The document discusses the association between human papillomavirus (HPV) and head and neck squamous cell carcinoma (HNSCC), detailing its increasing incidence, particularly in oropharyngeal cancer. It outlines the objectives of understanding HPV prevalence, identifying high-risk serotypes, and recognizing the prognostic significance of HPV-related HNSCC. Furthermore, it highlights the differences in risk factors and outcomes between HPV-positive and HPV-negative cancers, emphasizing the role of sexual behaviors in HPV transmission.

1. The American Head & Neck Society
Human 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. 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. Objectives
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.

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. 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 deaths
Paz IB. Cancer. 79(3):595-604;1997.

6. Trends in Survival According to Tumor
Site and Year of Diagnosis
Oropharynx

Carvalho et al. Int J Cancer 2005 (SEER Database)

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. New Facts: Disease Causation and HPV
Oral Cavity OC & OP
Figure 2
Figure 1
Cancer 2005 Shiboski et al.

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
19
Chaturvedi 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. A Increasing Problem – Oropharynx
OP
OP
Ernster JA. Laryngoscopy. 117:2115-2128;2007.

11. A Increasing Problem - Oropharynx
Ernster JA. Laryngoscope. 117:2115-2128;2007.

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. 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 interview
D’Souza G. NEJM. 356(19):1944-1956;2007.

14. Association of HPV and OP SCC
D’Souza G. NEJM. 356(19):1944-1956;2007.

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. 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. 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. 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. 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 metastases
Gillison ML. J Natl Cancer Inst. 92:709-720;2000.

20. Human Papillomavirus (HPV)
• Papillomaviridae
• Non-enveloped
• Circular double-stranded DNA
– 7,000 – 8,000 base pairs
• 45 – 55 nm
• Keratinocytes

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. Incidence of HPV – Normal Tissue
Ernster JA. Arch Oto Head Neck Surg. 135(6):554-557;2009.

23. Incidence of HPV – Normal Tissue
Ernster JA. Arch Oto Head Neck Surg. 135(6):554-557;2009.

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. 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 cancer
Kreimer AR. Cancer Epidemiol, Biomark & Prevention. 14(2):467-475;2005.

26. Systematic Review of HPV Status
 Oral Cavity
 Oropharynx
 Larynx/HP
Kreimer AR. Cancer Epidemiol, Biomark & Prevention. 14(2):467-475;2005.

27. Different Pathophysiologic Entity

28. HPV
Vidal L. Hematol Clin N Am. 22:1125-1142;2008.

29. P53 and HPV
• 66 patients with HNSCC
• PCR of p53 genome
• PCR of E6 and L1 for HPV
Haraf DJ. Clin Cancer Research. 2:755-762;1996.

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. 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. 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. 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. Two Different Kinds of HNC?
HPV-positive HPV-negative
Anatomic site Tonsil / BOT All sites
Histology PD, Basaloid Keratinized
Age Younger Older
Gender 3:1 men 3:1 men
Stage Tx, T1-2 variable
Risk factors Sexual behavior Alcohol / tobacco
Cofactors Marijuana Oral hygiene
immunosuppresion?
Incidence Increasing Decreasing
Survival Improved Unchanging

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-Years
Odds ratios adjusted for age, gender, race, tobacco, alcohol, oral hygiene, marijuana and oral sex, as appropriate
Gillison M et al, JNCI. 2008

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. 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. 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. Original Article
Case-Control Study of Human Papillomavirus and
Oropharyngeal Cancer
Gypsyamber D'Souza, Ph.D., Aimee R. Kreimer, Ph.D., Raphael Viscidi, M.D., Michael
Pawlita, 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. 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. Associations of Oropharyngeal Cancer with Sexual Behaviors
D'Souza G et al. N Engl J Med 2007;356:1944-1956

42. Association of Oropharyngeal Cancer with Exposure to HPV and with Biomarkers of Cancer
Associated with HPV-16
D'Souza G et al. N Engl J Med 2007;356:1944-1956

43. Odds Ratios for Associations of Oropharyngeal Cancer with Tobacco Use, Alcohol Use,
Seropositivity for HPV-16, and Oral Infection with HPV-16
D'Souza G et al. N Engl J Med 2007;356:1944-1956

44. Representative Case of Oropharyngeal Squamous-Cell Carcinoma That Was Positive for HPV-
16 on In Situ Hybridization
D'Souza G et al. N Engl J Med 2007;356:1944-1956

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. Prognosis

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. 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 Absent
Fakhry C. JNCI. 100(4):261-269;2008.

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 tumors
Fakhry C. JNCI. 100(4):261-269;2008.

50. ECOG 2399
• Response rates to chemo / chemoXRT
HPV+ HPV- P Value
Induction 82% 55% 0.01
Chemo
ChemoXRT 84% 57% 0.007
Fakhry C. JNCI. 100(4):261-269;2008.

51. Overall Survival (OS) Progression Free Survival (PFS)
Entire Study Population
Overall Survival (OS) Progression Free Survival (PFS)
Oropharynx Cancer Only
Fakhry C. JNCI. 100(4):261-269;2008.

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. 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. Surgically Treated OP SCC
Overall Survival Incidence of Relapse
Licitra L. JCO. 36(24):5630-5636;2006.

55. Surgically Treated OP SCC
Second Primary Tumors OS HPV vs. XRT
Licitra L. JCO. 36(24):5630-5636;2006.

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. RTOG 0129
HPV + 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. RTOG 0129
Overall 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. Meta-Analysis of Survival
• 37 studies evaluated
• 23 studies included in the meta-analysis
• 14 excluded due to lack of complete data
Ragin CCR. Int J Cancer. 121:1813-1820;2007.

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. 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. 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?

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