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Changing prevalence and treatment outcomes of patients with p16 human papillomavirus related oropharyngeal squamous cell carcinoma in New Zealand
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ScienceDirect British Journal of Oral and Maxillofacial Surgery xxx (2016) xxx–xxx
Changing Prevalence and Treatment Outcomes of Patients with p16 Human Papillomavirus Related Oropharyngeal Squamous Cell Carcinoma in New Zealand H.J. Kwon a , H.D. Brasch b,c , S. Benison c , R.W. Marsh b,d , T. Itinteang b , G.W. Titchener a , J. Evans e , S.T. Tan b,f,∗ a
Department of Otolaryngology - Head and Neck Surgery, Wellington Regional Hospital, Wellington, New Zealand Gillies McIndoe Research Institute, Wellington, New Zealand c Department of Pathology, Hutt Hospital, Wellington, New Zealand d Auckland University, Auckland, New Zealand e Wellington Blood and Cancer Centre, Wellington Regional Hospital, Wellington, New Zealand f Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Wellington, New Zealand b
Accepted 31 May 2016
Abstract There has, to our knowledge, been no previous report of changes in the prevalence and outcomes of treatment of HPV-positive (+) oropharyngeal squamous cell carcinoma (SCC) in New Zealand. We identified all affected patients in the greater Wellington region between 1 January 1994 and 30 November 2014 from the New Zealand Cancer Registry. Their personal details, characteristics of their tumours, treatment, complications, and outcomes were collected retrospectively from their casenotes and the New Zealand Death Registry, followed by p16 immunohistochemical staining. Of the 161 patients included, 131 (81%) were men. p16 immunohistochemical staining was done routinely in 13 patients during investigations, and retrospectively for 135 patients. The proportion of p16+ oropharyngeal SCC increased from 24% during 1994-1999, to 76% during 2009-2014 (p < 0.001). Oropharyngeal SCC among Europeans was more likely to be p16+ than in non-Europeans (67% compared with 44%, p = 0.036). Patients with p16+ disease were younger (mean (SD) 56 (±10) compared with 66 (±9) years, p < 0.01) with fewer coexisting conditions (mean (SD) Charlson Comorbidity Index: 2.45 (±0.82) compared with 2.92 (±1.16), p = 0.01), and less likely to have smoked (57/81(70%) compared with 38/42 (91%) p = 0.035), or misused alcohol (12/81 (15%) compared with 14/42 (31%), p = 0.042), or both. They were also more likely to have poorly differentiated tumours (30/52 (58%) compared with 9/34 (26%), p = 0.019) with nodal metastases (74/85 (87%) compared with 17/30 (57%), p = 0.001). Overall 5-year all-cause survival was more favourable for patients with p16+ disease (65/86 (76%) compared with 15/49 (31%), p = 0.000). Interestingly, all-cause age at death was younger in p16+ patients (62 (±11.1) compared with 71 (±11.2) years, p = 0.001). The prevalence of p16+ oropharyngeal SCC had tripled in this population between 1994 and 2014, and affected patients have distinct characteristics and outcomes of treatment. © 2016 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Keywords: Oropharyngeal; squamous cell carcinoma; alpha-papillomavirus; human papillomavirus; New Zealand
Introduction ∗
Corresponding author. Gillies McIndoe Research Institute, PO Box 7184, Newtown 6242, Wellington, New Zealand. Tel.: +64 4 2820366. E-mail address: [email protected] (S.T. Tan).
Many countries have reported a dramatic increase in the incidence of oropharyngeal squamous cell carcinoma (SCC) over the past 10-30 years,1–3 coinciding with a stable or
http://dx.doi.org/10.1016/j.bjoms.2016.05.033 0266-4356/© 2016 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kwon HJ, et al. Changing Prevalence and Treatment Outcomes of Patients with p16 Human Papillomavirus Related Oropharyngeal Squamous Cell Carcinoma in New Zealand. Br J Oral Maxillofac Surg (2016), http://dx.doi.org/10.1016/j.bjoms.2016.05.033
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decreasing rate of smoking and alcohol misuse.4,5 This has been attributed to a greater proportion of these tumours being associated with the human papillomavirus (HPV), which also implicated in cervical and anal malignancies.6 Clinically and epidemiologically, HPV positive (+) oropharyngeal SCC is distinct from HPV negative (-) oropharyngeal SCC, as it presents in younger patients and is associated with better survival.6 In New Zealand, the rapid rise in the incidence of oropharyngeal SCC began around 2005, increasing by 11.9% annually until 2010.7 It is not certain if this increase is attributable to HPV infection and whether overseas data can be applied to New Zealand, which has a unique multi-ethnic population, particularly M¯aori and Pacific Islanders. We have quantified changes in the prevalence of HPV+ oropharyngeal SCC in the greater Wellington region over a 20-year period, and compared characteristics of both tumours and patients and the outcomes of treatment in patients with HPV+ disease with their HPV- counterparts.
Patients and Methods Identification of patients All patients who lived in the greater Wellington region of New Zealand and were treated for SCC of the oropharynx (tongue base, palatine tonsil, soft palate, and lateral and posterior pharyngeal walls) between 1 January 1994 and 30 November 2014, were identified from the New Zealand Cancer Registry using ICD-10 codes: C01 (malignant neoplasm of base of tongue), C02 (malignant neoplasm of other and unspecified parts of tongue), C05 (malignant neoplasm of palate), C09 (malignant neoplasm of tonsil), C10 (malignant neoplasm of oropharynx), C14 (malignant neoplasm of other and ill-defined sites). All patients with tumours that were not oropharyngeal SCC were excluded. Patients’ clinical records were reviewed and their demographic data (age, sex, ethnicity, New Zealand Deprivation Index (NZDI - an estimate of socioeconomic status), smoking status (ever smoked or never smoked), alcohol misuse (if alcoholism or alcohol misuse was documented), coexisting conditions (myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease, connective tissue disease, peptic ulcers, diabetes mellitus, chronic renal disease, hemiplegia, leukaemia, lymphoma, solid tumour, metastatic tumour, liver disease, or HIV/AIDS); the characteristics of the tumour (anatomical site, stage, histological grade, status of prospective HPV testing); treatment (surgery, radiotherapy, or chemotherapy) and complications (unable to complete treatment, percutaneous gastrostomy tube or nasogastric tube feeding, severe mucositis or skin reaction, or both, trismus, tube feeding for longer than six months after treatment, or death during treatment); and the presence
and date of recurrence, were collected. Mortality data were obtained from the New Zealand Death Registry. Archived formalin-fixed, paraffin-embedded, tissue blocks of oropharyngeal SCC were retrieved from the laboratories at Wellington Regional Hospital, Hutt Hospital, and Aotea Pathology and, where adequate tissue was available, used for testing. Histological and immunohistochemical staining The diagnosis of oropharyngeal SCC in the tissues being studied was confirmed by reviewing the slides stained with haematoxylin and eosin. In two cases only metastatic regional nodes were available. After the slides had been reviewed (by pathologist HDB), formalin-fixed, paraffin-embedded sections, 4 m-thick, of oropharyngeal SCC were stained immunohistochemically with a monoclonal antibody to p16 (CINtec Histology kit, Clone E6H4) with a BondTM RX autostainer (Leica, Nussloch, Germany) according to the manufacturer’s instructions, using a published protocol.8 A known p16+ oropharyngeal SCC was used as positive control. All immunohistochemically-stained slides were examined independently by two pathologists (HDB and SB). Tumours showing ≥ 70% p16 staining of cells were deemed positive for HPV1 and the results were classified (0, negative; 1+, equivocal (focal positive staining involving < 70% of the tumour); 2+, > 70%) and compared. Statistical analysis Fisher’s exact test (FET) for categorical variables and Student’s t test after Levene’s test for variances was performed with the aid of IBM SPSS Statistics for Windows (version 22, IBM Corp, Armonk, NY, USA). FET results were confirmed with 2 . The level of statistical significance was p < 0.05. The reason for checking on Fishers exact test by also using 2 is that Fishers test is now known to have an asymmetrical bias. Interestingly so does 2 but in the opposite direction so if used together they allow the biases to cancel each other, by selecting an appropriate value between the two results.
