3rd March 2017, Volume 130 Number 1451

Muhammed Yakin, Ratu Osea Gavidi, Brian Cox, Alison Rich

Head and neck cancers are the fifth most common malignancy worldwide, accounting for an estimated 984,430 cases in 2012.1 Head and neck cancers are cancers arising in the lips, oral cavity, nasal cavity, paranasal sinuses, pharynx, salivary glands and thyroid glands. Approximately half of the head and neck cancers occur in the oral and oropharyngeal regions.1 There is confusion as to what lesions are classified as ‘oral cancer’, which poses difficulties when comparing different studies.2 The term oral cancer generally refers to the malignancies of the oral cavity and lip vermilion,3–5 90% of which are oral squamous cell carcinomas (OSCC). In this paper oral cancer will refer to OSCC unless otherwise specified, and thus exclude cancers of the skin of the lips, the oropharynx, all salivary gland and connective tissue neoplasms as well as intra-osseous squamous cell carcinomas.

Between 2000 and 2010, there were 1,916 cases of OSCC in New Zealand, with a male to female ratio of 1.85:1 and an age-standardised incidence rate of 42 persons per 1,000,000 population from 2000 to 2010.6 The age-specific incidence rates of OSCC steadily increased with age, whereas incidence was highest in the 6th decade of life (Figure 1). The most common site for OSCC was the tongue, which accounted for over 40% of OSCCs, followed by the lip vermilion, which accounted for more than 20% of all OSCCs (Figure 2).

Figure 1: Average annual age-specific rates and total number of cases of OSCC in New Zealand between 2000 and 2010.

c 

Figure 2: The site distribution of OSCC in New Zealand.

c 

Oral carcinogenesis is a multi-step process that involves progressive genetic mutations affecting tumour suppressor genes and proto-oncogenes, resulting in uncontrolled cell proliferation. Modifiable lifestyle factors such as tobacco and alcohol consumption are considered to contribute in up to 75% of cases of OSCC.3,7 In addition, a very small percentage of people have inherent genetic defects that make them prone to oral cancer.3,8,9

Risk factors in New Zealand

Oral cancer risk factors are grouped according to decreasing levels of evidence supporting their carcinogenicity from established, strongly suggestive, possible and proposed (Table 1).3 The traditional risk factors for oral cancer include tobacco, alcohol and betel quid use, whereas solar ultraviolet (UV) radiation is the main risk factor for cancer of the skin and vermilion of the lip.10–13 Genetic damage from these risk factors tends to accumulate over many years, and hence OSCCs are more common in people in their fifth to seventh decades of life than at younger ages.

Table 1: Risk factors for oral cancer grouped according to the level of evidence supporting their carcinogenicity (modified from Warnakulasuriya, 20093 and the IARC13).

Established

Strongly suggestive

Possible

Proposed

Smoking

Chewing tobacco

Alcohol consumption

Betel quid chewing

Human papilloma virus type 16

Sunlight (lip)

Radiation

Human papilloma virus type 18

Immune deficiency

 

Mouthwashes

Mate drinking

Familial 

For intra-oral cancer, the established group of risk factors includes tobacco, alcohol and betel quid chewing, whereas a very small subset are attributable to human papilloma virus (HPV) type 16.8,10,14,15

Tobacco

Tobacco use is a key risk factor for the development of oral cancer. Current smokers are at a four-fold increased risk of developing oral cancer compared with non-smokers, and heavy smokers are twenty times more likely to develop oral cancers than non-smokers.10 After five years of quitting tobacco smoking, the risk of developing oral and pharyngeal cancers appears to drop substantially.10 Tobacco products fall into three main types: rolls, oral preparations and pipes. Rolls include cigarettes, cigars and hand-rolled tobacco products, and are the most common type of tobacco product in New Zealand. The prevalence of the use of pipes and oral preparations in New Zealand is unknown. Most of the available data regarding tobacco smoking in New Zealand refers to the use of cigarettes. There are approximately 4,000 chemicals in cigarettes, many of which are known carcinogens.16

According to the 2015 New Zealand Health Survey, the prevalence of smoking among New Zealand adults decreased from 18% in 2011–2012 to 17% in 2014–2015. In 2014–2015 the percentage of New Zealand adults who smoked daily was 15%. This percentage was highest in adults aged 18–34 years, where approximately one in four adults was a current smoker, whereas only 6% of those younger than 18 years were smokers. Generally, men (18%) were more likely to smoke tobacco than women (15%), but in the Māori population more women (42%) smoked tobacco than men (34%). Smoking rates were higher in more socioeconomically disadvantaged areas. The latest data showed that 6% of Asian, 38% of Māori and 25% of Pacific adults were current smokers.17

The New Zealand Ministry of Health provides smoking cessation advice training to all healthcare professionals to support and encourage smokers to quit. A number of nicotine-replacement therapy products are subsidised for this purpose.18 It is of utmost importance that doctors and dentists are aware of the prevalence of tobacco smoking among different age groups in their clinic population in order to better provide patients with appropriate smoking cessation advice.

