NATURAL HISTORY OF

CERVICAL CANCER

Division of Gynecologic Oncology

Department of Obstetrics and Gynecology
Faculty of Medicine Universitas Padjadjaran
Natural History of
Cervical Cancer
≈
Natural History of
HPV Infection
 Worldwide Incidence and Distribution
of Cancers Attributable to Oncogenic Types of HPV, 2002

100%
500,000

Total Cancer
400,000 Cases
Total Cancers

HPV-related
300,000 Cases
3%

200,000

100,000
40% 12%
90% 40%
0
Cervix Vulva, Anus Oral Cavity Oropharynx Penis
Vagina

1. Parkin DM. Int J Cancer. 2006;118:3030–3044.

 NATURAL HISTORY

 The course of disease or infection

from onset to resolution

 It refers to the progression

and developments of a disease
that is left untreated
 How to measure the natural history of (cervical)
HPV infection?
 Cytologic examination
 Histopathologic examination
 DNA testing

 Problems:
 Interventional measures & treatments
 Tissue changes due to laboratory examination
 Technical limitations of HPV test methods
 Ethical issues
 HUMAN PAPILLOMAVIRUS (HPV)

Nonenveloped double- 130 types identified

stranded DNA virus ~30–40 anogenital
 ~15–20 oncogenic
(high risk)
– HPV 16 and HPV 18
types account for the
majority (70%) of
worldwide cervical
cancers.
 Nononcogenic types
(low risk)
– HPV 6 and 11 are most
Reprinted from Hagensee ME, Olson NH, Bakers TS, Galloway often associated with
DA. J Virol. 1994;68:4503–4505, by permission of the
American Society for Microbiology and Dr. Michael Hagensee. external anogenital
warts.
Family Papillomaviridae – Genus Papillomavirus1
Human papillomavirus (HPV) types within a species are related:
Alpha 7 Species: HPV 18, 39, 45, 59, 68, 70, c85
Alpha 9 Species: HPV 16, 31, 33, 35, 52, 58, 67
Alpha 10 Species: HPV 6, 11, 13, 44, 55, 74, PcPV, CCPV

HPV types are

organized into
genera and
species on the
basis of homology
in the sequence
of the L1 (major
capsid protein)
gene.

De Villiers EM et al. Virology. 2004;324:17–27. Reprinted with permission from Elsevier. 2

VIRUS
(Latin: toxin or poison)

* A small infectious agent that can replicate only inside the cells
of other organisms

* Too small to be seen directly with a light

microscope, around 1/100 of a bacterium’s size

Grouping:
I: dsDNA viruses
II: ssDNA viruses
III: dsRNA viruses
IV: (+)ssRNA viruses
V: (−)ssRNA viruses
VI: ssRNA-RT viruses
VII: dsDNA-RT viruses
Viruses consist of 2 or 3 parts:

1. genes made from either DNA or RNA, long

molecules that carry genetic information

2. a protein coat that protects the genes

(3. an envelope of fat that surrounds the viruses

when they are outside a cell)
Human Papillomavirus, oncogenic type
 INFECTION

 The detrimental colonization of a

host organism by a foreign species.

 In an infection, the infecting organism seeks to

utilize the host's resources to multiply, usually at
the expense of the host.

 The host's response to infection is inflammation.

GENITAL HPV INFECTION

 Sexual contact
 Through sexual intercourse
 Genital–genital, manual–genital, oral–genital
 Genital HPV infection in virgins is rare, but may result from
nonpenetrative sexual contact
 Proper condom use may help reduce the risk, but is not fully
protective against infection
 Nonsexual routes
 Mother to newborn (vertical transmission)
 Fomites (eg, undergarments, surgical gloves, biopsy
forceps)
 Hypothesized but not well documented; would be rare
 Most infected individuals are unaware that they are
infected and may unknowingly spread the virus
Determinants of HPV Infection

Women Men
 Young age (peak age group  Young age (peak age group
20–24 years of age) 25–29 years of age)
 Lifetime and recent number of  Lifetime number of sex
sex partners partners
 Early age of first sexual  Being uncircumcised
intercourse  Sexual partner with CIN
 Male partner sexual behavior
 Smoking*
 Oral contraceptive use*
 Uncircumcised male partners
*Findings not consistent across studies
Cumulative Risk of Any HPV Infection
by Age in Women
50
Age at Baseline
Cumulative Risk of HPV Infection (%)

15–19
20–24 N=1610
40
25–29
30–44
30 45+

20

10

0
0 1 2 3 4 5
Years
In a cohort of Colombian women

Adapted from Muñoz N, Méndez F, Posso H, et al. J Infect Dis. 2004;190:2077–2087. Reprinted with permission from The
University of Chicago Press. Copyright © 2004 by the Infectious Diseases Society of America. All rights reserved.
Cancers attributed/related to
HPV infection