Results Details of patients (Table 1) Of the 251 patients reviewed, 161 patients (131 men) with a mean (range) age 60 (28-88) years, were included in the study (Fig. 1A). Ninety cases were excluded as the tumours were outside the oropharynx. The most common ethnicity was European (n = 137, 85%), followed by M¯aori (n = 15, 9%), Asian (n = 7, 4%), and Pacific Islander (n = 3, 2%).
Please cite this article in press as: Kwon HJ, et al. Changing Prevalence and Treatment Outcomes of Patients with p16 Human Papillomavirus Related Oropharyngeal Squamous Cell Carcinoma in New Zealand. Br J Oral Maxillofac Surg (2016), http://dx.doi.org/10.1016/j.bjoms.2016.05.033
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Fig. 2. Changes in the proportions of p16+ oropharyngeal squamous cell carcinomas over time. Table 1 Patients’ details (n = 161). Variable
Mean (SD) age (years) Mean (SD) Charlson Comorbidity Index Smoker Alcohol misuse Mean (SD) NZ Deprivation Index
HPV status
p value
p16+ (n = 81)
p16− (n = 42)
56 (±10.0) 2.44 (±0.82)
66 (±8.5) 2.92 (±1.16)
0.000 0.009
57 (70) 12 (15) 5.73 (±2.97)
38 (90) 14 (31) 6.02 (±3.00)
0.013 0.021 0.582
HPV = human papilloma virus. Fig. 1. (A). Age distribution of patients with oropharyngeal squamous cell carcinoma by sex (blue columns = male; orange columns = female). Fig. 1 (B). Age distribution of patients with oropharyngeal squamous cell carcinoma by p16 status (blue column = p16+; orange columns = p16-).
p16 Immunohistochemical staining A total of 135 patients (84%) had p16 immunohistochemical staining of their oropharyngeal SCC. Twenty-six patients were not tested, because the samples of the primary tumour tissue were unavailable (n = 13), inadequate (n = 8), or showed only SCC in situ (n = 3), or because only cytological samples of the metastatic nodes were available and not stained for p16 (n = 2). In two patients only metastatic regional lymph nodes were available, and stained for p16. There was complete concordance between the two observers about the staining for HPV. In 13 patients the tissue samples stained p16+ both prospectively and retrospectively, which confirmed the reliability of retrospective staining of archival tissues in all 13 cases. p16 IHC staining was positive (p16+) in 86/136 (63%) of our group. Higher rates were found among Europeans than non-Europeans (76/113 (67%) compared with 10/23 (43%), p = 0.036). The proportion of p16+ oropharyngeal SCC increased from 24% during 1994-1999 to 76% during 2009-2014 (p < 0.0001) (Fig. 2). Compared to their p16- counterparts, p16+ patients were younger (mean (SD) age 56 (±10.0) compared with 66 (±8.5) years, t = p < 0.01); with fewer coexisting conditions (mean (SD) Charlson Comorbidity Index, 2.44 (±0.82) compared with 2.92 (±1.16), t = p = 0.01); and less likely to have smoked (57/81 (70%) compared with 38/42 (91%), p = 0.013)
or misused alcohol (12/81 (15%) compared with 14/42 (31%), p = 0.021), or both (Table 1). There were no significant differences in mean (SD) NZDI scores between the two groups (5.73 (±2.97) compared with 6.02 (±3.00), t = p = 0.582). p16+ patients had their primary tumour located exclusively on the palatine tonsils or tongue base (86/86 compared with 31/45 (65%), p = 0.000). p16+ tumours were more likely to be poorly differentiated (30/52 (58%) compared with 9/34 (26%), p = 0.007). p16+ patients were more likely to have nodal metastases (74/85 (87%) compared with 17/30 (57%), p = 0.001), although the overall staging did not differ significantly (p = 0.077) (Table 2). Outcomes of treatment p16+ patients with oropharyngeal SCC were more likely to be given both radiotherapy (81/86 (94%) compared with 34/49 (69%), p = 0.000) and chemotherapy (57/86 (66%) compared with 9/49 (18%), p = 0.000), and more likely to require feeding through a nasogastric tube or percutaneous gastrostomy (p = 0.015). There was no difference in the incidence of tube feeding six months after treatment (p = 1.000), of severe skin reactions (p = 0.268), or of severe mucositis (p = 0.668) between the two groups (Table 3). The overall 5-year, all-cause survival was more than double for p16+ patients (65/86 (76%) compared with 15/49 (31%), p = 0.000), and the all-cause age at death was younger in p16+ patients (62 (±11.1) compared with 71 (±11.2) years, t = p = 0.001) (Fig. 3).
