AHNS Human Papillomavirus and Head and Neck Cancer

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At the end of the lecture the audience should:

1. Know the prevalence of HPV associated SCC of the H&N.
2. Be able to identify the high-risk serotypes of HPV associated with SCC of the head and neck.
3. Have a strong understanding of the prognostic significance of an HPV related SCC of the head and neck.

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  • To date, probably the study that has come the closest to truly proving that not only is HPV-infection a risk factor for OP SCC but rather a true causative entity is the study published in the Journal of the National Cancer Institute in 2000 by Gillison from Johns Hopkins. In this study, she looked at 253 cases of H&N SCC. She did not only L1 PCR, but also E7 and E6 specific PCR and sequencing. She also did Southern Blot hybridization, P53 sequencing, and looked at morphology.
  • Here the final statement is by far the most important, and that is this:HPV positivity was found in all cancer stages including pre-invasive dysplastic/in situ disease, invasive primary tumors and lymph node metastases.
  • 90 types in DNA sequence analysis10% dissimilarity in E6, E7, L1
  • As with any disease process that we attribute to a risk factor, we must first undertake studies to determine the incidence in the normal or non diseased population. As it turns out, there have been 5 studies that have looked at the rate of HPV positivity in non-cancerous oropharyngeal tissue. Most of these studies looked at the rate of HPV positivity in the tonsils of people who had their tonsils removed for other indications such as infectious and sleep reasons. As you can see, the rate of positivity in these studies ranged from 0 – 6.3%----- Meeting Notes (3/3/11 20:22) -----When looking at studies that used either brushings or washings, the rate of positivity was between 0.8 & 4%.
  • The next step in the process is to determine whether the HPV actually represents a different disease entity than the typical smoker-drinker SCC. Now you have seen this schematic before. The first thing to remember is that multiple studies have shown a high rate of P53 mutations in SCC of traditional risk factor patients. However, we need to go back to the molecular level and look at the process by which the HPV E6 and E7 sequences might affect the cellular signaling and expression mechanisms. First, rather than mutating the P53 gene, the E6 region acts by deregulation of the P53 signaling pathway, leading to apoptosis resistance, gneomic instability and ultimately malignant progression. Additionall, the E7 portion of the HPV genome ultimately leads to a downregulation of the RB tumor suppressor gene, again leading to genomic instability and malignant progression. As part of this process, the cyclin-dependent kinase inhibitor P16 gets overexpressed. This then, can be used as a surrogate marker for HPV genomic interpolation into host tissue DNA.
  • AHNS Human Papillomavirus and Head and Neck Cancer

    1. 1. The American Head & Neck SocietyHuman Papillomavirus and Head & Neck Cancer The Education Committee Chris Holsinger, MD, Chair Contributing Authors: Wayne Harsha, MD Kerstin M. Stenson MD FACS Michael W.S. Moore, MD Erich M. Sturgis, MD, MPH
    2. 2. Outline• Objectives• Basic HNSCC statistics• HPV basics• HNSCC of the OC/OP on the rise• HPV positivity in HNSCC• Different pathophysiologic entity?• Oncogenesis• Prognosis
    3. 3. ObjectivesAt the end of the lecture the audience should:1. Know the prevalence of HPV associated SCC of the H&N.2. Be able to identify the high-risk serotypes of HPV associated with SCC of the head and neck.3. Have a strong understanding of the prognostic significance of an HPV related SCC of the head and neck.
    4. 4. H&N Cancer: Vital Statistics*Estimated new cases (USA), 2010* Deaths Oral cavity, pharynx 36,540 7,880 Larynx 12,720 3,600 Total 49,260 11,480 *CA Cancer J Clin. 2010 2006: “No change in survival over last 40 yrs.”
    5. 5. SCC of the Head and Neck• 400,000 annually worldwide• 48,000 new cases / year in US – 7th most common among men in US – 4th most common and 10th most common cause of death in AA men• 23,000 deathsPaz IB. Cancer. 79(3):595-604;1997.
