Download Human Papillomavirus and Cervical Cancer

Human Papillomavirus Infection
and Cervical Cancer
輔仁大學 實習醫學生 核心課程
新光 吳火獅紀念醫院 婦產科
黃莉文
Human Papillomavirus (HPV)
• HPV: species-specific, infect
human only.
• HPV virion is 55 nm, nonencapsulated, and has an
icosahedral capsid.
• The genome is a circular
double-stranded DNA
molecule consisting of 7900
base pairs.
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
2000;92:690
Viruses linked to Human Tumors
Virus types
Malignant tumors
EBV
Burkitt’s lymphoma, NPC
HBV
Hepatocellular carcinoma
HPV 5, 8, 14, 17, 20
Skin carcinoma
HPV 16, 18, 31, 33, 35, Cervical cancer, Vulvar cancer,
39, 45, 51, 52, 56, 58,
Penile cancer, Anal cancer
59, 61
HTLV-1
Adult T cell leukemia
Zur Hausen H, Sciences 1991;254:1167-73
Human diseases associated with HPV infection
Sites
Skin
diseases
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
Juvenile laryngeal papillomatosis,
squamous cell carcinoma of the larynx,
sinuses, and lung
Respiratory tract
Other
Conjunctival papillomatosis, carcinoma
of periungual areas
Beutner et al., Am J Med 1997;102:9-15
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
Human Papillomavirus
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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
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
Clinical manifestations of HPV infection
•
• cervical condyloma
• HPV 6, 11
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
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
Subclinical infection
In the cervix, koilocytotic change with human papillomavirus
infection, is seen here, with vacuolization of epithelial cells.
Prevalence of clinical manifestations of human
papillomavirus infection among men and women 15 to 49
years of age in the United States in 1994.
考題
•
The infectious agent that is involved in the development
of cervical cancer is
1.
2.
3.
4.
Herpes virus
Chlamydia
Syphilis
Human papillomavirus (HPV)
考題
•
By some estimates, up to what percent of the population
is infected with HPV at some point during their lifetime?
1. 10%
2. 25%
3. 50%
4. 75%
Prevalence of HPV infection in Taiwan
• Prevalence - 9% (N=1624)
in normal and abnormal
pap smear
• HPV 52 > HPV 16 > type
58
91% HPV (-)
• May 2000, Taiwan
9% HPV (+)
Prevalence of cervical
HPV in Asia
Korea
China
10.4% HPV (+)
9.3% HPV (+)
Japan
7.3% HPV (+)
9.2% HPV (+)
Philippines
Taiwan
9% HPV (+)
Prevalence of cervical HPV in relation to age
(The Netherlands)
25
20
15
HPV(+)
HPV16 or 18
10
5
0
15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54
Age intervals (yr)
Melkert et al., Int J Cancer 1993;53:919
Prevalence of cervical HPV in relation to age
(Taiwan)
16.0%
14.8%
14.0%
12.0%
10.0%
8.0%
6.0%
9.2%
6.6%
7.5%
7.3%
30-39
40-49
10.3%
HPV(+)
4.0%
2.0%
0.0%
20-29
50-59
Age intervals (yr)
60-69
> 70
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
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.
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 1987;69:554
– 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 1996;88:1060
– 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 1995;75:312
Natural history of HPV infection
-Ho GYL et al., N Engl J Med 1998;338:423
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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 > 6 months
were older age, high-risk types, and multiple types of
HPV.
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.
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.
Human Papillomavirus and CIN
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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 1992;16:641
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 1995;62:565
HPV and Cervical Intraepithelial Neoplasia
Schiffman, 1993, PCR
51 (28.0-94.0)
Olsen, 1995, PCR
67.2 (28.6-157.5)
Kjaer, 1996, PCR
18.4 (12.3-27.4)
Liaw, 1995, PCR
(Taiwan)
Wang, 1996, PCR
(Taiwan)
122.3 (38.5-388.9)
5.02 (2.54-8.01)
0
1
10
OR and 95% CI
100
HPV and Cervical Carcinoma
Munoz, 1992, (Spain, Colombia)
28.8 (15.7-52.6)
Eluf-Neto, 1994, (Brazil)
69.7 (28.6-169.9)
Chichareon, 1998, (Thailand)
119 (64-222)
Ngelangel, 1998, (Philippines)
156 (87-280)
Rolon, 2000, (Paraguay)
114 (36-361)
0
1
10
OR and 95% CI
100
Prevalence of HPV in cervical cancer:
a worldwide perspective
-Bosch FX et al., J Natl Cancer Inst, 1995,87:796• 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%)
HPV is a necessary cause of invasive cervical
cancer worldwide
-Walboomers JMM et al., J Pathol 1999;189:12• 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%.