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Table 2 Characteristics of oropharyngeal squamous cell carcinoma. Data are expressed as percentages. Details of tumours
Tonsil or base of tongue Histological differentiation: Well Moderate Poor T-stage: T1 T2 T3 T4 Nodal metastases AJCC† stage: I II III IV IVA IVB IVC
HPV status n/total (%)
HPV is a DNA virus that is implicated in carcinogenesis in the oropharynx, anus, and cervix.6 It spreads mostly by sexual contact, including oral sex.11 The HPV DNA is thought to be integrated into the host genome, which allows production of the viral-associated proteins E6 and E7.12 These interfere with the host p53 and retinoblastoma (Rb) tumour suppressor proteins,12 and inactivation of Rb by E7 results in over-expression of p16, which is commonly used as a marker of HPV association.12 Patients with HPV+ oropharyngeal SCC are more likely to have an increased number of sexual partners and more than four oral sex partners.13 The prevalence of oral HPV carriage at any one time was estimated to be 2.4% in the USA.6 Although most of these infections clear up, it is uncertain which factors are important in the progression to carcinogenesis.6 Smoking, HIV, and immunocompromise have been suggested as risk factors for reduced clearance of HPV.6 However, small samples and difficulties with followup make study of this challenging.14 The cause of the rapid rise in the prevalence of HPV+ oropharyngeal SCC in New Zealand is not clear. In Australia, the mean age at first sexual intercourse has decreased from 18 years for men and 19 years for women born during 19521961, to 16 years for both sexes born during 1986-1989.15 In New Zealand, the mean age at first sexual intercourse has remained at 17 years for men and 16 years for women since the 1980s.16 The interval between first vaginal intercourse and oral sex has decreased from six years in women born during 1952-1961 to one year in those born during 19861989 in Australia,15 but corresponding data are unavailable for New Zealand. In New Zealand, M¯aori people have higher rates of oropharyngeal SCC than Europeans, whereas Pacific Islanders have lower rates.17 Europeans have higher rates of HPV+ oropharyngeal SCC than non-Europeans, although the small sample size of each non-European ethnic group made subanalysis difficult. Higher rates of oropharyngeal SCC in M¯aori people could be the result of higher rates of smoking (39% compared with 15%) and hazardous drinking (29% compared with 15%) than Europeans.9,10 In the USA, although rates of oropharyngeal SCC are higher in African-Americans than European-Americans,
p value
p16+
–
86/86 (100)
31/45 (65)
0.000
0 22/52 (42) 30/52 (58)
2/34 (6) 23/34 (68) 9/34 (26)
0.007
18/82 (22) 34/82 (42) 14/82 (17) 16/82 (20) 74/85 (87)
5/31 (16) 8/31 (26) 10/31 (32) 8/31 (26) 17/30 (57)
3/82 (4) 4/82 (5) 14/82 (17) 61/82 (74) 52/82 (63) 9/82 (11) 0
1/24 (4) 3/24 (13) 7/24 (29) 13/24 (54) 8/24 (33) 2/24 (8) 3/24 (13)
0.055
0.001
0.077
†American Joint Committee on Cancer
Discussion We have shown that the proportion of HPV+ oropharyngeal SCC tripled between 1994 and 2014 in the greater Wellington region of New Zealand, which confirms the results of studies in the USA (from 16% during 1984-1989 to 72% during 2000-2004),1 Sweden (from 23% during 1970-1979 to 68% during 2000-2002),3 and Australia (from 19% during 1987-1990, to 66% during 2005-2006). 2 As with other countries, the increase in the prevalence of HPV+ oropharyngeal SCC in New Zealand occurred during the period when rates of smoking decreased from 25% in 1996 to 18% in 2012.9 Alcohol consumption decreased among men, but increased among women, between 1995 and 2000.10 Between 2006 and 2012 the proportion of adult New Zealanders who consumed alcohol decreased for both men (from 88% to 85%) and women (80% to 74%).10
Table 3 Outcomes of treatment of patients with p16+ and p16- oropharyngeal squamous cell carcinomas. HPV status n/total (%)
Radiotherapy Chemotherapy NGT or PEG feeding† NGT or PEG feeding† six months after radiotherapy Trismus Severe skin reaction Severe mucositis 5-year all-cause survival Mean (SD) age of death (years)
p values
p16+
p16-
81/86 (94) 57/86 (66) 53/76 (70) 2/75 (3) 3/86 (4) 12/73 (16) 41/75 (56) 65/86 (76) 62 (±11.1)
34/49 (69) 9/49 (18) 13/30 (43) 1/30 (3) 0/29 8/29 (28) 18/30 (60) 15/49 (31) 71 (±11.2)
0.000 0.000 0.015 1.000 0.571 0.268 0.668 0.000 0.001
†Nasogastric tube or percutaneous gastrostomy tube feeding.
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they have decreased from 1988 to 2004 for AfricanAmericans, but increased for European-Americans.18 European-Americans have higher rates of HPV+ oropharyngeal SCC than African-Americans (48% compared with 19%, p = 0.003).1 As in previous studies,19 our HPV+ group was younger, less likely to have smoked or misused alcohol, and had a > two-fold survival advantage, than their HPV- counterparts. Interestingly, the overall age at death was significantly younger in patients with HPV+ oropharyngeal SCC. To our knowledge this has not been reported previously. We are not sure whether this is simply because of an earlier age of onset of cancer, or whether other factors are involved. Of the patients who had curative treatment, p16+ and 16- patients who died had similar rates of recurrence (50% compared with 44%, p = 0.782). All HPV+ oropharyngeal SCC in our study developed in tonsillar tissues (palatine tonsils or tongue base). The reticulated epithelium of tonsillar tissue has been postulated to be an immune-privileged site for HPV infection and subsequent malignant transformation.20 Previous studies have shown that HPV+ oropharyngeal SCC presents with a lower T stage and greater likelihood of nodal metastases.6 Like previous studies6 we have shown that HPV+ oropharyngeal SCC are more likely to be poorly-differentiated and to present with metastases. HPV+ patients were more likely to be given chemotherapy and fed through a nasogastric tube or percutaneous gastrostomy. This may be attributed to historical changes in practice coupled with temporal increase in the proportion of HPV+ oropharyngeal SCC. Our hospital began to offer chemotherapy to patients with oropharyngeal SCC in 1999. 8/60 (13%) of the patients were given chemotherapy during the first 10 years of our study compared with 63/101 (62%) in the subsequent 11 years (p = 0.000). Similarly, tube feeding increased from 14/60 (23%) to 56/101 (55%) (p = 0.000) between the two periods. However, in the last 11 years of the study alone, HPV+ patients were still more likely to be treated by chemotherapy 51/68 (75%) than not 12/33 (36%), (p = 0.005) and tube feeding (44/68 (65%) compared with 12/33 (36%), p = 0.01). This may be because HPV+ patients were younger and had higher nodal staging. Patients with nodal metastasis were more likely to be given both chemotherapy (64/102 (63%) compared with 8/59 (14%), p = 0.000) and tube feeding 57/102 (56%) compared with 13/59 (22%), (p = 0.000). Although we found no difference in the complications of radiotherapy relative to HPV status, with the increasing use of transoral robotic surgery, future studies that specifically examine this area could be interesting.. HPV vaccines reduce extracervical (vaginal and vulval) infections in women and penile and anal infections in men.21,22 They also reduce the prevalence of oral carriage of HPV.23 Immunisation that covers high-risk HPV subtypes 6, 11, 16, and 18 was introduced in Australia for girls in 2007 and extended to boys in 2013. In New Zealand, the vaccination of girls started in 2008, but it has not yet been