Electronic, or e-cigarettes, are used in some countries to help smokers quit. However, their safety is still a matter for debate. Research has shown that their use, regardless of nicotine content, induces apoptosis and necrosis in epithelial cells. The ability of e-cigarette smoke to induce double-strand DNA breaks and clonal proliferation in oral epithelial cells is also of concern.19,20 E-cigarette use among New Zealand youths has tripled since 2012. In 2014, 20% of young people reported having ever used e-cigarettes.21 Most adults reported they used e-cigarettes to help them quit, whereas most youths used e-cigarettes because they were curious. There is need for health education regarding the potential risks of e-cigarette use in New Zealand, especially among the young.

Some oral preparations also enhance contact of carcinogens with the oral mucosa. The most common example is betel quid, to which tobacco may also be added. The main ingredient of a betel quid is areca nut wrapped in a betel leaf, usually with slaked lime, with or without the addition of tobacco (Figure 3). The quid is placed in the mandibular buccal sulcus and chewed, producing a mild euphoric effect. Tobacco is an ingredient of the betel quid in some cultures, particularly in India and South East Asia and migrant populations from these regions. The regular use of betel quid, with or without tobacco may lead to the development of sub-mucous fibrosis, a potentially malignant oral disorder.9 The use of betel quid without tobacco causes a three-fold increase in oral cancer risk in non-smokers and non-drinkers.12 When used with tobacco, the risk rises to seven-fold in non-smokers and non-drinkers and to 12- to 22-fold in smokers and drinkers.12,22 Very little data is available on the prevalence of use of these oral preparations in people of South East Asian origin now resident in New Zealand.23,24 The Oral Pathology Diagnostic Service at the University of Otago has reported eight cases of oral submucous fibrosis from January 2005 to June 2016 from over 23,000 specimen accessions during that period, and all patients were of South-East Asian origin.

Figure 3: Slaked lime, tobacco and areca nut on a betel leaf as a wrap. (Image credit: Mr Shremal Patel). 

c 

Another way to use tobacco products is pipe smoking. This includes direct pipe smoking through a wooden pipe, previously common in Western societies, but now uncommon. This category also includes water-pipe tobacco smoking, also known as shisha, nargileh and hookah. These are particularly popular social outdoor smoking activities in cafes and homes among Middle-Easterners. Water-pipe smoking consists of coals as a heat source often with flavoured tobacco that is smoked through water using pipes (Figure 4). The prevalence of water-pipe smoking in New Zealand is unknown. However, a study carried out in the Arabic-speaking population in south-west Sydney showed that one in four of over 700 participants reported that they smoked water-pipes.25 It should be noted that the rate reported in the Sydney study was much higher than that estimated worldwide among Arab youth in the Global Youth Tobacco Survey, where an average of 10.6% of Arab youth reported they were water-pipe smokers.26 What is more concerning is the popular belief that water-pipe smoking is less harmful than cigarette smoking. It has been shown that water-pipe use exposes smokers to substantially greater amounts of carcinogens than cigarettes. One 60-minute water-pipe smoking session is estimated to expose the user to carcinogens equivalent to as many as ten cigarettes.27 Two other studies have found that water-pipe smokers are at least four times more likely to develop clinically suspicious lesions than non-smokers.28,29 Given the lack of data regarding water-pipe smoking in New Zealand, research is required to estimate the actual prevalence of use of water-pipe smoking.

