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UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
UICC
HPV andCERVICALCANCERCURRICULUM
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
01 Chapter 3.
The role of HPV
Ahti Anttila PhDResearch Director, Finnish Cancer Registry
Helsinki, Finland
Harri Vertio MD, PhDSecretary general, Cancer Society of Finland
Helsinki, Finland
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
02 Papillomavirus (1)
• Non-enveloped DNA viruses with capsid coat
• Generally targets epithelia
• Widely distributed in higher vertebrates
- Tight species specificity
• Broad range of papillomavirus types
- ~200 types found in animals and humans
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
03 Papillomavirus (2)
• Detection and typing is based on nucleic acid sequence
- New type: >10% sequence variation
- Subtype: 2-10% sequence variation
- Variant: <2% sequence variation
• Types are assigned a sequential number based on order
of discovery
- No relation to phylogeny
• Double-stranded, ~8kb, static
- Recombination and mutations are rare events
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
04 Human papillomavirus
• Early region (6 ORF): E6 and E7 transforming oncoprotein;
others are required for viral replication
• Late region: encodes for 2 viral capsid proteins; L1 ORF =
most conserved and used for identification of new types
• Upstream regulatory region: sequences that control
transcription of the viral genome
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
05 Infectious cycle of HPV
Viral DNA amplification
in non-dividing cells
Virus infects a primitive
basal keratinocyte at low
(<10) copies/cell
Virus and cell
replicate together
Viral genomes at
1000’s per cell
Dividing cells
Only E genes
expressed
Very low levels
of protein made
Differentiated cells
E and L viral
genes expressed
Virus particles
assembled
Virus-laden cells ready for
desquamation and infection
of naïve individual
No viraemia, no cytolysis or death, long infectious cycle
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
06 Human papillomavirus
• Differing affinities for site of infection
- Cutaneous: keratinised squamous epithelium
- Mucosal: non-keratinised epithelium
• Types
- Low-risk (HPV 6, 11, 42, 43, 44): mainly in low-grade
lesions, condyloma
- High-risk (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56,
58, 59 and 68): mainly in high grade lesions and cancer
- Other possible HR types include HPV 26, 53, 66, 73, 82
- Species: minimal differences of the DNA sequence may
affect cross-protection
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
07 EpidemiologyHigh-risk and low-risk HPV infections
Cancer cases attributed to the
most frequent HPV genotypes (%)
HPV
genoty
pe
2.3
2.2
1.4
1.3
1.2
1.0
0.7
0.6
0.5
0.3
1.2
4.4
53.5
2.6
17.26.7
2.9
0 10 20 30 40 50 60 70 80 90 100
X
Other
82
73
68
39
51
56
59
35
58
52
33
31
45
18
16
Adapted from Muñoz N et al. Int J Cancer 2004; 111: 278–85.
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
08Risk of cervical cancer by HPV type
0.1 10 100 1000 10,000
Negative
16
18
45
31
52
33
58
35
59
51
6
11
Odds Ratio (95% confidence interval)
Adapted from Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527.
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
09HPV and cancer: increased risk
Cancer Relative risk
Lung cancer - smoking 10
Liver cancer - HCV 20
Liver cancer - HBV 50-100
Cervical cancer – HPV* 300-500
* Risk associated with persistent oncogenic HPV infection
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
10HPV prevalence by region
14.6
3.7
6.8
2.3
3.2
1.7
2.9
1.5
13.6
4.2
6
1.9
0 2 4 6 8 10 12 14 16
Africa
Asia
South Africa
Europe
Low-risk HPV HPV 16 Other high-risk HPv
Percentage
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
11HPV prevalence among women with
normal cytology
Adapted from de Sanjosé S et al. Lancet Inf Dis 2007;7:7 453-459.