5
extended to boys. Our results highlight a four-fold greater burden of oropharyngeal SCC in men, and that the proportion of HPV+ oropharyngeal SCC has tripled over the study period. It is now the second most common cancer associated with HPV. Chaturvedi et al1 estimated that by 2020 the incidence of HPV+ oropharyngeal SCC will be greater than that of cervical cancer, and half of all head and neck cancers will be HPV+ by 2030 in the USA. We recommend extension of HPV vaccination to boys in New Zealand as a cost-effective preventative measure for HPV-related cancers. Limitations of our study include its retrospective design, as routine testing of HPV status has been prospective only within the last three years of the study period in our region. The use of formalin-fixed, paraffin-embedded, tissues meant that HPV mRNA E6/E7 testing, the current gold standard, was not possible. p16 immunohistochemical staining was chosen as it is already used prospectively as part of the diagnostic investigations in our region and our pathologists are familiar with its interpretation. It has been verified on archival cervical cancer tissues, extensively studied as a prognostic marker for oropharyngeal SCC, and correlated with other markers for HPV+ oropharyngeal SCC.6,19,24 HPV subtypes were not analysed, as p16 is a surrogate marker for HPV infection but not specific for a particular subtype of HPV. HPV16 has been consistently shown to be the predominant (80%-90%) subtype internationally.2 The strength of our study includes a high rate of retrieval and testing of tissue (84%), compared with studies from the USA (4.7%)1 and Sweden (46%). 3 The completeness of reporting to the New Zealand Cancer Registry (a legal requirement) accounts for all patients treated for oropharyngeal SCC in our region during the study period. To our knowledge, this is the first study that has described a temporal rise in the proportion of HPV+ oropharyngeal SCC, and compared characteristics of patients and tumours and the outcomes of treatment according to HPV status, in New Zealand. Results of this study were presented, in part, at the 68th Annual Scientific Meeting of the New Zealand Society of Otolaryngology - Head and Neck Surgery, 20-23 October 2015, Nelson, New Zealand; and presented, in part, at the Annual Scientific Meeting of the Australian Society of Otolaryngology – Head and Neck Surgery, 6-8 March 2016, Melbourne, Australia. Conflict of Interest We have no conflict of interest.
Ethics Statement/confirmation of patients’ permission This study was approved by the Central Health and Disability Ethics Committee (reference number 14/CEN/129/AM01).
Please cite this article in press as: Kwon HJ, et al. Changing Prevalence and Treatment Outcomes of Patients with p16 Human Papillomavirus Related Oropharyngeal Squamous Cell Carcinoma in New Zealand. Br J Oral Maxillofac Surg (2016), http://dx.doi.org/10.1016/j.bjoms.2016.05.033
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Acknowledgements We thank Mrs Liz Jones of the Gillies McIndoe Research Institute for the immunohistochemical staining.
References 1. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus (HPV) and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011;29:4294–301. 2. Hong AM, Grulich AE, Jones D, et al. Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets. Vaccine 2010;28:3269–72. 3. Näsman A, Attner P, Hammarstedt L, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009;125: 362–6. 4. Ng M, Freeman MK, Fleming TD, et al. Smoking prevalence and cigarette consumption in 187 countries, 1980-2012. JAMA 2014;311: 183–92. 5. WHO. Global status report on alcohol and health. Geneva: WHO; 2014 (updated 12 May 2014). (last accessed 25 May 2016) www.who.int/iris/bitstream/10665/112736/1/9789240692763 eng.pdf. 6. Pytynia KB, Dahlstrom KR, Sturgis EM. Epidemiology of HPVassociated oropharyngeal cancer. Oral Oncol 2014;50:380–6. 7. Elwood JM, Youlden DR, Chelimo C, et al. Comparison of oropharyngeal and oral cavity squamous cell cancer incidence and trends in New Zealand and Queensland, Australia. Cancer Epidemiol 2014;38:16–21. 8. Tan EM, Chudakova DA, Davis PE, et al. Characterisation of subpopulations of myeloid cells in infantile haemangioma. J Clin Pathol 2015;68:571–4. 9. Ministry of Health. Tobacco Use 2012/13: New Zealand Health Survey. Wellington: Ministry of Health; 2012, http://www.health.govt.nz/ publication/tobacco-use-2012-13-new-zealand-health-survey, (updated 4 Dec 2014). (last accessed 25 May 2016). 10. Ministry of Health. Hazardous drinking in 2011/12: Findings from the New Zealand Health Survey. Wellington: Ministry of Health; 2011, http://www.health.govt.nz/publication/hazardous-drinking-201112-findings-new-zealand-health-survey, (updated 16 Apr 2013). (last accessed 25 May 2016).
11. D’Souza G, Agrawal Y, Halpern J, et al. Oral sexual behaviors associated with prevalent oral human papillomavirus infection. J Infect Dis 2009;199(9):1263–9. 12. Doorbar J, Quint Wi, Banks L, et al. The biology and life-cycle of human papillomaviruses. Vaccine 2012;30(suppl 5):F55–70. 13. Heck JE, Berthiller J, Vaccarella S, et al. Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int J Epidemiol 2010;39:166–81. 14. Kreimer AR, Pierce Campbell CM, Lin HY, et al. Incidence and clearance of oral human papillomavirus infection in men: the HIM cohort study. Lancet 2013;382:877–87. 15. Rissel CE, Richters J, Grulich AE, et al. Sex in Australia: First experiences of vaginal intercourse and oral sex among a representative sample of adults. Aust NZ J Public Health 2003;27:131–7. 16. Psutka R, Connor J, Cousins K, et al. Sexual health, risks, and experiences of New Zealand university students: findings from a national cross-sectional study. NZ Med J 2012;125:62–73. 17. Chelimo C, Elwood JM. Sociodemographic differences in the incidence of oropharyngeal and oral cavity squamous cell cancers in New Zealand. Aust NZ J Public Health 2015;39:162–7. 18. Chaturvedi AK, Engels EA, Anderson WF, et al. Incidence trends for human Papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 2008;26:612–9. 19. Kian Ang K, Ang KK, Harris J, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24–35. 20. Westra WH. The morphologic profile of hpv-related head and neck squamous carcinoma: implications for diagnosis, prognosis, and clinical management. Head Neck Pathol 2012;6(suppl 1):S48–54. 21. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med 2011;364:401–11. Erratum: N Engl J Med 2011; 364:1481. 22. Joura EA, Garland SM, Paavonen J, et al. Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data. BMJ 2012;344:e1401. 23. Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One 2013;8:e68329. 24. Lesnikova I, Lidang M, Hamilton-Dutoit S, et al. p16 as a diagnostic marker of cervical neoplasia: a tissue microarray study of 796 archival specimens. Diagn Pathol 2009;4:22.