    6. 6. Trends in Survival According to Tumor Site and Year of Diagnosis Oropharynx  Carvalho et al. Int J Cancer 2005 (SEER Database)
    7. 7. Changing Epidemiology of HNC – 1973-2001 Surveillance, Epidemiology and End Results (SEER) database evidence show that there is increasing incidence of both oral tongue and tonsil/base of tongue cancer. – Oral cancer (anterior tongue, floor of mouth, gingiva) remained stable or declined Cancer 2005 Shiboski et al.
    8. 8. New Facts: Disease Causation and HPV Oral Cavity OC & OP Figure 2Figure 1 Cancer 2005 Shiboski et al.
    9. 9. % of all HNSCCs that are Oropharynx 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 19 73 19 74 19 75 19 18% 76 19 77 19 78 19 79 19 80 19 81 19 82 19 83 19 84 19 85 19 86 19 87 19 88 19 89 19 90 19 Calendar year 91 19 92 19 93 19Chaturvedi A. J Clin Oncol 2008 94 19 95 risen from 28% in the 1970s 19 96 to 68% in this decade (>2000) 19 97 19 Proportion of tonsil cancers has 98 19 99 20 00 20 01 20 02 20 03 20 04 31% 20 05
    10. 10. A Increasing Problem – Oropharynx OP OPErnster JA. Laryngoscopy. 117:2115-2128;2007.
    11. 11. A Increasing Problem - OropharynxErnster JA. Laryngoscope. 117:2115-2128;2007.
    12. 12. Cancer and Sexually Associated infections: HPV?• HPV is well-known to be associated with the development of sexual- associated tumors of the uterine cervix and anogenital region• Schiffman M et al. Human papillomavirus and cervical cancer. The Lancet 2007•• Parkin DM. The global health burden of infection-associated cancers in the year 2002. International Journal of Cancer 2006• Could oropharyngeal cancer be due to sexually associated infection?
    13. 13. Association of HPV and OP SCC• Case-Control Study – 100 patients with new OP SCC – 200 control patients• Saline oral rinses with cytologic brushings• Serum samples• Histologic specimens – In situ hybridization for HPV-16 – PCR• Computer-assisted self-administered interviewD’Souza G. NEJM. 356(19):1944-1956;2007.
    14. 14. Association of HPV and OP SCCD’Souza G. NEJM. 356(19):1944-1956;2007.
    15. 15. Association of HPV and OP SCC• Serologic Markers – Seropositivity to HPV-16 L1 capsid (OR, 32.2; 95% CI, 14.6 to 71.3) – Oral HPV-16 infection (OR, 14.6; 95% CI, 6.3 to 36.6) – Oral HPV infection (Any of 37 types) (OR, 12.3; 95% CI, 5.4 to 26.4)D’Souza G. NEJM. 356(19):1944-1956;2007.
    16. 16. Association of HPV and OP SCC• Multivariate analysis associations with OPSCC – HPV-16 seropositivity (OR, 32.2; 95% CI, 14.6 to 71.3) – Poor dentition (OR, 4.1; 95% CI, 1.6 to 10.6) – Family Hx of HNSCC (OR, 5.4; 95% CI, 1.0 to 30.8) – Heavy tobacco use (OR, 2.5; 95% CI, 1.1 to 6.0)• 90% of cases of OPSCC• 55% attributable to HPV-16 alone! D’Souza G. NEJM. 356(19):1944-1956;2007.
    17. 17. Causal Association• 253 new or recurrent HNSCC• Consensus L1 PCR• E7 Type-Specific PCR• E6 Frame Sequencing• Southern Blot Hybridization• TP53 Sequencing• Histologic morphology (basaloid histology) Gillison ML. J Natl Cancer Inst. 92:709-720;2000.
    18. 18. Causal Association• HPV+ DNA in 62 / 253 (25%) of tumors – HPV 16 in 56 (90%)• Subsites (OR = 9.7, 95% CI = 4.2-22) – OP – 34/60 (57%) • 32 / 52 (62%) for tonsil/BOT – Larynx – 16/86 (19%) – OC – 10/84 (12%) – HP – 2/21 (10%)Gillison ML. J Natl Cancer Inst. 92:709-720;2000.
