Human Papillomavirus Infection and Cervical Cancer

1
Human Papillomavirus Infection and Cervical
Cancer

• ???? ????? ????
• ?? ??????? ???
• ???

2
Human Papillomavirus (HPV)

• HPV species-specific, infect human only.
• HPV virion is 55 nm, non-encapsulated, and has an
  icosahedral capsid.
• The genome is a circular double-stranded DNA
  molecule consisting of 7900 base pairs.

3
HPV infection as the main etiologic factor of
cervical cancer

• There is now compelling evidence both from
  biologic and from epidemiologic standpoints to
  consider HPV infection as the cause of cervical
  cancer.
• zur Hausen H, J Natl Cancer Inst
  200092690

4
Viruses linked to Human Tumors
Virus types Malignant tumors
EBV Burkitts lymphoma, NPC
HBV Hepatocellular carcinoma
HPV 5, 8, 14, 17, 20 Skin carcinoma
HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 61 Cervical cancer, Vulvar cancer, Penile cancer, Anal cancer
HTLV-1 Adult T cell leukemia
Zur Hausen H, Sciences 19912541167-73
5
Human diseases associated with HPV infection
Sites diseases
Skin Deep plantar warts, common warts
Anogenital tract Anogenital warts, Bowenoid-papulosis, Cervical, vulvar, and perianal intraepithelial neoplasia, Carcinomas of the cervix, vulva, penis, and anus
Respiratory tract Juvenile laryngeal papillomatosis, squamous cell carcinoma of the larynx, sinuses, and lung
Other Conjunctival papillomatosis, carcinoma of periungual areas
Beutner et al., Am J Med 19971029-15
6
Human Papillomavirus (HPV)

• The more than 200 different HPV genotypes
• Less than 90 homology in the L1 ORF with any of
  the known types
• More than 40 HPV types infect the anogenital
  mucosa
• Type 6, 11, 16, 18, 26, 31, 33, 35, 39, 42, 43,
  44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 66, 68
  (23 types) infect cervical epithelia
• HPV 16 is the most prevalent type and found in at
  least 50 of the cervical cancer

Bosch et al., 1995 Walboomers et al., 1999
7
Human Papillomavirus

• Clinical manifestations of HPV
• Epidemiology of HPV
• Natural history of HPV
• Molecular biology and oncogenesis of HPV
• HPV and CIN
• HPV and cervical cancer
• Diagnosis of HPV infection

8
Clinical manifestations of genital HPV infection

1. Clinical infection condyloma, dysplasia, and
   cancer
2. Subclinical infection colposcopic and
   microscopic identification
3. Latent infection detectable HPV DNA only

9
Clinical manifestations of HPV infection

• cervical condyloma
• HPV 6, 11

10
Clinical manifestations of HPV infection

• Cervical intraepithelial lesions
• HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53,
  56, 58, 59, 66, 68, 73, 82

11
Clinical manifestations of HPV infection

• Cervical carcinoma
• HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53,
  56, 58, 59, 66, 68, 73, 82

12
Subclinical infection
In the cervix, koilocytotic change with human
papillomavirus infection, is seen here, with
vacuolization of epithelial cells.
13
Prevalence of clinical manifestations of human
papillomavirus infection among men and women 15
to 49 years of age in the United States in 1994.
14
??

• The infectious agent that is involved in the
  development of cervical cancer is
• Herpes virus
• Chlamydia
• Syphilis
• Human papillomavirus (HPV)

15
??