Please cite this article in press as: Kwon HJ, et al. Changing Prevalence and Treatment Outcomes of Patients with p16 Human Papillomavirus Related Oropharyngeal Squamous Cell Carcinoma in New Zealand. Br J Oral Maxillofac Surg (2016), http://dx.doi.org/10.1016/j.bjoms.2016.05.033
ARTICLE IN PRESS Available online at www.sciencedirect.com
ScienceDirect British Journal of Oral and Maxillofacial Surgery xxx (2016) xxx–xxx
Changing Prevalence and Treatment Outcomes of Patients with p16 Human Papillomavirus Related Oropharyngeal Squamous Cell Carcinoma in New Zealand H.J. Kwon a , H.D. Brasch b,c , S. Benison c , R.W. Marsh b,d , T. Itinteang b , G.W. Titchener a , J. Evans e , S.T. Tan b,f,∗ a
Department of Otolaryngology - Head and Neck Surgery, Wellington Regional Hospital, Wellington, New Zealand Gillies McIndoe Research Institute, Wellington, New Zealand c Department of Pathology, Hutt Hospital, Wellington, New Zealand d Auckland University, Auckland, New Zealand e Wellington Blood and Cancer Centre, Wellington Regional Hospital, Wellington, New Zealand f Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Wellington, New Zealand b
Accepted 31 May 2016
Abstract There has, to our knowledge, been no previous report of changes in the prevalence and outcomes of treatment of HPV-positive (+) oropharyngeal squamous cell carcinoma (SCC) in New Zealand. We identified all affected patients in the greater Wellington region between 1 January 1994 and 30 November 2014 from the New Zealand Cancer Registry. Their personal details, characteristics of their tumours, treatment, complications, and outcomes were collected retrospectively from their casenotes and the New Zealand Death Registry, followed by p16 immunohistochemical staining. Of the 161 patients included, 131 (81%) were men. p16 immunohistochemical staining was done routinely in 13 patients during investigations, and retrospectively for 135 patients. The proportion of p16+ oropharyngeal SCC increased from 24% during 1994-1999, to 76% during 2009-2014 (p < 0.001). Oropharyngeal SCC among Europeans was more likely to be p16+ than in non-Europeans (67% compared with 44%, p = 0.036). Patients with p16+ disease were younger (mean (SD) 56 (±10) compared with 66 (±9) years, p < 0.01) with fewer coexisting conditions (mean (SD) Charlson Comorbidity Index: 2.45 (±0.82) compared with 2.92 (±1.16), p = 0.01), and less likely to have smoked (57/81(70%) compared with 38/42 (91%) p = 0.035), or misused alcohol (12/81 (15%) compared with 14/42 (31%), p = 0.042), or both. They were also more likely to have poorly differentiated tumours (30/52 (58%) compared with 9/34 (26%), p = 0.019) with nodal metastases (74/85 (87%) compared with 17/30 (57%), p = 0.001). Overall 5-year all-cause survival was more favourable for patients with p16+ disease (65/86 (76%) compared with 15/49 (31%), p = 0.000). Interestingly, all-cause age at death was younger in p16+ patients (62 (±11.1) compared with 71 (±11.2) years, p = 0.001). The prevalence of p16+ oropharyngeal SCC had tripled in this population between 1994 and 2014, and affected patients have distinct characteristics and outcomes of treatment. © 2016 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Keywords: Oropharyngeal; squamous cell carcinoma; alpha-papillomavirus; human papillomavirus; New Zealand
Introduction ∗
Corresponding author. Gillies McIndoe Research Institute, PO Box 7184, Newtown 6242, Wellington, New Zealand. Tel.: +64 4 2820366. E-mail address: [email protected] (S.T. Tan).
Many countries have reported a dramatic increase in the incidence of oropharyngeal squamous cell carcinoma (SCC) over the past 10-30 years,1–3 coinciding with a stable or
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Please cite this article in press as: Kwon HJ, et al. Changing Prevalence and Treatment Outcomes of Patients with p16 Human Papillomavirus Related Oropharyngeal Squamous Cell Carcinoma in New Zealand. Br J Oral Maxillofac Surg (2016), http://dx.doi.org/10.1016/j.bjoms.2016.05.033
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decreasing rate of smoking and alcohol misuse.4,5 This has been attributed to a greater proportion of these tumours being associated with the human papillomavirus (HPV), which also implicated in cervical and anal malignancies.6 Clinically and epidemiologically, HPV positive (+) oropharyngeal SCC is distinct from HPV negative (-) oropharyngeal SCC, as it presents in younger patients and is associated with better survival.6 In New Zealand, the rapid rise in the incidence of oropharyngeal SCC began around 2005, increasing by 11.9% annually until 2010.7 It is not certain if this increase is attributable to HPV infection and whether overseas data can be applied to New Zealand, which has a unique multi-ethnic population, particularly M¯aori and Pacific Islanders. We have quantified changes in the prevalence of HPV+ oropharyngeal SCC in the greater Wellington region over a 20-year period, and compared characteristics of both tumours and patients and the outcomes of treatment in patients with HPV+ disease with their HPV- counterparts.
