck, 34(3), 441–447. doi:10.1002/hed.21705.CrossRefGoogle Scholar
  32. 32.
    Hecht, S. S. (1998). Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chemical Research in Toxicology, 11(6), 559–603. doi:10.1021/tx980005y.CrossRefPubMedGoogle Scholar
  33. 33.
    Balbo, S., James-Yi, S., Johnson, C. S., O'Sullivan, M. G., Stepanov, I., Wang, M., et al. (2013). (S)-N′-Nitrosonornicotine, a constituent of smokeless tobacco, is a powerful oral cavity carcinogen in rats. Carcinogenesis, 34(9), 2178–2183. doi:10.1093/carcin/bgt162.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yuan, J. M., Koh, W. P., Murphy, S. E., Fan, Y., Wang, R., Carmella, S. G., et al. (2009). Urinary levels of tobacco-specific nitrosamine metabolites in relation to lung cancer development in two prospective cohorts of cigarette smokers. Cancer Research, 69(7), 2990–2995. doi:10.1158/0008-5472.can-08-4330.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Yuan, J. M., Knezevich, A. D., Wang, R., Gao, Y. T., Hecht, S. S., & Stepanov, I. (2011). Urinary levels of the tobacco-specific carcinogen N′-nitrosonornicotine and its glucuronide are strongly associated with esophageal cancer risk in smokers. Carcinogenesis, 32(9), 1366–1371. doi:10.1093/carcin/bgr125.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Khariwala, S. S., Carmella, S. G., Stepanov, I., Bandyopadhyay, D., Nelson, H. H., Yueh, B., et al. (2015). Self-reported tobacco use does not correlate with carcinogen exposure in smokers with head and neck cancer. Laryngoscope, 125(8), 1844–1848. doi:10.1002/lary.25290.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Hecht, S. S. (2003). Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nature Reviews. Cancer, 3(10), 733–744. doi:10.1038/nrc1190.CrossRefPubMedGoogle Scholar
  38. 38.
    Lacko, M., Braakhuis, B. J., Sturgis, E. M., Boedeker, C. C., Suarez, C., Rinaldo, A., et al. (2014). Genetic susceptibility to head and neck squamous cell carcinoma. International Journal of Radiation Oncology, Biology, Physics, 89(1), 38–48. doi:10.1016/j.ijrobp.2013.09.034.CrossRefPubMedGoogle Scholar
  39. 39.
    Riaz, N., Morris, L. G., Lee, W., & Chan, T. A. (2014). Unraveling the molecular genetics of head and neck cancer through genome-wide approaches. Genes Dis, 1(1), 75–86. doi:10.1016/j.gendis.2014.07.002.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lao, Y., Yu, N., Kassie, F., Villalta, P. W., & Hecht, S. S. (2007). Analysis of pyridyloxobutyl DNA adducts in F344 rats chronically treated with (R)- and (S)-N′-nitrosonornicotine. Chemical Research in Toxicology, 20(2), 246–256. doi:10.1021/tx060208j.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hecht, S. S., Spratt, T. E., & Trushin, N. (1988). Evidence for 4-(3-pyridyl)-4-oxobutylation of DNA in F344 rats treated with the tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N′-nitrosonornicotine. Carcinogenesis, 9(1), 161–165.CrossRefPubMedGoogle Scholar
  42. 42.
    Wang, M., Cheng, G., Sturla, S. J., Shi, Y., McIntee, E. J., Villalta, P. W., et al. (2003). Identification of adducts formed by pyridyloxobutylation of deoxyguanosine and DNA by 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone, a chemically activated form of tobacco specific carcinogens. Chemical Research in Toxicology, 16(5), 616–626. doi:10.1021/tx034003b.CrossRefPubMedGoogle Scholar
  43. 43.
    Stepanov, I., Muzic, J., Le, C. T., Sebero, E., Villalta, P., Ma, B., et al. (2013). Analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing DNA adducts in human exfoliated oral mucosa cells by liquid chromatography-electrospray ionization-tandem mass spectrometry. Chemical Research in Toxicology, 26(1), 37–45. doi:10.1021/tx300282k.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hecht, S. S., Stepanov, I., & Carmella, S. G. (2016). Exposure and metabolic activation biomarkers of carcinogenic tobacco-specific nitrosamines. Accounts of Chemical Research, 49(1), 106–114. doi:10.1021/acs.accounts.5b00472.CrossRefPubMedGoogle Scholar
  45. 45.
    Zhang, S., Wang, M., Villalta, P. W., Lindgren, B. R., Upadhyaya, P., Lao, Y., et al. (2009). Analysis of pyridyloxobutyl and pyridylhydroxybutyl DNA adducts in extrahepatic tissues of F344 rats treated chronically with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Chemical Research in Toxicology, 22(5), 926–936. doi:10.1021/tx900015d.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ma, B., Ruszczak, C., Jain, V., Khariwala, S. S., Lindgren, B., Hatsukami, D. K., et al. (2016). Optimized liquid chromatography nanoelectrospray-high-resolution tandem mass spectrometry method for the analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in human oral cells. Chemical Research in Toxicology, 29(11), 1849–1856. doi:10.1021/acs.chemrestox.6b00254.CrossRefPubMedGoogle Scholar
  47. 47.
    Chen, A. M., Chen, L. M., Vaughan, A., Sreeraman, R., Farwell, D. G., Luu, Q., et al. (2011). Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcome. International Journal of Radiation Oncology, Biology, Physics, 79(2), 414–419. doi:10.1016/j.ijrobp.2009.10.050.CrossRefPubMedGoogle Scholar
  48. 48.
    Hatcher, J. L., Sterba, K. R., Tooze, J. A., Day, T. A., Carpenter, M. J., Alberg, A. J., et al. (2016). Tobacco use and surgical outcomes in patients with head and neck cancer. Head & Neck, 38(5), 700–706. doi:10.1002/hed.23944.CrossRefGoogle Scholar
  49. 49.
    Marin, V. P., Pytynia, K. B., Langstein, H. N., Dahlstrom, K. R., Wei, Q., & Sturgis, E. M. (2008). Serum cotinine concentration and wound complications in head and neck reconstruction. Plastic and Reconstructive Surgery, 121(2), 451–457. doi:10.1097/01.prs.0000297833.53794.27.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Otolaryngology-Head and Neck SurgeryUniversity of MinnesotaMinneapolisUSA

Personalised recommendations