Figure 4: A water-pipe consists of flavoured tobacco smoked through water via a pipe. 

c 

Alcohol

Alcohol is another major risk factor for oral cancer. Regular and heavy alcohol drinkers have approximately two-and-a-half and five times higher risk of developing oral cancer than non-drinkers, respectively.10 The effects of alcohol plus tobacco are synergistic. People who are heavy smokers and heavy drinkers are at a 48-fold risk of developing oral and pharyngeal cancers than non-smoking non-drinkers.10 In New Zealand, in 2014–2015, 80% of adults drank alcohol regularly.17 Among the Asian and Pacific populations of New Zealand, 56% of adults were regular alcohol drinkers. Of all adult New Zealanders, 18% were defined as hazardous drinkers, that is, had a drinking pattern that caused physical or mental harm to the drinkers themselves or their social circle.17 People in socioeconomically disadvantaged areas are less likely to be regular alcohol drinkers, but more likely to be hazardous drinkers.17 The prevalence of hazardous drinking was highest in young adults and in men, where one in four men reported hazardous drinking. A high rate of hazardous drinking was reported among the Māori and Pacific populations; close to one-third and one-fourth of these populations were hazardous drinkers, respectively.17 The risk of oral and upper aero-digestive tract cancers as a result of alcohol-containing mouthwash use remains controversial. While some studies have found no association,30 a systematic review has shown that alcohol-containing mouthwash users have a slightly higher risk of oral cancer than non-users.31

Ultraviolet radiation

New Zealand has relatively high levels of ambient UV radiation (UV index 13–8 in summer) and relatively low levels of pollution.32 In addition, approximately 75% of New Zealanders are of European descent with light skin tones and have a liking for the sun.32,33 This, coupled with sun protection behaviour patterns, accounts for the high rate of melanoma and non-melanoma skin cancer in New Zealand.32,34 While the aetiology of mucosal and skin of lip cancers is different, the lip vermilion is a bridge between the two, and is a common site for oral cancer, as it is directly exposed to UV radiation from sunlight. The magnitude of the risk for developing malignancy depends on the ambient UV radiation, which generally decreases with increasing latitude and duration of exposure determined by lifestyle.32 In addition, artificial UV radiation such as those used in tanning beds pose a risk of cancer.35 Although New Zealanders do not have a higher lip to oral cavity SCC ratio than other populations, protection from UV radiation is essential to avoid lip and skin cancers.

Human papilloma virus

High risk, or oncogenic, HPV types are those that integrate their genome into the host DNA and subsequently produce E6 and E7 oncogenes, which work to deregulate key molecules involved in the cell cycle.36,37 The aetiopathogenetic role of HPV in head and neck cancers, specifically oropharyngeal carcinoma and tonsillar carcinoma, has been established. People who develop these cancers have distinct demographic features, as they particularly affect younger individuals in their third or fourth decades of life.11,13 The role of HPV infection in the pathogenesis of OSCC is less certain.15,38 The rate of HPV-positive OSCC has been estimated to be 1–3%, which is much lower than that of oropharyngeal SCC, in which HPV-positive SCCs contribute as much as 65%.14,15,38 There are a number of methods used to detect the presence of HPV in tissues. The tumour suppressor protein p16 serves as a useful surrogate marker for significant infection by high-risk HPV and its E7 oncogene,39 and can be detected on formalin-fixed specimens using immunohistochemistry (IHC). However, p16 IHC alone is insufficient to confirm the involvement of high-risk HPV.40 Detection of viral oncogenes using polymerase chain reaction (PCR) of E6/E7 mRNA, quantitative PCR, or in-situ hybridisation of viral DNA or mRNA are required to confirm the role of HPV in carcinogenesis. This information is important, at least for some head and neck squamous cell carcinomas (HNSCC), since high-risk HPV-positive HNSCC, including oropharyngeal carcinoma, is more responsive to radiotherapy, and has a better prognosis than conventional SCC.41–43 It is not yet clear whether HPV status influences the prognosis of OSCC.

HPV vaccination programmes for young females have been in place in New Zealand since 2008, as well as in Australia where the programme includes both males and females.44,45 The vaccination programme is to be extended to boys in New Zealand. One study reported the presence of high-risk HPV in the oral cavity of two of 219 New Zealand women.46 Another study showed that 41 of 55 patients investigated had HPV-related oropharyngeal cancers.47 No other data exists regarding the presence of high-risk HPV in the oral and oropharyngeal sites of New Zealanders.

Conclusions

This paper presented an overview of the main risk factors for oral and oropharyngeal cancers and their prevalence New Zealand. Alcohol consumption is the most prevalent risk factor in New Zealand, followed by tobacco. Given the high prevalence of these two risk factors and their synergistic effect, it is important for doctors and dentists to encourage smoking cessation in smokers and to recommend judicious alcohol intake. Research is needed to determine the prevalence of use of oral preparations of tobacco and water-pipe smoking in New Zealand, especially due to changing demography and increases in migrant populations. UV radiation is also an important risk factor. Further investigations are also needed to determine the prevalence of oral and oropharyngeal cancers attributable to oncogenic HPV infection.