Patients and Methods Identification of patients All patients who lived in the greater Wellington region of New Zealand and were treated for SCC of the oropharynx (tongue base, palatine tonsil, soft palate, and lateral and posterior pharyngeal walls) between 1 January 1994 and 30 November 2014, were identified from the New Zealand Cancer Registry using ICD-10 codes: C01 (malignant neoplasm of base of tongue), C02 (malignant neoplasm of other and unspecified parts of tongue), C05 (malignant neoplasm of palate), C09 (malignant neoplasm of tonsil), C10 (malignant neoplasm of oropharynx), C14 (malignant neoplasm of other and ill-defined sites). All patients with tumours that were not oropharyngeal SCC were excluded. Patients’ clinical records were reviewed and their demographic data (age, sex, ethnicity, New Zealand Deprivation Index (NZDI - an estimate of socioeconomic status), smoking status (ever smoked or never smoked), alcohol misuse (if alcoholism or alcohol misuse was documented), coexisting conditions (myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease, connective tissue disease, peptic ulcers, diabetes mellitus, chronic renal disease, hemiplegia, leukaemia, lymphoma, solid tumour, metastatic tumour, liver disease, or HIV/AIDS); the characteristics of the tumour (anatomical site, stage, histological grade, status of prospective HPV testing); treatment (surgery, radiotherapy, or chemotherapy) and complications (unable to complete treatment, percutaneous gastrostomy tube or nasogastric tube feeding, severe mucositis or skin reaction, or both, trismus, tube feeding for longer than six months after treatment, or death during treatment); and the presence
and date of recurrence, were collected. Mortality data were obtained from the New Zealand Death Registry. Archived formalin-fixed, paraffin-embedded, tissue blocks of oropharyngeal SCC were retrieved from the laboratories at Wellington Regional Hospital, Hutt Hospital, and Aotea Pathology and, where adequate tissue was available, used for testing. Histological and immunohistochemical staining The diagnosis of oropharyngeal SCC in the tissues being studied was confirmed by reviewing the slides stained with haematoxylin and eosin. In two cases only metastatic regional nodes were available. After the slides had been reviewed (by pathologist HDB), formalin-fixed, paraffin-embedded sections, 4 m-thick, of oropharyngeal SCC were stained immunohistochemically with a monoclonal antibody to p16 (CINtec Histology kit, Clone E6H4) with a BondTM RX autostainer (Leica, Nussloch, Germany) according to the manufacturer’s instructions, using a published protocol.8 A known p16+ oropharyngeal SCC was used as positive control. All immunohistochemically-stained slides were examined independently by two pathologists (HDB and SB). Tumours showing ≥ 70% p16 staining of cells were deemed positive for HPV1 and the results were classified (0, negative; 1+, equivocal (focal positive staining involving < 70% of the tumour); 2+, > 70%) and compared. Statistical analysis Fisher’s exact test (FET) for categorical variables and Student’s t test after Levene’s test for variances was performed with the aid of IBM SPSS Statistics for Windows (version 22, IBM Corp, Armonk, NY, USA). FET results were confirmed with 2 . The level of statistical significance was p < 0.05. The reason for checking on Fishers exact test by also using 2 is that Fishers test is now known to have an asymmetrical bias. Interestingly so does 2 but in the opposite direction so if used together they allow the biases to cancel each other, by selecting an appropriate value between the two results.
Results Details of patients (Table 1) Of the 251 patients reviewed, 161 patients (131 men) with a mean (range) age 60 (28-88) years, were included in the study (Fig. 1A). Ninety cases were excluded as the tumours were outside the oropharynx. The most common ethnicity was European (n = 137, 85%), followed by M¯aori (n = 15, 9%), Asian (n = 7, 4%), and Pacific Islander (n = 3, 2%).
Please cite this article in press as: Kwon HJ, et al. Changing Prevalence and Treatment Outcomes of Patients with p16 Human Papillomavirus Related Oropharyngeal Squamous Cell Carcinoma in New Zealand. Br J Oral Maxillofac Surg (2016), http://dx.doi.org/10.1016/j.bjoms.2016.05.033
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Fig. 2. Changes in the proportions of p16+ oropharyngeal squamous cell carcinomas over time. Table 1 Patients’ details (n = 161). Variable
Mean (SD) age (years) Mean (SD) Charlson Comorbidity Index Smoker Alcohol misuse Mean (SD) NZ Deprivation Index
HPV status
p value
p16+ (n = 81)
p16− (n = 42)
56 (±10.0) 2.44 (±0.82)
66 (±8.5) 2.92 (±1.16)
0.000 0.009
57 (70) 12 (15) 5.73 (±2.97)
38 (90) 14 (31) 6.02 (±3.00)
0.013 0.021 0.582
HPV = human papilloma virus. Fig. 1. (A). Age distribution of patients with oropharyngeal squamous cell carcinoma by sex (blue columns = male; orange columns = female). Fig. 1 (B). Age distribution of patients with oropharyngeal squamous cell carcinoma by p16 status (blue column = p16+; orange columns = p16-).
p16 Immunohistochemical staining A total of 135 patients (84%) had p16 immunohistochemical staining of their oropharyngeal SCC. Twenty-six patients were not tested, because the samples of the primary tumour tissue were unavailable (n = 13), inadequate (n = 8), or showed only SCC in situ (n = 3), or because only cytological samples of the metastatic nodes were available and not stained for p16 (n = 2). In two patients only metastatic regional lymph nodes were available, and stained for p16. There was complete concordance between the two observers about the staining for HPV. In 13 patients the tissue samples stained p16+ both prospectively and retrospectively, which confirmed the reliability of retrospective staining of archival tissues in all 13 cases. p16 IHC staining was positive (p16+) in 86/136 (63%) of our group. Higher rates were found among Europeans than non-Europeans (76/113 (67%) compared with 10/23 (43%), p = 0.036). The proportion of p16+ oropharyngeal SCC increased from 24% during 1994-1999 to 76% during 2009-2014 (p < 0.0001) (Fig. 2). Compared to their p16- counterparts, p16+ patients were younger (mean (SD) age 56 (±10.0) compared with 66 (±8.5) years, t = p < 0.01); with fewer coexisting conditions (mean (SD) Charlson Comorbidity Index, 2.44 (±0.82) compared with 2.92 (±1.16), t = p = 0.01); and less likely to have smoked (57/81 (70%) compared with 38/42 (91%), p = 0.013)
or misused alcohol (12/81 (15%) compared with 14/42 (31%), p = 0.021), or both (Table 1). There were no significant differences in mean (SD) NZDI scores between the two groups (5.73 (±2.97) compared with 6.02 (±3.00), t = p = 0.582). p16+ patients had their primary tumour located exclusively on the palatine tonsils or tongue base (86/86 compared with 31/45 (65%), p = 0.000). p16+ tumours were more likely to be poorly differentiated (30/52 (58%) compared with 9/34 (26%), p = 0.007). p16+ patients were more likely to have nodal metastases (74/85 (87%) compared with 17/30 (57%), p = 0.001), although the overall staging did not differ significantly (p = 0.077) (Table 2). Outcomes of treatment p16+ patients with oropharyngeal SCC were more likely to be given both radiotherapy (81/86 (94%) compared with 34/49 (69%), p = 0.000) and chemotherapy (57/86 (66%) compared with 9/49 (18%), p = 0.000), and more likely to require feeding through a nasogastric tube or percutaneous gastrostomy (p = 0.015). There was no difference in the incidence of tube feeding six months after treatment (p = 1.000), of severe skin reactions (p = 0.268), or of severe mucositis (p = 0.668) between the two groups (Table 3). The overall 5-year, all-cause survival was more than double for p16+ patients (65/86 (76%) compared with 15/49 (31%), p = 0.000), and the all-cause age at death was younger in p16+ patients (62 (±11.1) compared with 71 (±11.2) years, t = p = 0.001) (Fig. 3).