• By some estimates, up to what percent of the
  population is infected with HPV at some point
  during their lifetime?
• 10
• 25
• 50
• 75

16
Prevalence of HPV infection in Taiwan

• Prevalence - 9 (N1624) in normal and abnormal
  pap smear
• HPV 52 gt HPV 16 gt type 58
• May 2000, Taiwan

91 HPV (-)
9 HPV ()
17
Prevalence of cervical HPV in Asia
Korea
9.3 HPV ()
China
10.4 HPV ()
Japan
7.3 HPV ()
Taiwan
9.2 HPV ()
9 HPV ()
Philippines
18
Prevalence of cervical HPV in relation to age
(The Netherlands)
HPV prevalence
Age intervals (yr)
Melkert et al., Int J Cancer 199353919
19
Prevalence of cervical HPV in relation to age
(Taiwan)
HPV prevalence
Age intervals (yr)
20
Transmission of HPV infection

• Sexual
• HPV is primarily transmitted through
  genital-to-genital sexual contact.
• Risk increases with the numbers of sexual
  partners, e.g. from 17 to 83 in women with one
  and five partners
• The number of sexual partners as one of the most
  significant risk factors for genital HPV
  infections
• The most common time from exposure to HPV to
  development of genital warts is 4 weeks to 8
  months

21
Transmission of HPV infection

• Non-sexual
• There is no evidence that contaminated toilet
  seats, doorknobs, towels, soaps, swimming pools
  or hot tubs, contaminated instruments and
  underwear can transmit HPV.
• Autoinoculation HPV lesions in one area of the
  lower genital tract probably already have HPV in
  other genital tract areas
• Vertical transmission from infected mother to her
  newborn baby. Transmission to the baby of HPV 6
  or 11 is known to occur during the birth process
  but is not common.

22
(No Transcript)
23
(No Transcript)
24
Transmission of HPV infection

• HPV status of partners
• 1/3 to 1/2 of couples have been shown to harbor
  the same HPV type
  Schneider A et al, Obstet Gynecol 198769554
• The number of extramarital sexual partners a man
  had was associated with an increased risk of
  cervical cancer in his wife.
• Bosch FX et
  al, J Natl Cancer Inst 1996881060
• In a study of 25 male partners of women with SIL
  or high-risk HPV, 18 (72) of the men had
  detectable HPV DNA.
• Strand A et
  al, Acta Derm Venereol 199575312

25
Natural history of HPV infection-Ho GYL et al.,
N Engl J Med 1998338423

• 608 college women, at 6 month intervals for three
  years
• The cumulative 36 month incidence of HPV 43.
• The mean duration of new infection was 8 months.
• By 12 months, 70 of were no longer infected.
• By 24 months only 9 continued to be infected.
• The risk factor for persistent infection of gt 6
  months were older age, high-risk types, and
  multiple types of HPV.

26
(No Transcript)
27
Will I always have HPV?

• The answer to this question is not clear.
• Most people (up to 90) who test positive for HPV
  with very sensitive tests for HPV (polymerase
  chain reaction PCR and Hybrid Capture 2) will
  become HPV negative on the same tests within 6 to
  24 months from first testing positive.
• What is not known is whether this means that the
  virus is actually eliminated from the body or
  just suppressed to such a low number of HPVs (as
  in latency) that even these sensitive tests
  cannot detect it.

28
(No Transcript)
29
(No Transcript)
30
Why do most people get very little from being
infected with HPV, while others get warts, and a
few get cancer?

• For most individuals immunity appears to dominate
  and lesions never develop, or they develop and
  are suppressed by an immune response before the
  person ever realizes the presence of the lesions.
  
• Long-term persistence of HPV is not the norm, but
  is required for the complex interplay of HPV,
  host immunity, various co-factors, and perhaps,
  spontaneous mutations in the host cell that may
  eventually result in the development of cancer of
  the cervix, vagina, vulva, anus, or penis.

31
Human Papillomavirus and CIN

• 129 cervix biopsy specimens
• 85 of low-grade CIN contained HPV DNA
• 92 of high-grade CIN contained HPV DNA
• HPV 16 21 in low-grade, and 57 in high-grade
  CIN
• HPV 18 only 3 of CIN
• HPV 30, 39, 45, 51, 52, 56, 58, and 61 were
  detected in 44 of low-grade but only 8 of
  high-grade CIN
• 
  Bergeron C et al., Am J Surg Pathol 199216641