Summary

Oral cancer is a significant health issue with high morbidity and mortality rates. With late diagnosis, approximately half of the affected patients die of the disease within five years. Certain factors, particularly alcohol and tobacco consumption, place individuals at a higher risk of getting oral cancer. In New Zealand, four out of five individuals consume alcohol and approximately two out of five use tobacco, which places them at higher risk of developing oral cancer. We have provided an overview of these and other oral cancer risk factors and their prevalence in New Zealand. We hope that this will further encourage doctors and dentists to provide regular advice regarding tobacco cessation and judicious alcohol use.

Abstract

Oral cancer constitutes the majority of head and neck cancers, which are the fifth most common malignancy worldwide, accounting for an estimated 984,430 cases in 2012. Between 2000 and 2010, there were 1,916 cases of OSCC in New Zealand with a male to female ratio of 1.85:1, and an age-standardised incidence rate of 42 persons per 1,000,000 population. This article presents an overview of the main risk factors for oral and oropharyngeal cancers and their prevalence in New Zealand. Alcohol consumption is the most prevalent risk factor in New Zealand, followed by tobacco. Given the high prevalence of these two risk factors and their synergistic effect, it is important for doctors and dentists to encourage smoking cessation in smokers and to recommend judicious alcohol intake. Research is needed to determine the prevalence of use of oral preparations of tobacco and water-pipe smoking in New Zealand, especially due to changing demography and increases in migrant populations. UV radiation is also an important risk factor. Further investigations are also needed to determine the prevalence of oral and oropharyngeal cancers attributable to oncogenic HPV infection.

Author Information

Muhammed Yakin, Previously at Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin; Ratu Osea Gavidi, Department of Oral Health, College of Medicine, Nursing and Health Sciences, Fiji National University, Fiji; Brian Cox, Hugh Adam Cancer Epidemiology Unit, Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin; Alison Rich, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin.

Correspondence

Muhammed Yakin, Previously at Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, PO Box 647, Dunedin 9054.

Correspondence Email

muhammedyakin@yahoo.com

Competing Interests

Nil.