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Table 2 Characteristics of oropharyngeal squamous cell carcinoma. Data are expressed as percentages. Details of tumours
Tonsil or base of tongue Histological differentiation: Well Moderate Poor T-stage: T1 T2 T3 T4 Nodal metastases AJCC† stage: I II III IV IVA IVB IVC
HPV status n/total (%)
HPV is a DNA virus that is implicated in carcinogenesis in the oropharynx, anus, and cervix.6 It spreads mostly by sexual contact, including oral sex.11 The HPV DNA is thought to be integrated into the host genome, which allows production of the viral-associated proteins E6 and E7.12 These interfere with the host p53 and retinoblastoma (Rb) tumour suppressor proteins,12 and inactivation of Rb by E7 results in over-expression of p16, which is commonly used as a marker of HPV association.12 Patients with HPV+ oropharyngeal SCC are more likely to have an increased number of sexual partners and more than four oral sex partners.13 The prevalence of oral HPV carriage at any one time was estimated to be 2.4% in the USA.6 Although most of these infections clear up, it is uncertain which factors are important in the progression to carcinogenesis.6 Smoking, HIV, and immunocompromise have been suggested as risk factors for reduced clearance of HPV.6 However, small samples and difficulties with followup make study of this challenging.14 The cause of the rapid rise in the prevalence of HPV+ oropharyngeal SCC in New Zealand is not clear. In Australia, the mean age at first sexual intercourse has decreased from 18 years for men and 19 years for women born during 19521961, to 16 years for both sexes born during 1986-1989.15 In New Zealand, the mean age at first sexual intercourse has remained at 17 years for men and 16 years for women since the 1980s.16 The interval between first vaginal intercourse and oral sex has decreased from six years in women born during 1952-1961 to one year in those born during 19861989 in Australia,15 but corresponding data are unavailable for New Zealand. In New Zealand, M¯aori people have higher rates of oropharyngeal SCC than Europeans, whereas Pacific Islanders have lower rates.17 Europeans have higher rates of HPV+ oropharyngeal SCC than non-Europeans, although the small sample size of each non-European ethnic group made subanalysis difficult. Higher rates of oropharyngeal SCC in M¯aori people could be the result of higher rates of smoking (39% compared with 15%) and hazardous drinking (29% compared with 15%) than Europeans.9,10 In the USA, although rates of oropharyngeal SCC are higher in African-Americans than European-Americans,
p value
p16+
–
86/86 (100)
31/45 (65)
0.000
0 22/52 (42) 30/52 (58)
2/34 (6) 23/34 (68) 9/34 (26)
0.007
18/82 (22) 34/82 (42) 14/82 (17) 16/82 (20) 74/85 (87)
5/31 (16) 8/31 (26) 10/31 (32) 8/31 (26) 17/30 (57)
3/82 (4) 4/82 (5) 14/82 (17) 61/82 (74) 52/82 (63) 9/82 (11) 0
1/24 (4) 3/24 (13) 7/24 (29) 13/24 (54) 8/24 (33) 2/24 (8) 3/24 (13)
0.055
0.001
0.077
†American Joint Committee on Cancer
Discussion We have shown that the proportion of HPV+ oropharyngeal SCC tripled between 1994 and 2014 in the greater Wellington region of New Zealand, which confirms the results of studies in the USA (from 16% during 1984-1989 to 72% during 2000-2004),1 Sweden (from 23% during 1970-1979 to 68% during 2000-2002),3 and Australia (from 19% during 1987-1990, to 66% during 2005-2006). 2 As with other countries, the increase in the prevalence of HPV+ oropharyngeal SCC in New Zealand occurred during the period when rates of smoking decreased from 25% in 1996 to 18% in 2012.9 Alcohol consumption decreased among men, but increased among women, between 1995 and 2000.10 Between 2006 and 2012 the proportion of adult New Zealanders who consumed alcohol decreased for both men (from 88% to 85%) and women (80% to 74%).10
Table 3 Outcomes of treatment of patients with p16+ and p16- oropharyngeal squamous cell carcinomas. HPV status n/total (%)
Radiotherapy Chemotherapy NGT or PEG feeding† NGT or PEG feeding† six months after radiotherapy Trismus Severe skin reaction Severe mucositis 5-year all-cause survival Mean (SD) age of death (years)
p values
p16+
p16-
81/86 (94) 57/86 (66) 53/76 (70) 2/75 (3) 3/86 (4) 12/73 (16) 41/75 (56) 65/86 (76) 62 (±11.1)
34/49 (69) 9/49 (18) 13/30 (43) 1/30 (3) 0/29 8/29 (28) 18/30 (60) 15/49 (31) 71 (±11.2)
0.000 0.000 0.015 1.000 0.571 0.268 0.668 0.000 0.001
†Nasogastric tube or percutaneous gastrostomy tube feeding.
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they have decreased from 1988 to 2004 for AfricanAmericans, but increased for European-Americans.18 European-Americans have higher rates of HPV+ oropharyngeal SCC than African-Americans (48% compared with 19%, p = 0.003).1 As in previous studies,19 our HPV+ group was younger, less likely to have smoked or misused alcohol, and had a > two-fold survival advantage, than their HPV- counterparts. Interestingly, the overall age at death was significantly younger in patients with HPV+ oropharyngeal SCC. To our knowledge this has not been reported previously. We are not sure whether this is simply because of an earlier age of onset of cancer, or whether other factors are involved. Of the patients who had curative treatment, p16+ and 16- patients who died had similar rates of recurrence (50% compared with 44%, p = 0.782). All HPV+ oropharyngeal SCC in our study developed in tonsillar tissues (palatine tonsils or tongue base). The reticulated epithelium of tonsillar tissue has been postulated to be an immune-privileged site for HPV infection and subsequent malignant transformation.20 Previous studies have shown that HPV+ oropharyngeal SCC presents with a lower T stage and greater likelihood of nodal metastases.6 Like previous studies6 we have shown that HPV+ oropharyngeal SCC are more likely to be poorly-differentiated and to present with metastases. HPV+ patients were more likely to be given chemotherapy and fed through a nasogastric tube or percutaneous gastrostomy. This may be attributed to historical changes in practice coupled with temporal increase in the proportion of HPV+ oropharyngeal SCC. Our hospital began to offer chemotherapy to patients with oropharyngeal SCC in 1999. 8/60 (13%) of the patients were given chemotherapy during the first 10 years of our study compared with 63/101 (62%) in the subsequent 11 years (p = 0.000). Similarly, tube feeding increased from 14/60 (23%) to 56/101 (55%) (p = 0.000) between the two periods. However, in the last 11 years of the study alone, HPV+ patients were still more likely to be treated by chemotherapy 51/68 (75%) than not 12/33 (36%), (p = 0.005) and tube feeding (44/68 (65%) compared with 12/33 (36%), p = 0.01). This may be because HPV+ patients were younger and had higher nodal staging. Patients with nodal metastasis were more likely to be given both chemotherapy (64/102 (63%) compared with 8/59 (14%), p = 0.000) and tube feeding 57/102 (56%) compared with 13/59 (22%), (p = 0.000). Although we found no difference in the complications of radiotherapy relative to HPV status, with the increasing use of transoral robotic surgery, future studies that specifically examine this area could be interesting.. HPV vaccines reduce extracervical (vaginal and vulval) infections in women and penile and anal infections in men.21,22 They also reduce the prevalence of oral carriage of HPV.23 Immunisation that covers high-risk HPV subtypes 6, 11, 16, and 18 was introduced in Australia for girls in 2007 and extended to boys in 2013. In New Zealand, the vaccination of girls started in 2008, but it has not yet been