HPV prevalence %
ADJUSTED MODEL
UNADJUSTED
30
25
20
15
10
5
0
<20 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 >69
Age group
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
12Prevalence of HPV types specific to
lesions of the cervix
• Overall HPV prevalence with any HPV type:
- 71% of low-grade squamous lesions of the cervix
- 84% of high-grade squamous cervical lesions
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
13Incidence rates of cervical cancer
globally
Estimated age-standardised incidence rate per 100,000
Cervix uteri, all ages
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
14Estimated incidence and mortality
rates
Source: IARC GLOBOCAN 2008
Estimated global age-standardised incidence
and mortality rates of cervical cancer by region
Less developed
More developed
World
0 2 4 6 8 10 12 14 16 18 20
N = 453,000
N = 242,000
N = 77,000
N = 33,000
N = 530,000
N = 275,000
Rate per 100,000 (AS-w)
Mortality rate
Incidence rate
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
15 Burden of HPV infections
• HPV infection tends to cause cancer at ‘transformation
zone’ of epithelial tissues:
- Cervix, anus, vulva, vagina, and penis are examples of
sites with transformation zones
• HPV infection is associated with increased risk of cancer
of the oropharynx that may include the oral cavity,
oesophagus, larynx, and skin
• The burden of HPV-related cancer from among these
primary sites is by far largest in the cervix
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
16Natural history of anogenital infection
• The most important determinants of anogenital HPV
infection are:
- Age at first sexual intercourse
- The lifetime number of sexual partners of the woman or
her partner
• Most studies have shown significant, but incomplete
protection from condom use
- Incorrect or inconsistent use
- HPV infection may exist in wider area of genital
epithelium than is covered by the condom
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
17HPV infection through the stages of
disease: a complex natural history
Normal
cervix
Productive
Infection
Pre-cancer
lesion
Invasive
lesion
Clearance Regression
Progression
CIN 1+ CIN 2+ CIN 3+ Cancer
Transient
infection
Persistent
infection
Initial infection
(exposure)
Adapted from IARC, 2007
High-risk HPVs take much longer to clear than low-risk
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
18 Risk factors
• Young age at first sexual intercourse
• Young age at first delivery
• High number of pregnancies
• Immunosuppression
- HIV, other diseases, or chemotherapy
• Smoking
• Long-term use of hormonal contraceptives
• Infection with HIV or other STIs
- Herpes virus or Chlamydia trachomatis
• Failure to be screened and treated for signs of precancer
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
19 Co-factors
• Impact of HPV with some co-factors related to the natural
history of the disease not yet completely understood
• With viral co-factors, their effect over time on the
development of cervical cancer cannot be fully assessed
• High rate of acquisition and spontaneous clearance
- High-risk exposure profile or natural immunity
• Impaired immunity of the host may be of importance also
for developing neoplasia or cervical cancer
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
20 Role of HIV co-infection
• A high proportion of HIV-positive women are infected with
multiple HPV types
• HPV infection is more likely to persist in HIV-positive
women than in HIV-negative women
• In the regions with the highest global cervical cancer
burden, particularly in Africa, also the prevalence of HIV
infections and related Kaposi sarcoma burden is very high
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
21Prevention of HPV-related cancer
• Effectiveness of population-based organised screening
cytological programmes for cervical cancer
• In high-resource countries, screening has contributed to
70%-80% reduction of cervical cancer incidence since the
1960s
• Coverage and quality assurance are crucial
• Screening programmes in low resourced countries either
do not exist or are ineffective
- Attributed to limited resources (supplies, trained
personnel, equipment, quality control, healthcare
infrastructure, and effective follow-up procedures)
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
22Prevention of HPV-related cancer
• Lack of complete data on:
- Sustainability and effectiveness of alternative screening
methods (e.g., HPV screening or visual inspection) on
cancer incidence and mortality outcomes
- Sustainability and effectiveness information for other
medical prevention methods such as HPV vaccination
• Assessment of multi-factorial etiology, and health
promotion by health education and related counselling of
women and men are important and should be an integral
part of all cervical cancer control programmes
UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD
Slide
23
Thank you
This presentation is available at
www.uicc.org/cervicalcancercurriculum