    19. 19. Causal Association• HPV+ tumors were more likely to have basaloid morphology – (OR = 19.8; 95% CI = 5.3 – 74)• In the oropharynx: – Poor tumor grade, basaloid morphology, & wild-type TP53 increased likelihood of HPV+ – TP53 mutations inversely associated with HPV+ (p=0.001)• HPV can be found in all cancer stages! – Pre-invasive, invasive, and lymph node metastasesGillison ML. J Natl Cancer Inst. 92:709-720;2000.
    20. 20. Human Papillomavirus (HPV)• Papillomaviridae• Non-enveloped• Circular double-stranded DNA – 7,000 – 8,000 base pairs• 45 – 55 nm• Keratinocytes
    21. 21. HPV• >100 known types• 90 types DNA sequenced• E6, E7, L1• Genome encodes – Two regulatory proteins (E1 & E2) – Three Oncoproteins (E5, E6, & E7) – Two structural capsid proteins (L1 & L2)• ♀ age 14-59 ~ 26.8% – HPV 16 ~1.5%• ♂ ~ 60% Paz IB. Cancer. 79(3):595-604;1997.
    22. 22. Incidence of HPV – Normal TissueErnster JA. Arch Oto Head Neck Surg. 135(6):554-557;2009.
    23. 23. Incidence of HPV – Normal TissueErnster JA. Arch Oto Head Neck Surg. 135(6):554-557;2009.
    24. 24. Systematic Review of HPV Status• Inclusion criteria – Specific HPV results – Minimum of 40 cases or 20 site-specific cases – PCR-based testing methods• 60 studies – 5,046 cases • 2,642 OC cases • 969 OP cases • 1,435 Larynx/HP cases Kreimer AR. Cancer Epidemiol, Biomark & Prevention. 14(2):467-475;2005.
    25. 25. Systematic Review of HPV Status• 26% of all HNSCC was HPV+ – 35.6% HPV+ in OP – 23.5% HPV+ in OC – 24.0% HPV+ in Larynx• HPV 16 accounted for: – 86.7% of HPV+ OP cancer – 68.2% of HPV+ OC cancer – 69.2% of HPV+ Laryngeal cancerKreimer AR. Cancer Epidemiol, Biomark & Prevention. 14(2):467-475;2005.
    26. 26. Systematic Review of HPV Status Oral Cavity Oropharynx Larynx/HP Kreimer AR. Cancer Epidemiol, Biomark & Prevention. 14(2):467-475;2005.
    27. 27. Different Pathophysiologic Entity
    28. 28. HPVVidal L. Hematol Clin N Am. 22:1125-1142;2008.
    29. 29. P53 and HPV• 66 patients with HNSCC• PCR of p53 genome• PCR of E6 and L1 for HPVHaraf DJ. Clin Cancer Research. 2:755-762;1996.
    30. 30. P53 and HPV• 24% had p53 mutation• 18% were HPV+• ONE patient was p53+/HPV+• Tonsil cancer – Strongly correlated with HPV+ status (p=0.0001) – Inversely correlated with p53 (p=0.03)• Trend toward heavier smoking in p53+ Haraf DJ. Clin Cancer Research. 2:755-762;1996.
    31. 31. HPV and Gene Expression in HNSCC• 36 HNSCC specimens• 8 / 36 (22%) were HPV+• Gene expression by Significance Analysis of Microarrays – 91 differentially expressed genes were highly statistically significant – Cyclin-dependent kinase inhibitor 2A (p16)! Slebos RJC. Clin Cancer Res. 12(3):701-709;2006.
