NATURAL HISTORY OF

CERVICAL CANCER

Prof. Herman Susanto, dr., Sp.OG(K)

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Natural History 2007
DEFINITION
● Precancerous lesion of cervical cancer:
Perubahan displasia epitel serviks dengan berbagai
derajat kelainan maturasi
● Cervical cancer/in situ:
Mengenai seluruh ketebalan epitel serviks
Membrana basalis masih utuh
● Cervical cancer/invasive:
Menembus membrana basalis dan menyebar

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Natural History 2007
 EPIDEMIOLOGY

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Natural History 2007
 Masalah
● 466,000 kasus baru setiap tahun
● 80% diantaranya di negara berkembang`
● 231,000 wanita meninggal setiap
tahunnya karena kanker serviks
● Ranking ke-2 di negara berkembang, di
dunia ke-7

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Natural History 2007
NATURAL HISTORY

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Natural History 2007
Natural History of Cervical Cancer
Normal Cervix

About 60%
regress within HPV Infection
2-3 yrs
HPV-related Changes

Low-Grade SIL (Atypia, CIN I)

Cofactors
High-Risk HPV Types
About 15% progress within 3-4 yrs
(16, 18, 33, etc.)

High-Grade SIL (CIN II, III/CIS)

30%-70% progress within 10 yrs

Source: Sherris 1998; Bishop et al 1995

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Natural History 2007
 The Natural History of HPV Infection
Inoculation

Sustained
Immune About clinical
First lesion response 9 mo remission

Active growth Host

Incubation (1-8 mo) Late
(1 – 8 mo) Containment stage
(3-6 mo)

Persistent
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Natural History or recurrent disease
2007
 HPV
Human Papilloma Virus
➢ > 150 tipe
➢ 40 tipe mengenai anogenital
➢ pada remaja & dewasa muda

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Natural History 2007
 Woodman et al. Nature Reviews Cancer 7, 11–22 (January 2007) | doi:10.1038/nrc2050

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 High Risk Group

➢ Infeksi HPV
➢ Berganti-ganti pasangan
➢ Status ekonomi rendah
➢ Perokok
➢ Riwayat PMS

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Natural History 2007
Multi Step Carcinogenesis
Pro carcinogenesis Anti carcinogenesis
factor Normal Cell factor

Radiation, chemical,
mutagenic, virus, spontan DNA Repair
mutation
Initiated Cell
Tumor promotor growth
factor, virus
GF Inhibition

Preneoplasia Differentiation,
Radiation, chemical, Immune factors,
mutagenic, virus, spontan Surveillance lack,
mutation Angiogenesis,
Invasive Tumor Apoptosis
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Natural History 2007
 Transient C. trachomatis
Infection

HPV
Infection

Persistent Low Gr High Gr Invasive

Infection CIN CIN Cancer
4-5g l l 5g

• HPV type and variants • Hormonal factors

• Age at infection • Genetic factors
• Immunological factors

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Natural History The Causes of Cervical Cancer 2007
 HPV

Decreasing
Immune Basal epithelial cells Viral Age
Surveillance persistence
20
Morphologically non-expressed (latent) HPV
25
CIN3, VIN3, VAIN3
30
In activation of Oncogenic HPV
tumor suppressor
gene Cancer 45

Viral integration
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Expression of HPV as Early Cytologic and Histologic Abnormalities
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Natural History 2007
Jalur Transmisi Potential
● oral sex - rare
● perinatal - rare
● digital - rare
● “outercourse” – rare
● anal intercourse - common
● vaginal intercourse - common
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Natural History 2007
Tipe HPV
● High Risk types :
16, 18,
31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82
● Probable high risk types :
26, 53, and 66
● Low risk type :
6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108
(Munos et al, N Engl J Med 2003; 348:518-27)

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Natural History 2007
 - HPV tipe 16 & 18: 70-80%
- HPV 18 berhubungan dg tipe
Adeno

- HPV DNA ditemukan hampir

100% pada kanker serviks

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Natural History 2007
 Bagaimana
HPV dapat dicegah?

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Natural History 2007
Pencegahan HPV Genital
● Abstinens, monogami
● Kondom kurang dapat mencegah kanker
● Vaksin menawarkan pencegahan yang
menggembirakan di masa mendatang

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Natural History 2007
 Take Home Messages

● Prakanker serviks dan kanker serviks

dapat dicegah
● Prakanker serviks berlangsung lama
sebelum menjadi kanker, yang
memberikan kesempatan untuk deteksi
dini dan penghancuran tumor tanpa
menggangu fungsi reproduksi
● Pencegahan meliputi kehidupan seksual
yang baik, vaksinasi, skrining
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 Terima
Natural History
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2007
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Natural History 2007
 Woodman et al. Nature Reviews Cancer 7, 11–22 (January 2007) | doi:10.1038/nrc2050

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 Gene Function
DNA-dependent ATPase, ATP dependent helicase: allow unwinding of the viral genome
E1 and act as an elongation factor for DNA replication.

Responsible for recognition and binding of origin of replication. Exists in two forms:
full length (transcriptional transactivator) and truncated (transcriptional repressor).
E2 The ratio of these found in the heterotrimeric complex formed before complexing
with E1 regulates transcription of viral genome.

E3 ???

Late Expression: C terminal binds intermediate filament, allowing release of virus-like

E4 particles. Also involved in transformation of host cell by deregulation of host cell
mitogenic signalling pathway.

Obstruction of growth suppression mechanisms: e.g EGF receptor; activation of mitogenic

signalling pathways via transcription factors: c-Jun and c-Fos (important in ubiquitin
E5 pathway degradation of p53 complex by E6). Inactivation of p21 (p53 induced expression
halts cell cycle until DNA is proof-read for mutations).

E6 E6 Transformation of host cell by binding p53 tumor suppressor protein.

E7 Transforming protein, binds to pRB/p107.

E8 ???

L1 Major capsid protein: can form virus-like particles.

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Natural History
L2 Minor capsid protein: possible DNA packaging protein. 2007