 Cancer of uterine cervix

 Cancer of vagina
 Cancer of vulva
 Cancer of anus
 Cancer of penis
 Cancer of head and neck
 Worldwide Incidence and Distribution
of Cancers Attributable to Oncogenic Types of HPV, 2002

100%
500,000

Total Cancer
400,000 Cases
Total Cancers

HPV-related
300,000 Cases
3%

200,000

100,000
40% 12%
90% 40%
0
Cervix Vulva, Anus Oral Cavity Oropharynx Penis
Vagina

1. Parkin DM. Int J Cancer. 2006;118:3030–3044.

CURRENT UNDERSTANDING
OF THE NATURAL HISTORY
OF HPV INFECTION
Natural History of HPV Infection
(in Uterine Cervix)
Natural History of External Genital Warts and CIN 1
Natural History of High-risk HPV Infection and
Potential Progression to Cervical Cancer
The Cervical Transformation Zone
Cancer of the uterine cervix

HPV targets:

 the basal cells in the stratified squamous epithelium

 the metaplastic cells at the squamocolumnar

junction

 additionally, HPV may infect the glandular

epithelium of the endocervix
 glandular neoplasms: adenocarcinoma
(in situ or invasive)
Productive Life Cycle of HPV
 The viral oncogenes E6 and E7
(E” designation indicates: the two genes are
expressed early in the HPV life cycle)
promote cell growth by inactivating the tumor
suppressor proteins p53 and pRb
The expression of the viral late genes, L1 and L2, is
exclusively restricted to differentiating keratinocytes
in the outermost layers of the skin or mucosal
surface.

The increased expression of L1 and L2 is typically

correlated with a dramatic increase in the number of
copies of the viral genome.

Since the outer layers of stratified squamous

epithelia are subject to relatively limited surveillance
by cells of the immune system, it is thought that this
restriction of viral late gene expression represents a
form of immune evasion.
 Genetic organization

Genome organization of Human papillomavirus type 16

The papillomavirus genome is divided into an early region (E), encoding various genes that are expressed
immediately after initial infection of a host cell, and a late region (L) encoding the capsid genes L1 and L2. All the
genes are encoded on one DNA strand.
HPV-mediated progression to cervical cancer.
 HPV Infection and Life Cycle
Shedding of Virus-
Laden Epithelial Cells
Cervical Surface
Mature
Squamous    Viral Assembly
Layer    (L1 and L2)
  
Viral DNA Replication

Squamous
Layer .
  (E6 and E7)

. . . Episomal Viral DNA

Parabasal in Cell Nucleus
Cells . . . (E1 and E2, E6 and E7)

Basal (Stem) Infection of Basal

Cells Cells (E1 and E2)
Basement Membrane
Normal Infected
Epithelium Epithelium
1. Frazer IH. Nature Rev Immunol. 2004;4:46–54. Adapted with permission from Nature Reviews Immunology © 2004
Macmillan Magazines Ltd.
Spectrum of Changes in Cervical Squamous
Epithelium Caused by HPV Infection
Normal HPV Infection / CIN 2 / CIN 3 /
Cervix CIN Cervical Cancer

*CIN = cervical intraepithelial neoplasia

Adapted from Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564. Copyright © 2003 Massachusetts Medical Society. All
rights reserved. Adapted with permission.
Infection of the metaplastic epithelium of the cervical transformation zone with one of the
carcinogenic types of HPV infection; this infection is either cleared quickly through either
the innate immune system or other mechansisms. The majority of established infections
which often manifest as microscopoic abnormalities are then either cleared at some point
by host immune responses. Viral persistence leads to clonal progression of the
persistently-infected epithelium and cervical intraepithelial neoplasia (CIN)-3/precancers
arise; events which remain unknown lead infected cells to cervical invasion. Reprinted
from Oxford Press University.
 Intrepithelial Squamous cell
Normal lesion carcinoma

57 % 1%
CIN I Progression
Regression 43 % 5%
CIN II
32 % 12 %
CIN III

(OstÖr)
Cofactors for persistence and
progression

 Predominating transient nature of the infection 

other factors also play a role
 Not clear at which step(s) in the carcinogenic
process these factors are most involved

 Ubiquity of HPV  the most critical step in cervical

carcinogenesis is not acquisition of the infection, but
rather the step involving progression to clinically
important lesions (i.e. CIN-3)
Established and Potential Cofactors
Involved in HPV Carcinogenesis1
Coinfection
With Other
High Parity Sexually
Transmitted
Infections
OCs*
HPV Diet
Smoking

Endogenous
HIV Hormones

Cervical Genetic
Cancer Factors
Overview of factors most consistently reported to play a role at different stages
in the natural history of HPV and cervical neoplasia.