32
HPV and Cervical Neoplasms-A case-control study
in Taiwan-

• 88 cases- 40 CIN I, 9 CIN II, 36 CIN III, 3 CC
• PCR-bases test MY09/MY11
• HPV DNA positive
• 92 of high-grade (CIN II, III and CC)
• 54 of low-grade (CIN I)
• 9 of control
• HPV-positive high-grade type 52 and/or 58 (48)
• HPV-positive low-grade type 52 and/or 58 (25)

Laiw et al, Int J Cancer 199562565
33
HPV and Cervical Intraepithelial Neoplasia
51 (28.0-94.0)
Schiffman, 1993, PCR
67.2 (28.6-157.5)
Olsen, 1995, PCR
18.4 (12.3-27.4)
Kjaer, 1996, PCR
122.3 (38.5-388.9)
Liaw, 1995, PCR (Taiwan)
5.02 (2.54-8.01)
Wang, 1996, PCR (Taiwan)
0
1
10
100
OR and 95 CI
34
HPV and Cervical Carcinoma
28.8 (15.7-52.6)
Munoz, 1992, (Spain, Colombia)
69.7 (28.6-169.9)
Eluf-Neto, 1994, (Brazil)
119 (64-222)
Chichareon, 1998, (Thailand)
156 (87-280)
Ngelangel, 1998, (Philippines)
114 (36-361)
Rolon, 2000, (Paraguay)
0
1
10
100
OR and 95 CI
35
(No Transcript)
36
Prevalence of HPV in cervical cancer a
worldwide perspective-Bosch FX et al., J Natl
Cancer Inst, 1995,87796-

• Over 1000 cases with cervical cancer from 32
  hospitals in 22 countries
• International Biological Study on Cervical Cancer
  (IBSCC)
• HPV DNA was detected in 93 of the tumors
• HPV 16 was present in 50 of the Squamous cell
  tumors
• HPV 18 in 14, HPV 45 in 8, and HPV 31 in 5
• HPV 18 predominated in adenocarcinomas (56), and
  adenosquamous tumors (39)

37
HPV is a necessary cause of invasive cervical
cancer worldwide -Walboomers JMM et al., J
Pathol 199918912-

• The formerly HPV-negative cases from IBSCC 66
  cases
• Three PCR-based HPV assays
• Type-specific E7, E1 and /or L1 consensus PCR
• The world HPV prevalence in cervical carcinomas
  is 99.7.

38
Press Release WHO/47 3 July 1996
CERVICAL CANCER
EXPERTS CONFIRMED VIRUS A MAJOR CAUSE, NEW
DETECTION TECHNOLOGIES AVAILABLE Experts have
formally labelled the human papilloma virus (HPV)
types 16 and 18 as "carcinogenic to humans", HPV
types 31 and 33 as "probably carcinogenic", and
suggested that some other HPV types were
"possibly carcinogenic".
39
Epidemiologic classification of HPV types
associated with cervical cancer
High risk Low risk
Lorincz AT 1992 16, 18, 45, 56 31, 33, 35, 51, 52, 58 6, 11, 42, 43, 44
Munoz N IARC 2003 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 (26, 53, 66) 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 (CP8304), CP6180
40
(No Transcript)
41
(No Transcript)
42
Participation of oncogenic human papillomavirus
E6 in cell cycle regulation.
43
(No Transcript)
44
Participation of oncogenic human papillomavirus
E7 in cell cycle regulation. For definitions,
please refer to the list of abbreviations
45
(No Transcript)
46
Do HPV-negative cervical carcinomas exist?

• HPV DNA is present but has not been identified
  (false negative).
• Insensitivity of the detection system
• DNA integrity
• Validity of tumor samples
• HPV DNA is not present (true negative).
• Hit-and-run mechanism
• HPV-independent pathway

47
Diagnostic technique of HPV infection

• Pap smear
• koilocytosis
• Colposcopy
• Histopathology
• Condyloma, flat, giant, inverted condyloma,
  papulosis
• Hybridization
• PCR
• serology

48
Screening for Pre-malignant Lesions

• PAP smear test is the gold standard but has
  limitations.