    32. 32. HPV• Risk Factor Profile Risk factors for HPV infection are risk factors for HPV-positive HNSCC *number of lifetime vaginal/oral partners, casual sex, unprotected sex, STD *exposure to marijuana (increasing association with intensity and duration of marjuana use) Versus HPV-unrelated HNSCC whose associations are smoking, alcohol and poor oral hygiene Gillison M, D’Souza G, Westra W, et al; Distinct Risk Factors for Human Papillomavirus Type 16-Positive for Human Papillomavirus Type 16-Negative Head and Neck Cancers. J Natl Cancer Inst. 2008; 100: 407-420. D’Souza G, Kreimer A, Viscidi R, et al; Case-Control Study of Human Papillomavirus and Oropharyngeal Cancer. N Engl J Med. 2007; 356: 1944- 1956.
    33. 33. HPV• Prevention Natural history of HPV infection is unknown; routine screening for HPV-associated HNSCC not recommended. Preventive vaccines: immunogenic non-infectious virus-like particles *Gardasil (targets HPV 6, 11, 16 and 18) *cervatrix (targets 16 and 18) Recent report on adverse events after immunization (JAMA2009:302; 750) disproportionate reporting of syncope and venous thromboembolism Impact of the vaccines on incidence of persistent oral HPV infection not investigated (yet!)
    34. 34. Two Different Kinds of HNC? HPV-positive HPV-negativeAnatomic site Tonsil / BOT All sitesHistology PD, Basaloid KeratinizedAge Younger OlderGender 3:1 men 3:1 menStage Tx, T1-2 variableRisk factors Sexual behavior Alcohol / tobaccoCofactors Marijuana Oral hygiene immunosuppresion?Incidence Increasing DecreasingSurvival Improved Unchanging
    35. 35. Risk Factors for HPV+ Head and Neck Cancer Tobacco Alcohol Dentition Oral Sex Marijuana 20 trend p=0.60 trend p=0.45 trend p=0.39 trend trend p=0.008 p=0.002 for HPV-Positive Cancer 10 Adjusted Odds Ratio 5 HPV + 2 1 0.5 0.25 20 trend p<0.001 trend p=0.015 trend p=0.002 trend p=0.49 trend p=0.38 for HPV-Negative Cancer 10 Adjusted Odds Ratio 5 HPV - 2 1 0.5 0.25 NS 1 -2 0 2 1 -5 0 > 5 0 ND 0 -2 0 2 1 -4 0 > 4 0 No n e S o m e A l l 0 1 -5 6 -1 5 > 1 5 0 1 -4 5 -1 4 > 1 4 Number of Number of Number of Number of Lifetime Number of Pac k -Years Drink -Years Teeth Los t Oral Sex Partners Marijuana-YearsOdds ratios adjusted for age, gender, race, tobacco, alcohol, oral hygiene, marijuana and oral sex, as appropriateGillison M et al, JNCI. 2008
    36. 36. HPV and HNC: The Role of Surgery• Rich, et.al. Transoral Laser Microsurgery (TLM) + Adjuvant Therapy for advanced stage oropharyngeal cancer. Laryngoscope 119:1709-19, 2009.  84 pts with Stage III/IV oropharyngeal cancer treated with TLM. p 16 overexpression seen in 69 pts.  Had significantly higher overall survival.
