Understanding the recent epidemic of HPV related oropharynx cancer

1. HPV Infection and Cancer of the
Oropharynx
Non-HPV = Yellow, HPV = blue
Robert Miller MD
www.aboutcancer.com
Watch the video at https://youtu.be/ISyagHODIvY

2. HPV = Human Papillomavirus
Most HPV infections don't lead to cancer but certain types of HPV infection cause
cancers. More than 100 varieties of human papillomavirus (HPV) exist.
HPV is a very common virus; nearly 80 million people—about one in four—are
currently infected in the United States.

3. Dramatic Rise in HPV +
Tonsil Cancer
HPV Most Common
Smoking Less Common

4. Human Papillomavirus and Rising
Oropharyngeal Cancer Incidence in the
United States
JCO November 10, 2011 vol. 29 no. 32 4294-4301

5. Cancers caused by HPV
• Cervix 100%
• Anal 95%
• Oropharynx 70%
• Vaginal 65%
• Vulva 50%
• Penis 5%
In the US , 3% of all cancers in women and 2% of all cancers in men

6. Estimated average
annual percentage and
estimated number of
cancers attributable to
human papillomavirus
(HPV),* by anatomic site
and sex — United
States, 2008–2012
MMWR Weekly / July
8, 2016 /
65(26);661–666

7. Vaccine to Prevent HPV
Since mid-2006, a licensed human papillomavirus (HPV) vaccine has
been available and recommended
CDC analyzed data from the 2007–2013 National Immunization Survey-
Teen (NIS-Teen) and national post licensure vaccine safety data among
females and males.
Vaccination coverage with ≥1 dose of any HPV vaccine increased
significantly from 53.8% (2012) to 57.3% (2013) among adolescent girls
and from 20.8% (2012) to 34.6% (2013) among adolescent boys.
MMWR July 25, 2014 / 63(29);620-4

9. Human papillomavirus (HPV) vaccines. Administer a 3-dose series of HPV
vaccine on a schedule of 0, 1-2, and 6 months to all adolescents aged 11
through 12 years. The vaccine series may be started at age 9 years,
Catch-up vaccination:
Administer the at age 13 through 18 years if not previously vaccinated.
Use recommended routine dosing intervals (see above) for vaccine series
catch-up.

10. HPV Types

11. HPV Prevalence
In the general population, the overall prevalence of HPV DNA in oral
exfoliated cells was 6.9 percent, and the prevalence of HPV-16 was 1
percent. HPV prevalence was approximately three-fold more common
in men compared with women (10.1 versus 3.6 percent)
presence of HPV in patients with HPV associated oropharyngeal cancer
and their long-term sexual partners. In the 164 patients with
oropharyngeal cancer, oral HPV was detected in 65 percent of cases,
and an oncogenic HPV strain was identified in 61 percent
Among the 93 partners available for testing, the overall incidence of
HPV infection was 4 percent, and only one had the oncogenic HPV-16.
These findings suggest that most partners effectively clear any active
infection to which they are exposed.

12. HPV + By Cancer Site
Oropharynx Cancer 40.6% , 22.4%
Oral Cavity Cancer 14.9%, 4.4%
Larynx Cancer 13.4%, 3.5%
Oropharynx = tonsil, base of tongue, pharyngeal wall, soft palate
Oral Cavity = buccal mucosa, floor mouth, anterior tongue, hard palate
studies from the 1990s suggested that approximately 50 percent of
oropharyngeal cancers were attributable to HPV, while more recent studies
suggest that HPV accounts for 70 to 80 percent of cases in North America
and Europe

13. TonsilTonsil
Base of
Tongue

14. Oropharynx (base of tongue or
tonsil)

15. How HPV causes cancer
Human papillomavirus (HPV) is a small deoxyribonucleic
acid (DNA) virus of approximately 7900 base pairs.
Of the genes contained in the virus are viral oncogenes
E6 and E7 which have transforming properties by their
interaction with growth-regulating host cell proteins
E6 interferes with the p53 protein that normally regulates
growth, and E7 interferes with Rb protein which also
normally regulates growth.
When Rb protein is knocked out, another regulatory
protein (p16) is overexpressed (i.e. increased)

16. Using P16 or HPV
Either HPV status or p16 status can be used as a marker of HPV
infection. In one multi-institutional trial Ten percent of those positive by
p16 were negative for HPV, and 7 percent of those negative for p16
were positive for HPV.
However, studies using p16 (tumor suppressor protein) as a surrogate
marker for HPV positivity appear to have demonstrated a similar impact
on survival.
The p16 status, as assessed by immunohistochemistry, may provide
additional information beyond HPV positivity. In a study comparing the
effect of p16 expression and HPV DNA presence, cases that were HPV
positive with high p16 expression had a better prognosis than those that
were HPV positive but with low expression.

