uicc hpv and cervical cancer role of hpv final... · uicc hpv and cervical cancer curriculum the...

UICC HPV and Cervical Cancer Curriculum The role of HPVAhti Anttila Phd, Harri Vertio MD PhD

UICC

HPV andCERVICALCANCERCURRICULUM


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


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


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


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


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


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


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.


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.


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


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


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


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


Slide

13Incidence rates of cervical cancer

globally

Estimated age-standardised incidence rate per 100,000

Cervix uteri, all ages


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


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


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


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


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


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


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


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)


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


Slide

23

Thank you

This presentation is available at

www.uicc.org/cervicalcancercurriculum

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