5
extended to boys. Our results highlight a four-fold greater burden of oropharyngeal SCC in men, and that the proportion of HPV+ oropharyngeal SCC has tripled over the study period. It is now the second most common cancer associated with HPV. Chaturvedi et al1 estimated that by 2020 the incidence of HPV+ oropharyngeal SCC will be greater than that of cervical cancer, and half of all head and neck cancers will be HPV+ by 2030 in the USA. We recommend extension of HPV vaccination to boys in New Zealand as a cost-effective preventative measure for HPV-related cancers. Limitations of our study include its retrospective design, as routine testing of HPV status has been prospective only within the last three years of the study period in our region. The use of formalin-fixed, paraffin-embedded, tissues meant that HPV mRNA E6/E7 testing, the current gold standard, was not possible. p16 immunohistochemical staining was chosen as it is already used prospectively as part of the diagnostic investigations in our region and our pathologists are familiar with its interpretation. It has been verified on archival cervical cancer tissues, extensively studied as a prognostic marker for oropharyngeal SCC, and correlated with other markers for HPV+ oropharyngeal SCC.6,19,24 HPV subtypes were not analysed, as p16 is a surrogate marker for HPV infection but not specific for a particular subtype of HPV. HPV16 has been consistently shown to be the predominant (80%-90%) subtype internationally.2 The strength of our study includes a high rate of retrieval and testing of tissue (84%), compared with studies from the USA (4.7%)1 and Sweden (46%). 3 The completeness of reporting to the New Zealand Cancer Registry (a legal requirement) accounts for all patients treated for oropharyngeal SCC in our region during the study period. To our knowledge, this is the first study that has described a temporal rise in the proportion of HPV+ oropharyngeal SCC, and compared characteristics of patients and tumours and the outcomes of treatment according to HPV status, in New Zealand. Results of this study were presented, in part, at the 68th Annual Scientific Meeting of the New Zealand Society of Otolaryngology - Head and Neck Surgery, 20-23 October 2015, Nelson, New Zealand; and presented, in part, at the Annual Scientific Meeting of the Australian Society of Otolaryngology – Head and Neck Surgery, 6-8 March 2016, Melbourne, Australia. Conflict of Interest We have no conflict of interest.
Ethics Statement/confirmation of patients’ permission This study was approved by the Central Health and Disability Ethics Committee (reference number 14/CEN/129/AM01).
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Acknowledgements We thank Mrs Liz Jones of the Gillies McIndoe Research Institute for the immunohistochemical staining.
References 1. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus (HPV) and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011;29:4294–301. 2. Hong AM, Grulich AE, Jones D, et al. Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets. Vaccine 2010;28:3269–72. 3. Näsman A, Attner P, Hammarstedt L, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009;125: 362–6. 4. Ng M, Freeman MK, Fleming TD, et al. Smoking prevalence and cigarette consumption in 187 countries, 1980-2012. JAMA 2014;311: 183–92. 5. WHO. Global status report on alcohol and health. Geneva: WHO; 2014 (updated 12 May 2014). (last accessed 25 May 2016) www.who.int/iris/bitstream/10665/112736/1/9789240692763 eng.pdf. 6. Pytynia KB, Dahlstrom KR, Sturgis EM. Epidemiology of HPVassociated oropharyngeal cancer. Oral Oncol 2014;50:380–6. 7. Elwood JM, Youlden DR, Chelimo C, et al. Comparison of oropharyngeal and oral cavity squamous cell cancer incidence and trends in New Zealand and Queensland, Australia. Cancer Epidemiol 2014;38:16–21. 8. Tan EM, Chudakova DA, Davis PE, et al. Characterisation of subpopulations of myeloid cells in infantile haemangioma. J Clin Pathol 2015;68:571–4. 9. Ministry of Health. Tobacco Use 2012/13: New Zealand Health Survey. Wellington: Ministry of Health; 2012, http://www.health.govt.nz/ publication/tobacco-use-2012-13-new-zealand-health-survey, (updated 4 Dec 2014). (last accessed 25 May 2016). 10. Ministry of Health. Hazardous drinking in 2011/12: Findings from the New Zealand Health Survey. Wellington: Ministry of Health; 2011, http://www.health.govt.nz/publication/hazardous-drinking-201112-findings-new-zealand-health-survey, (updated 16 Apr 2013). (last accessed 25 May 2016).
11. D’Souza G, Agrawal Y, Halpern J, et al. Oral sexual behaviors associated with prevalent oral human papillomavirus infection. J Infect Dis 2009;199(9):1263–9. 12. Doorbar J, Quint Wi, Banks L, et al. The biology and life-cycle of human papillomaviruses. Vaccine 2012;30(suppl 5):F55–70. 13. Heck JE, Berthiller J, Vaccarella S, et al. Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int J Epidemiol 2010;39:166–81. 14. Kreimer AR, Pierce Campbell CM, Lin HY, et al. Incidence and clearance of oral human papillomavirus infection in men: the HIM cohort study. Lancet 2013;382:877–87. 15. Rissel CE, Richters J, Grulich AE, et al. Sex in Australia: First experiences of vaginal intercourse and oral sex among a representative sample of adults. Aust NZ J Public Health 2003;27:131–7. 16. Psutka R, Connor J, Cousins K, et al. Sexual health, risks, and experiences of New Zealand university students: findings from a national cross-sectional study. NZ Med J 2012;125:62–73. 17. Chelimo C, Elwood JM. Sociodemographic differences in the incidence of oropharyngeal and oral cavity squamous cell cancers in New Zealand. Aust NZ J Public Health 2015;39:162–7. 18. Chaturvedi AK, Engels EA, Anderson WF, et al. Incidence trends for human Papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 2008;26:612–9. 19. Kian Ang K, Ang KK, Harris J, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24–35. 20. Westra WH. The morphologic profile of hpv-related head and neck squamous carcinoma: implications for diagnosis, prognosis, and clinical management. Head Neck Pathol 2012;6(suppl 1):S48–54. 21. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med 2011;364:401–11. Erratum: N Engl J Med 2011; 364:1481. 22. Joura EA, Garland SM, Paavonen J, et al. Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data. BMJ 2012;344:e1401. 23. Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One 2013;8:e68329. 24. Lesnikova I, Lidang M, Hamilton-Dutoit S, et al. p16 as a diagnostic marker of cervical neoplasia: a tissue microarray study of 796 archival specimens. Diagn Pathol 2009;4:22.
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