49
In the cervix, koilocytotic change with human
papillomavirus infection, is seen here, with
vacuolization of epithelial cells.
50
Bosch et al., J Clin Pathol 200255244-265
51
Hybrid Capture 2 HPV DNA Test Cervical Sampler
52
FDA Approves Expanded Use of HPV Test

• The HPV DNA test is not intended to substitute
  for regular Pap screening.
• Nor is it intended to screen women under 30 who
  have normal Pap tests.
• Although the rate of HPV infection in this group
  is high, most infections are short-lived and not
  associated with cervical cancer.

53
HPV ????

• ???????????????????
• 99?????????????????????
• ???????????????????
• PCR - DNA Sequencing ???????????,??HPV???? ????
  HPV ????

?????????
54
HPV genotypes in cervical cancer worldwide

• Proper characterization of the distribution of
  the various HPV types in cervical cancer from
  different geographic areas is essential to the
  development of vaccination strategies

55
Type-specific prevalence of HPV in 10058
worldwide cases of invasive cervical cancer
Clifford et al., Br J Cancer 2003 88, 63-73
56
Type-specific prevalence of HPV in 10058
worldwide cases of invasive cervical cancer
57
Prevalence of HPV Genotypes in Cervical Cancers
(SKMH)

16
18
31
33
58
58
Prevalence of the HPV types in Taiwanese and
Chinese Women with cervical carcinoma
59
(No Transcript)
60
Cumulative prevalence of HPV types in cervical
cancer the IARC multi-centric case-control study
Boschet al., J Clin Pathol, 200255(4)244-265
61
Cumulative prevalence of HPV types in cervical
cancer the IARC multi-centric case-control study

• Types 16, 18, 45, 31, 33, 52, 58, and 35
  accounted for 95 percent of the squamous-cell
  carcinomas positive for HPV DNA.
• They imply that an effective vaccine against the
  five most common HPV types (types 16, 18, 45, 31,
  33) could prevent about 90 percent of the cases
  of cervical cancer worldwide.
• Munoz
  et al., N Engl J Med 2003348518

62
Cumulative prevalence of HPV types in cervical
cancer (SKMH)
HPV type
66
80
84
88
92

63
HPV types 16, 18, 31, 33, and 58 accounted for
90 of the cervical carcinomas in Taiwan
64
From basic studies to clinical applications

• Cancer therapy
• Therapeutic vaccine
• Molecular and chemotherapy
• Cancer screening
• HPV-based cervical cancer screening program
• Cancer prevention
• Immunization against type-specific HPV
  (prophylactic vaccine)

65
(No Transcript)
66
(No Transcript)
67
HPV-16 L1 VLP vaccine (Merck, 2002)
68
HPV-16 and HPV-18 L1 VLP vaccine (GSK, 2004)
69
HPV-6, 11, 16, 18 L1 VLP vaccine (Merck, 2005)
70
(No Transcript)
71
???????,????????,????Gardasil?????????????????????
??? Gardasil???????????,?????????????HPV16?18?????
??????????,?????????????
72
FDA Licenses New Vaccine for Prevention of
Cervical Cancer

• Proper name Quadrivalent Human Papillomavirus
  (Types 6, 11, 16, 18) Recombinant Vaccine
• Tradename GARDASIL
• Manufacturer Merck Co., Inc., West Point, PA,
  License 0002
• Indication for Use Vaccination in females 9 to
  26 years of age for
• prevention of the following diseases caused by
  Human Papillomavirus (HPV) Types 6, 11, 16, and
  18
• 1. Cervical cancer
• 2. Genital warts (condyloma acuminata)
• 3. following precancerous or dysplastic lesions
  
• Cervical adenocarcinoma in situ (AIS)
• Cervical intraepithelial neoplasia (CIN)
  grade 2 and grade 3
• Vulvar intraepithelial neoplasia (VIN) grade
  2 and grade 3
• Vaginal intraepithelial neoplasia (VaIN)
  grade 2 and grade 3
• Cervical intraepithelial neoplasia (CIN)
  grade 1
• Approval Date 6/8/2006