    37. 37. HPV and HNC: In the Larynx?• Baumann, et al. HPV in early laryngeal carcinoma. Laryngoscope 119:1531-37, 2009 38 cases of T1 glottic cancer eval for HPV using PCR technique – HPV detected in 6/38 lesions; subtypes 16 (2), 26, 31, 39, 52 P16 detected in 10 cases. Pts were younger in age and less likely to have smoking history More favorable clinical course 1/6 HPV+ patients recurred vs. 14/29 HPV- patients (NS)
    38. 38. HPV and HNC: Prognosis• Sedaghat et al. Prognostic Significance of HPV in oropharyngeal Squamous cell carcinomas. Laryngoscope 119:1542-49, 2009. – 49 patients with oropharyngeal carcinoma treated with the same concurrent chemoradiation protocol. HPV DNA detected with ISH; *found in 26/49 patients **Pts with HPV+ status estimated to have 86% reduction in risk of recurrence c/w pts with HPV- tumors. (multivariable analysis)
    39. 39. Original Article Case-Control Study of Human Papillomavirus and Oropharyngeal CancerGypsyamber DSouza, Ph.D., Aimee R. Kreimer, Ph.D., Raphael Viscidi, M.D., MichaelPawlita, M.D., Carole Fakhry, M.D., M.P.H., Wayne M. Koch, M.D., William H. Westra, M.D., and Maura L. Gillison, M.D., Ph.D. N Engl J Med Volume 356(19):1944-1956 May 10, 2007
    40. 40. Study Overview• This study offers persuasive evidence of a strong association between exposure to or oral infection with the human papillomavirus and oropharyngeal cancer• The data indicate that sexual behaviors can spread the virus to the oral cavity• The use of tobacco, alcohol, or both did not strengthen the association between exposure to HPV and oropharyngeal cancer• Among patients who had no evidence of exposure to HPV, however, tobacco and alcohol use were strongly associated with oropharyngeal cancer
    41. 41. Associations of Oropharyngeal Cancer with Sexual Behaviors DSouza G et al. N Engl J Med 2007;356:1944-1956
    42. 42. Association of Oropharyngeal Cancer with Exposure to HPV and with Biomarkers of Cancer Associated with HPV-16 DSouza G et al. N Engl J Med 2007;356:1944-1956
    43. 43. Odds Ratios for Associations of Oropharyngeal Cancer with Tobacco Use, Alcohol Use, Seropositivity for HPV-16, and Oral Infection with HPV-16 DSouza G et al. N Engl J Med 2007;356:1944-1956
    44. 44. Representative Case of Oropharyngeal Squamous-Cell Carcinoma That Was Positive for HPV- 16 on In Situ Hybridization DSouza G et al. N Engl J Med 2007;356:1944-1956
    45. 45. Conclusion• Oral HPV infection is strongly associated with oropharyngeal cancer among subjects with or without the established risk factors of tobacco and alcohol use
    46. 46. Prognosis
    47. 47. ECOG 2399• Phase II trial of organ preservation• Stage III or IV – (T2N1-2 or T3-4N0-3M0) resectable SCC of the – OP or larynx• 96 patients enrolled 2 cycles of induction paclitaxel & carboplatin CR / PR 7 weekly IV doses of paclitaxel 30 No PR mg/m2 + 70 Gy in 35 fractions in 7 weeks Surgical Resection Fakhry C. JNCI. 100(4):261-269;2008.
    48. 48. ECOG 2399• Lab Analysis – Presence of basaloid features • 0 = absent • 1= present but partially developed • 2 = fully developed – HPV detection • PCR – p16 IHC • Present or AbsentFakhry C. JNCI. 100(4):261-269;2008.
    49. 49. ECOG 2399• 38 / 96 (40%) were HPV+ – 36 were HPV 16 – 1 was HPV 33 – 1 was HPV 35• 38 / 60 (63%) OP tumors were HPV+• HPV + tumors – Poorly differentiated (p=0.03) – Basaloid features (p<0.001)• Similar differences in OP tumorsFakhry C. JNCI. 100(4):261-269;2008.
    50. 50. ECOG 2399• Response rates to chemo / chemoXRT HPV+ HPV- P Value Induction 82% 55% 0.01 ChemoChemoXRT 84% 57% 0.007Fakhry C. JNCI. 100(4):261-269;2008.
    51. 51. Overall Survival (OS) Progression Free Survival (PFS) Entire Study Population Overall Survival (OS) Progression Free Survival (PFS) Oropharynx Cancer OnlyFakhry C. JNCI. 100(4):261-269;2008.
    52. 52. ECOG 2399• Multivariate Analysis  HPV+ tumors had a 64% lower risk of death (p=0.02)  HPV+ tumors had a 73% lower risk of progression (p=0.01)• Restricted to OP SCC  HPV+ tumors had a 61% lower risk of death (p=0.06)  HPV+ tumors had a 62% lower risk of progression (p=0.09)Fakhry C. JNCI. 100(4):261-269;2008.