17. Human Papillomavirus (HPV) infection of
epithelial cells.
HPVs infect basal cells of squamous epithelia through sites of mechanical trauma.
Infections with high-risk HPVs can lead to dysplasia and carcinoma in situ and to
invasive squamous cell carcinoma. Progression is a rare and slow process and
many lesions regress spontaneously.

18. HPV and Oropharyngeal
Cancer
Latency from infection:
Cervix (29 years) peak infection (20y) to
cancer (49y)
HPV (10-30y) peak infection (25-30 and
55-60) and cancer 58y
HPV Vaccine impact expected by 2050

19. Latency from Infection to Cancer

20. Site Male Female
Tongue 11,700 4,400
Mouth 7,600 5,310
Pharynx 13,350 3,070
Oral (other) 2,130 770
New Cancer Cases in the US
in 2016

21. Age: 10 y younger on one study median age 57
(versus 61 for HPV -)
Gender: 76% male
Smaller primary: T1/T2 64% (versus 44% for
HPV -)
More Neck Nodes: N2/N3 in 69% (versus 51%
for HPV -)
Less likely to have a second primary: 6% versus
13%

22. Most Common in White Men

23. Median Age for Women is 62

24. Median Age for Men is 59

25. Typical smoking related
oropharynx cancer, presented with
months of throat pain radiating into
ear

26. In HPV + cancers the primary may
be small and hard to see
Squamous Cell Carcinoma. This human
papillomavirus-positive tumor presented as a diffuse
erythroplakia of the left soft palate and tonsillar
region.

27. Oropharynx Symptoms Based
on HPV Status
HPV + HPV –
Neck mass (51%) Sore Throat (53%)
Sore Throat (28%) Dysphagia (41%)
Dysphagia (10%) Neck Mass (18%)

28. 50 yo non-smoker, white male present with a
lump in his left neck and the PET scan as noted

29. Typical Imaging for HPV Oropharynx Cancer
CT = large cystic node metastases PET = large neck
mass with small primary in tonsil

30. CT Scan Typical HPV + Patient
Large, Lobulated
neck mass of
lymph nodes
with no obvious
primary source
Neck biopsy =
squamous

31. Ultrasound Typical HPV + Patient
Large, Lobulated
neck mass of
lymph nodes
with no obvious
primary source

32. PET Scan Typical
HPV + Patient
Large lymph
node
metastases in
the neck with
no obvious
primary
source

33. Small cancer in
left base of
tongue
Large, necrotic
lymph node
mass
Stage IVA
Squamous
Cancer Left Base
of Tongue, HPV +

34. HPV Oropharynx Cancer
50 yo man, non-smoker presented with cystic neck
nodes and occult primary in the base of tongue

35. HPV Oropharynx Cancer
53 yo man
with large
cystic neck
node and
occult
primary in
base of
tongue

36. HPV Tonsil Cancer
63 yo non-
smoker man
presents with
neck mass
and small
lesion in tonsil
He was non-
smoker
Bx =
squamous
ISH = high risk
HPV
IVA (T1N2b)

37. HPV Tonsil Cancer

38. 53 yo non-smoker
presents with a
painless lump in the
neck and no symptoms
inside his throat. On
exam 3-4 cm right
cervical node and right
tonsil ? firm

39. PET-CT = hot, cystic neck node and small lesion in tonsil
Path = squamous cancer, HPV +

40. Survival for Tonsil Cancer
HPV +
HPV -

41. Long-term prognosis and risk factors among
patients with HPV-associated
oropharyngeal squamous cell carcinoma
Cancer
Volume 119, Issue 19, pages 3462–3471, 1 October 2013
patients with human papillomavirus
(HPV)-associated oropharyngeal
squamous cell carcinoma (HPV-OSCC)
HPV-OSCC who received treatment at the
Johns Hopkins Hospital between 1997
and 2008 and who had tissue available
for HPV testing

42. Long-term prognosis and risk factors among
patients with HPV-associated
oropharyngeal squamous cell carcinoma
Cancer
Volume 119, Issue 19, pages 3462–3471, 1 October 2013
In total, 157 of 176 patients (90%) with
OSCC had HPV-associated disease (HPV-
OSCC).
In the patients with HPV-OSCC, the 3-
year and 5-year OS rates were 93% and
89% respectively.

43. Trials of Oropharynx Cancer
Improved Survival with HPV +
Author Survival HPV + HPV –
Ang 82%/3y 57%/3y
Ang 86%/3y 60%
Gillison 49%/5y 19.6%
Posner 82%/5y 35%
Rischin 91%/2y 74%
Cancer Control July 2016, Vo.23, No 3

44. Effect of HPV-Associated p16INK4AExpression on Response
to Radiotherapy in Squamous Cell Carcinoma of the Head and
Neck
JCO April 20, 2009 vol. 27 no. 12 1992-1998
Local Control