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. CA Cancer J Clin. 2015 Mar; 65(2):87–108.
  2. Tapia JL, Goldberg LJ. The Challenges of Defining Oral Cancer: Analysis of an Ontological Approach. Head Neck Pathol. 2011 Dec; 5(4):376–84.
  3. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009 Apr–May; 45(4–5):309–16. Review.
  4. Warnakulasuriya S. Living with oral cancer: Epidemiology with particular reference to prevalence and life-style changes that influence survival.Oral Oncol. 2010 Jun; 46(6):407–10. Review.
  5. Speight P, Warnakulasuriya S, Odgen G. Early Detection and Prevention of Oral Cancer: a management Strategy for Dental Practice. British Dental Association; 2010. Available from: http://www.bda.org/dentists/policy-campaigns/public-health-science/public-health/Documents/early_detection_of_oral_cancer.pdf [Accessed 25 May 2016].
  6. Gavidi RO, Rich AM, Cox B, King T. Comparing the occurrence of oral squamous cell carcinoma in New Zealand and the Fiji Islands from 2000-2010. Int J Cancer Res. 2014 Mar; 48(1):1212–25.
  7. Blot WJ, McLaughlin JK, Winn DM, Austin DF, Greenberg RS, Preston-Martin S. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res. 1988 Jun 1; 48(11):3282–7.
  8. Petti S. Lifestyle risk factors for oral cancer. Oral Oncol. 2009 Apr-May; 45(4-5):340–50. Review.
  9. Sarode SC, Sarode GS, Tupkari JV. Oral potentially malignant disorders: Precising the definition. Oral Oncol. 2012 Sep; 48(9):759–60.
  10. Rodriguez T, Altieri A, Chatenoud L, Gallus S, Bosetti C, Negri E, Franceschi S, Levi F, Talamini R, La Vecchia C. Risk factors for oral and pharyngeal cancer in young adults. Oral Oncol. 2004 Feb; 40(2):207–13.
  11. Cogliano VJ, Baan R, Straif K, Grosse Y, Lauby-Secretan B, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L, Wild CP. Preventable exposures associated with human cancers. J Natl Cancer Inst. 2011 Dec 21; 103(24):1827–39.
  12. Guha N, Warnakulasuriya S, Vlaanderen J, Straif K. Betel quid chewing and the risk of oral and oropharyngeal cancers: A meta-analysis with implications for cancer control. Int J Cancer. 2014 Sep 15; 135(6):1433–43.
  13. International Agency for Research on Cancer. List of Classifications by cancer sites with sufficient or limited evidence in humans, Volumes 1 to. 2015. Available from: http://monographs.iarc.fr/ENG/Classification/Table4.pdf [Accessed 7 May 2016].
  14. Lopes V, Murray P, Williams H, Woodman C, Watkinson J, Robinson M. Squamous cell carcinoma of the oral cavity rarely harbours oncogenic human papillomavirus. Oral Oncol. 2011 Aug; 47(8):698–701.
  15. Lingen MW, Xiao W, Schmitt A, Jiang B, Pickard R, Kreinbrink P, Perez-Ordonez B, Jordan RC, Gillison ML. Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas. Oral Oncol. 2013 Jan; 49(1):1–8.
  16. World Health Organisation. Tobacco : deadly in any form or disguise. Report of the Tobacco Free Initiative, WHO/Non-communicable Diseases and Mental Health. Geneva: 2006. Available from: http://www.who.int/tobacco/communications/events/wntd/2006/Report_v8_4May06.pdf [Accessed 23 Feb 2016].
  17. Ministry of Health. New Zealand Health Survey. 2015. Available from: http://www.health.govt.nz/publication/annual-update-key-results-2014-15-new-zealand-health-survey [Accessed 15 Feb 2016].
  18. Ministry of Health. The New Zealand Guidelines for Helping People to Stop Smoking. 2014. Available from: http://www.health.govt.nz/publication/new-zealand-guidelines-helping-people-stop-smoking [Accessed 15 Feb 2016].
  19. Yu V, Rahimy M, Korrapati A, Xuan Y, Zou AE, Krishnan AR, Tsui T, Aguilera JA, Advani S, Crotty Alexander LE, Brumund KT, Wang-Rodriguez J, Ongkeko WM. Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines. Oral Oncol. 2016 Jan; 52:58–65.
  20. Cervellati F, Muresan XM, Sticozzi C, Gambari R, Montagner G, Forman HJ, Torricelli C, Maioli E, Valacchi G. Comparative effects between electronic and cigarette smoke in human keratinocytes and epithelial lung cells. Toxicol In Vitro. 2014 Aug; 28(5):999–1005.
  21. White J, Li J, Newcombe R, Walton D. Tripling use of electronic cigarettes among New Zealand adolescents between 2012 and 2014. J Adolesc Health. 2015 May; 56(5):522–8.
  22. Znaor A, Brennan P, Gajalakshmi V, Mathew A, Shanta V, Varghese C, Boffetta P. Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer. 2003 Jul 10; 105(5):681–6.
  23. Lokhande S, Glover M, Selket K. Chewing tobacco use among South-East Asian men in Auckland. Int J Migr Heal Soc Care. 2013 Jan; 9(1):46–52.
  24. Yoganathan P. Betel chewing creeps into the New World. N Z Dent J. 2002 Jun; 98(432):40–5. 