    53. 53. Surgically Treated OP SCC• 100 consecutive OP SCC treated with Sx• 65% postop XRT• P53 mutation• HPV 16 & 18 PCR – HPV+/TP53wt – HPV-/TP53wt – HPV±/TP53mut Licitra L. JCO. 36(24):5630-5636;2006.
    54. 54. Surgically Treated OP SCC Overall Survival Incidence of RelapseLicitra L. JCO. 36(24):5630-5636;2006.
    55. 55. Surgically Treated OP SCCSecond Primary Tumors OS HPV vs. XRTLicitra L. JCO. 36(24):5630-5636;2006.
    56. 56. RTOG 0129• 743 enrolled• Restricted to 433 OP cancers• Overall survival• Progression-free survival• HPV status determined in 323/433 (74.6%)• Median 4.8 year follow-up• Accelerated-fractionation vs. standard- fractionation radiotherapy Ang KK. NEJM. 363(1):24-36;2010.
    57. 57. RTOG 0129HPV + tumors • 58% reduction in the risk of death • 51% reduction in the risk of relapse or death Ang KK. NEJM. 363(1):24-36;2010.
    58. 58. RTOG 0129Overall Survival Progression-free Survival•P16 overexpression positive – 83.6% •P16 overexpression positive – 74.4%•P16 overexpression negative – 51.3% •P16 overexpression negative – 38.4% Ang KK. NEJM. 363(1):24-36;2010.
    59. 59. Meta-Analysis of Survival• 37 studies evaluated• 23 studies included in the meta-analysis• 14 excluded due to lack of complete dataRagin CCR. Int J Cancer. 121:1813-1820;2007.
    60. 60. Meta-Analysis of Survival• HPV+ HNSCC – 18% lower risk of dying (HR=0.85, 95% CI: 0.7-1.0) – 38% lower risk of disease failure (HR=0.62, 95% CI: 0.5- 0.8)• HPV+ OPSCC – 28% reduced risk of death (HR=0.72, 95% CI: 0.5-1.0) – 49% lower risk of disease failure (HR=0.52, 95% CI: 0.4- 0.7) Ragin CCR. Int J Cancer. 121:1813-1820;2007.
    61. 61. Meta-Analysis of Survival• HPV+ Non-OP HNSCC – No difference in the risk of death (HR=0.79, 95% CI: 0.5- 1.3)• HPV+ Laryngeal SCC – 2 times greater risk of death (HR=2.45, 95% CI: 0.3-23.6) Ragin CCR. Int J Cancer. 121:1813-1820;2007.
    62. 62. Summary• The rate of OP cancer is on the rise• 20-25% of HNSCC is HPV+• 40-65% of OP SCC is HPV+ – Highest in Palatine and Lingual Tonsils• HPV 16 predominates – HPV 18, 31, 33, & 35 found in varying amounts• OS and DFS better in HPV+ HNSCC, probably regardless of treatment – Surgery – XRT – Chemo-XRT• Changes in staging and treatments?
    63. 63. References1. Paz IB. Cancer. 79(3):595-604;1997.2. Shiboski CH. Cancer. 103(9):1843-1849;2005.3. Loning T. J Invest Dermatol. 84:417-420;1985.4. Vidal L. Hematol Clin N Am. 22:1125-1142;2008.5. Ernster JA. Laryngoscopy. 117:2115-2128;2007.6. Chaturvedi AK. J Clin Oncol. 26(4):612-619;2008.7. Ernster JA. Arch Oto Head Neck Surg. 135(6):554-557;2009.8. Ringström E. Clinical Cancer Research. 8:3187-3192;2002.9. D’Souza G. NEJM. 356(19):1944-1956;2007.10. Hobbs CGL. Clin Otolaryngol. 31:259-266;2006.11. Kreimer AR. Cancer Epidemiol, Biomark & Prevention. 14(2):467-475;2005.12. Haraf DJ. Clin Cancer Research. 2:755-762;1996.13. Smith EM. Cancer Epidemiol Biomarkers Prev. 17(2):421-427;2008.14. Slebos RJC. Clin Cancer Res. 12(3):701-709;2006.15. Gillison ML. J Natl Cancer Inst. 92:709-720;2000.16. Ragin CCR. Int J Cancer. 121:1813-1820;2007.17. Fakhry C. JNCI. 100(4):261-269;2008.18. Devaraj K. Crit Rev Oral Biol Med. 14(5):345-362;2003.19. Lee DW. Arch Oto HNS. 134(12):1316-1323;200820. Psyrri A. Cur Opin Oncol. 21:201-205;2009.