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".
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
Participation of oncogenic human papillomavirus E6 in cell cycle regulation.
Participation of oncogenic human papillomavirus E7 in cell cycle regulation. For definitions, please refer to
the list of abbreviations
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
Diagnostic technique of HPV infection
• Pap smear
– koilocytosis
• Colposcopy
• Histopathology
– Condyloma, flat, giant, inverted condyloma, papulosis
• Hybridization
• PCR
• serology
Screening for Pre-malignant Lesions
• PAP smear test is the gold standard –but has limitations*.
In the cervix, koilocytotic change with human papillomavirus infection, is
seen here, with vacuolization of epithelial cells.
Bosch et al., J Clin Pathol 2002;55:244-265
Hybrid Capture® 2 HPV DNA Test Cervical
Sampler™
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.
HPV 檢驗晶片
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子宮頸癌是台灣地區婦女癌症發生率的首位
99%以上的子宮頸癌組織切片可發現人類乳突瘤病毒
目前醫界認為子宮頸癌是『會傳染的癌症』
PCR - DNA Sequencing 並無法鑑別多重病毒感染，市
售HPV檢測產品 無法鑑別 HPV 的基因型
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
Type-specific prevalence of HPV in 10058 worldwide cases of invasive
cervical cancer
Clifford et al., Br J Cancer 2003; 88, 63-73
Type-specific prevalence of HPV in 10058 worldwide cases of invasive
cervical cancer
Prevalence of HPV Genotypes in Cervical Cancers
(SKMH)
%
65.9
70
60
50
40
22.8
30
14.4
20
10
0
16
18
31
HPV
9
33
9
58
Prevalence of the HPV types in Taiwanese and Chinese
Women with cervical carcinoma
Author
Lo et al.
Lin et al.
Chen et al.
Areas
No.
China
Jianqxi
Taiwan (NTUH)
809 (%)
77 (%)
433 (%)
99 (%)*
136 (%)
94 (%)
167 (%)
Positive HPV
677 (83.7)
72 (93.5)
342 (79)
80 (81)
113 (83)
81 (86.2)
164 (98.2)
16
541 (79.6)
37 (48.1)
200 (46.2)
38 (38.4)
86 (58)
45 (47.5)
110 (65.9)
18
51 (7.5)
4 (5.2)
53 (12.2)
4 ( 4.0)
11 (16)
8 ( 8.5)
38 (22.8)
31
5 (0.7)
2 (2.6)
8(5)
3 ( 3.2)
24 (14.4)
33
12 (1.8)
3 (3.9)
3 ( 3.2)
15 ( 9.0)
52
18 (2.6)
4 ( 5.2)
13 (13.1)
2 ( 2.1)
5 ( 3.0)
58
26 (3.8)
14 (18.2)
13 (13.1)
17 (18.1)
15 ( 9.0)
Mixed
3 (0.8)
11 (14.3)
1(1)
1 ( 1.1)
49 (29.3)
Liaw et al.
Taiwan
28 ( 6.5)
7 (1.6)
Yang et al.
Lai et al.
Taiwan (MMH) Taiwan (TSGH)
Huang et al.
Taiwan (SKMH)
Cumulative prevalence of HPV types in cervical cancer
the IARC multi-centric case-control study
Boschet al., J Clin Pathol, 2002;55(4):244-265
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 2003;348:518
Cumulative prevalence of HPV types
in cervical cancer (SKMH)
HPV type
66%
16
80%
16+18
84%
16+18+31
88%
16+18+31+58
92%
16+18+31+58+33
0
20
40
%
60
80
100
HPV types 16, 18, 31, 33, and 58
accounted for 90% of the cervical
carcinomas in Taiwan
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)
HPV-16 L1 VLP vaccine (Merck, 2002)
HPV-16 and HPV-18 L1 VLP vaccine (GSK, 2004)
HPV-6, 11, 16, 18 L1 VLP vaccine (Merck, 2005)
默克大藥廠表示，臨床試驗結果顯示，一種名為Gardasil的實驗性
疫苗預防子宮頸癌的短期效果可達百分之百。 Gardasil是一種基因
工程合成疫苗，可預防感染兩種人類乳突病毒HPV16、18。這兩
種病毒主要經由性行為傳染，是大約七成子宮頸癌的元凶。
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