  25. Perusco A, Rikard-Bell G, Mohsin M, Millen E, Sabry M, Poder N, Williams M, Farag L, Hua M, Guirguis S. Tobacco control priorities for Arabic speakers: key findings from a baseline telephone survey of Arabic speakers residing in Sydney’s south-west. Health Promot J Austr. 2007 Aug; 18(2):121–6.
  26. Kheirallah KA, Alsulaiman JW, Mohammad H A-S, Alzyoud S, Veeranki SP, Ward KD. Waterpipe Tobacco Smoking among Arab Youth; a Cross-Country Study. Ethn Dis. 2016 Jan 21; 26(1):107–12.
  27. Daher N, Saleh R, Jaroudi E, Sheheitli H, Badr T, Sepetdjian E, Al Rashidi M, Saliba N, Shihadeh A. Comparison of carcinogen, carbon monoxide, and ultrafine particle emissions from narghile waterpipe and cigarette smoking: Sidestream smoke measurements and assessment of second-hand smoke emission factors. Atmos Environ (1994). 2010 Jan 1; 44(1):8–14.
  28. Dangi J, Kinnunen TH, Zavras AI. Challenges in global improvement of oral cancer outcomes: Findings from rural Northern India. Tob Induc Dis. 2012 Apr 12; 10:5.
  29. Schmidt-Westhausen AM, Al Sanabani J, Al-Sharabi AK. Prevalence of oral white lesions due to qat chewing among women in Yemen. Oral Dis. 2014 Oct; 20(7):675–81.
  30. Ahrens W, Pohlabeln H, Foraita R, Nelis M, Lagiou P, Lagiou A, Bouchardy C, Slamova A, Schejbalova M, Merletti F, Richiardi L, Kjaerheim K, Agudo A, Castellsague X, Macfarlane TV, Macfarlane GJ, Lee YC, Talamini R, Barzan L, Canova C, Simonato L, Thomson P, McKinney PA, McMahon AD, Znaor A, Healy CM, McCartan BE, Metspalu A, Marron M, Hashibe M, Conway DI, Brennan P. Oral health, dental care and mouthwash associated with upper aerodigestive tract cancer risk in Europe: The ARCAGE study. Oral Oncol. 2014 Jun; 50(6):616–25.
  31. Wilson G, Conway DI. Mouthwash use and associated head and neck cancer risk. Evid Based Dent. 2016 Mar; 17(1):8–9.
  32. Sneyd MJ, Cox B. A comparison of trends in melanoma mortality in New Zealand and Australia: the two countries with the highest melanoma incidence and mortality in the world. BMC Cancer. 2013 Aug 6; 13:372.
  33. Major ethnic groups in New Zealand – 2013 Census. 2013. Available from: http://www.stats.govt.nz/Census/2013-census/profile-and-summary-reports/infographic-culture-identity.aspx [Accessed 7 Sep 2016].
  34. Salmon PJM, Chan WC, Griffin J, McKenzie R, Rademaker M. Extremely high levels of melanoma in Tauranga, New Zealand: possible causes and comparisons with Australia and the northern hemisphere. Australas J Dermatol. 2007 Nov; 48(4):208–16.
  35. Colantonio S, Bracken MB, Beecker J. The association of indoor tanning and melanoma in adults: Systematic review and meta-analysis. J Am Acad Dermatol. 2014 May; 70(5):847–57.e1-18.
  36. Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol. 1989 Oct; 63(10):4417–21.
  37. Münger K, Baldwin A, Edwards KM, Hayakawa H, Nguyen CL, Owens M, Grace M, Huh K. Mechanisms of Human Papillomavirus-Induced Oncogenesis. J Virol. 2004 Nov; 78(21):11451–60.
  38. Combes JD, Franceschi S. Role of human papillomavirus in non-oropharyngeal head and neck cancers. Oral Oncol. 2014 May; 50(5):370–9.
  39. El-Naggar AK, Westra WH. p16 expression as a surrogate marker for HPV-related oropharyngeal carcinoma: a guide for interpretative relevance and consistency. Head Neck. 2012 Apr; 34(4):459–61. 
  40. Zafereo ME, Xu L, Dahlstrom KR, Viamonte CA, El-Naggar AK, Wei Q, Li G, Sturgis EM. Squamous cell carcinoma of the oral cavity often overexpresses p16 but is rarely driven by human papillomavirus. Oral Oncol. 2016 May; 56:47–53.
  41. Robinson M, Sloan P, Shaw R. Refining the diagnosis of oropharyngeal squamous cell carcinoma using human papillomavirus testing. Oral Oncol. 2010 Jul; 46(7):492–6. 
  42. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010 Jul 1; 363(1):24–35.
  43. Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol. 2014 Jun; 50(6):565–74.
  44. Elwood JM, Youlden DR, Chelimo C, Ioannides SJ, Baade PD. Comparison of oropharyngeal and oral cavity squamous cell cancer incidence and trends in New Zealand and Queensland, Australia. Cancer Epidemiol. 2014 Feb; 38(1):16–21.
  45. Ministry of Health - New Zealand. HPV Immunisation Programme Implementation Evaluation. 2012. Available from: http://www.health.govt.nz/system/files/documents/publications/hpv-immunisation-programme-evaluation-v2.doc [Accessed 7 Sep 2016].
  46. Lucas-Roxburgh R, Benschop J, Dunowska M, Perrott M. Prevalence of human papillomaviruses in the mouths of New Zealand women. N Z Med J. 2015 Sep 25; 128(1422):45–52.
  47. Ou P, Gear K, Rahnama F, Thomas S, Nagappan R, Kee D, Waldvogel-Thurlow S, Jain R, McIvor N, Izzard M, Douglas R. Human papillomavirus and oropharyngeal squamous cell carcinoma: a New Zealand cohort study. ANZ J Surg. 2016 Sep 20.