    64. 64. 1. Hausen H; Papillomavirus in the Causation of Human Cancers- A Brief Historical Account. Virology. 2009; 384: 260-265.2. Fakhry C, Gillison M; Clinical Implications of Human Papillomavirus in Head and Neck Cancers. J Clin Oncol. 2006; 24: 2606-2611 .3. Gillison M; Human Papillomavirus and Prognosis of Oropharyngeal Squamous Cell Carcinoma: Implications for Clinical Research in Head and Neck Cancers. J Clin Oncol. 2006; 24: 5623-5625.4. Begum S, Gillison M, Nicol T, et al; Detection of Human Papillomavirus-16 in Fine-Needle Aspirates to Determine Tumor Origin in Patients with Metastatic Squamous Cell Carcinoma of the Head and Neck. Clin Cancer Res. 2007; 13: 1186-1191.5. Chaturvedi A, Engels E, Anderson W, et al; Incidence Trends for Human Papillomavirus-Related and-Unrelated Oral Squamous Cell Carcinomas in the United States. J Clin Oncol. 2008; 26: 612- 619.6. Fakhry C, Westra W, Li S, et al; Improved Survival of Patients with Human Papillomavirus- Positive Head and Neck Squamous Cell Carcinoma in a Prospective Clinical Trial. J Natl cancer Inst. 2008; 100: 261-269.
    65. 65. 7. Gillison M, D’Souza G, Westra W, et al; Distinct Risk Factors for Human Papillomavirus Type 16-Positive for Human Papillomavirus Type 16-Negative Head and Neck Cancers. J Natl Cancer Inst. 2008; 100: 407-420.8. Weinberger P, Yu Z, Haffty B, et al; Molecular Classification Identifies a Subset of Human Papillomavirus-Associated Oropharyngeal Cancers with Favorable Prognosis. J Clin Oncol. 2006; 24: 736-747.9. Psyrri A, Gouveris P, Vermorken J; Human Papillomavirus-Related Head and Neck Tumors: Clinical and Research Implication; Curr Opin Oncol. 2009; 21: 201-205.10. Shiboski C, Schmidt B, Jordan R; Tongue and Tonsil Carcinoma: Cancer. 2005; 103: 1843- 1849.11. D’Souza G, Kreimer A, Viscidi R, et al; Case-Control Study of Human Papillomavirus and Oropharyngeal Cancer. N Engl J Med. 2007; 356: 1944-1956.12. Termine N, Panzarella V, Falaschini S, el al; HPV in Oral Squamous Cell Carcinoma VS Head and Neck Squamous Cell Carcinoma Biopsies: a Meta-Analysis (1988-2007). Ann Oncol. 2008; 19: 1681-1690.
    66. 66. 13.Goldenberg D, Begum S, Westra W, et al; Cystic Lymph Node Metastasis in Patients with Head and Neck Cancer: An HPV-Associated Phenomenon. Head Neck. 2008; 30: 898-903.14. Ragin C, Taioli E; Second Primary Head and Neck Tumor Risk in Patients with cervical Cancer-Seer Data Analysis. Head Neck. 2008; 30: 58-66.15. Chen R, Aaltonen L, Vaheri A; Human Papillomavirus Type 16 in Head and Neck Carcinogenesis. Rev Med Virol. 2005; 15: 351-363.16. Slade B, Leidel L, Vellozzi C; Postlicensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine. JAMA. 2009; 302: 750-757

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