45. JCO April 20, 2009 vol. 27 no. 12 1992-1998
Overall Survival

46. Better Survival Out To 10 Years
JCO June 10, 2012 vol. 30 no. 17 2102-2111
Non-smokers
smokers
SURVIVAL
Years

47. www.NCCN.org

48. Chemotherapy
plus radiation
(cisplatin or
erbitux + 70Gy)

49. As of 2016 the
NCCN
guidelines do
not recommend
treating HPV +
patients with
less intense
therapy

50. parotid
parotid
cancer in tonsil
cancer in nodes
Radiation zone
brain
Typical Radiation Field for Cancer
in Right Oropharynx
Part of the radiation includes the obvious cancer and other lymph node sites in the
next but tries to spare normal structures like the parotid and brain

51. Quick Response to Radiation
combined with chemotherapy, Tonsil
cancer gone by 2 ½ weeks
Squamous
Tonsil Cancer
2.5 weeks after
chemoradiation

52. Chemoradiation for Tonsil
Cancer

53. Chemoradiation
JCO September 20, 2010 vol. 28 no. 27 4142-4148
HPV +
HPV -

54. Local Control Very High with Erbitux +
XRT in HPV + Patients

55. Survival Very High with Erbitux + XRT
in HPV + Patients

56. Standard Stage System (AJCC
7th)

57. Standard Stage System (AJCC
7th)

58. Standard Stage System (AJCC
7th)

59. Standard Stage System (AJCC
7th)
Single
node
and
stage III

60. Standard Stage System (AJCC
7th)
Nodes
and
Stage
IVa

61. Superior Cure Rates if HPV +
JCO March 10, 2015 836-845
5 Year Survival
HPV +
HPV -

62. Survival with Oropharynx
Cancer if HPV +
JCO March 10, 2015 836-845

63. JCO March 10, 2015 836-845
Survival with Oropharynx
Cancer if HPV -

64. 5 Year Survival in 1907 patients with
HPV+ oropharyngeal cancer
Stage I: 88% II: 82% , III: 84%, and IVA:
81%, IVB: 60%
5-year overall survival did not differ among N0 (80%) N1–
N2a (87%), and N2b (83%) subsets, but was significantly
lower for those with N3 disease (59% )
So need to change the staging system (only deeply invasive
T4b or huge nodes (N3 > 6cm) do poorly
Lancet Oncology Volume 17, No. 4, p440–451, April 2016

65. Survival Related to HPV, Stage and
Smoking

66. Survival if HPV +
based on smoking (PY = pack years) age and stage
JCO March 10, 2015 836-845

67. Survival for HPV + Using Nasopharyngeal Node Categories for Staging. Series of 661 from MD
Anderson, stage I disease into two groups: stage IA, defined as T1, N0-N2; and stage IB, defined
as T2, N0-N2. Stage II would be defined as T1-T2, N3 or T3, N0-N3; stage III would be defined as
T4 regardless of nodal involvement, and stage IV would be all M1 tumors
Dahlstrom JCO 2016;34:183
Overall Survival
Months

68. New ICON-S staging system was
proposed for patients with HPV
positive oropharyngeal cancer
Stage TNM 5 Year Survival
Stage I T1-2N0-1 85-88%
Stage II T3 or N2 78-81%
Stage III T4 or N3 53-65%

69. Short Term Side Effects of Radiation to
the Throat and Neck
1. Skin irritation
2. Dry Mouth and changes in taste
and possible problems with teeth
3. Sore throat and problems with
swallowing and dehydration and
possible need for a feeding tube
4. Pain management problems
5. Laryngitis
6. Fatigue

70. Long Term Side Effects of Radiation to
the Throat and Neck
1. The dryness may be permanent,
depending on the amount of saliva
glands in the field
2. Teeth may be vulnerable to decay,
and caution is need with future dental
care to avoid jaw bone problems
(osteonecrosis)
3. Problems with swallowing
4. Persistent hoarseness
5. Small risk of low thyroid
6. Carotid stenosis

71. Because of the favorable outcome for HPV patients and the
severity of side effects of standard chemoradiation, there are
numerous research trials on going to see if less intensive
treatment will be effective using a lower dose of chemotherapy or
radiation
Toxicity from High Dose Chemo-Radiation
Large Tonsil cancer Last Day of Treatment

73. De-Escalation Trials for HPV…Can we use less
chemotherapy or lower dose radiation and get the
same result with less toxicity?

74. Cancer Control July 2016, Vo.23, No 3

75. Cancer Control July 2016, Vo.23, No 3

76. Cancer Control July 2016, Vo.23, No 3

78. Cancer Control July 2016, Vo.23,
No 3

79. Projected Numbers of New Cases in
the Future
Oropharynx (all)
Oropharynx (men)
Cervix)
Oropharynx
(women)

80. Projected Numbers of New Cases in
the Future
Oropharynx
Oral Cavity
Larynx
Other pharynx
Calendar Year

81. HPV Infection and Cancer
of the Oropharynx
1.Prevention: get kids vaccinated
2.Diagnosis: younger white men
with a lump in the neck
3.Treatment: very high cure rates
with modern chemo-radiation and
perhaps with less intense therapy
in the future.