Cancer Serviks

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HPV dan kanker serviks
Dr. Toto Imam Soeparmono, SpOG, K. Onk
Subbag Ginekologi Onkologi
Dep Obgin RSPAD Gatot Soebroto
Jakarta


Nama :
Dr. Toto Imam Soeparmono, SpOG, K.Onk

Pangkat : Letkol CKM / Nrp 31418
Jabatan : Kasub Instal Rawat Inap B
Jabatan lain :1. Kadep obgin RSPAD
2. Ka Komite Penanggulangan
Kanker terpadu RSPAD
3. Konsultan Kanker
Kandungan



 Umur : 48 thn
 Status : K4
 Dik Umum :1. Dokter umum (FK
Unair 1987)
2. SpOG (FK Unsri 1997)
3. Konsultan Kanker Kan-
dungan (FK UI 2005)
 Dik Militer :1. PDAD (1987)
2. Selapa Kes (2006)



Hmmmmmmmmm………….

TAPI, KENA
KANKER SERVIKS



Why?
 Cervical cancer is a significant public health problem
in many countries.
 Cervical cancer is a sexually transmitted disease.
 Cervical cancer is preventable (i.e., Methods of
screening and treatment for precancerous lesions
exist).
 Pap Smear as a screening methods may not be
appropriate or adequate for many low-resource
settings.



 Cervical cancer is one of the most
common cancers, accounting for 6%
of all malignancies in women. There
are an estimated 16,000 new cases of
invasive cancer of the cervix and
5,000 deaths in the U.S each year



•Number 1 fatal cancer in women
internationally.
•More than 400,000 new diagnoses
each year
•More than 200,000 deaths
(80% in developing countries)*

*Reproductive Health Online, 2004. Available: http://www.rho.org



 5th most common cancer in humans
 2nd most common cancer in women
 1st most common woman cancer in INA
 Relatively early age of death
 median of 57 years versus 72 years for other
cancers
 Great loss of productive years of life for
each case



Ranking of global female cancer incidence and
mortality by site, 2002
Site Incidence Proportion (%)
Mortality
1 Breast 1,151,298 410,712 0.36
2 Cervix uteri 493,243 273,505 0.55
3 Colon/rectum 472,687 250,532 0.53
4 Lung 386,891 330,786 0.85
5 Stomach 330,518 254,297 0.77
6 Ovary 204,499 124,860 0.61

7 Corpus uteri 198,783 50,327 0.25

8 Liver 184,043 181,439 0.98

Parkin DM, et al.Global Cancer Statistic, 2002



Ranking of cancer incidence by site in Indonesia,
1998
Site Number Proportion of total (%)

1 Cervix uteri 3686 17.85
2 Breast 2617 12.67

3 Skin 1270 6.15
4 Nasopharynx 1137 5,51
5 Rectum 1051 5.09
6 Ovary 1048 5.08

7 Lymphoma 926 4.48

8 Colon 653 3.16
Mangunkusumo R, 2005), Pidato Pengukuhan



1. Cervical Ca still a leading type of Ca among the
woman
2. Ca Cervix represent 11 % of total cancer in woman
and 66 % of gynecology Cancer
3. Overall survival rate cervical cancer in INA is low
4. Patients come to hosp. in the late stages
5. Death can prevent only by screening routinely
6. Adeno Ca of the cervix is increasing
7. Developing of the early detection and
the management of the cervical cancer is
important



Normal Prakanker Kanker

R S B



Cervical Cancer

NATURAL HYSTORY

PRA -CANCER CANCER
15 % 30 % 45 %

MILD MODERATE SEVERE
NORMAL DYSPLASIA DYSPLASIA DYSPLASIA CANCER CANCER
IN CITU INVASIVE

40 % 20 %

Low Grade SIL High Grade SIL
SCREENING


 STAGE. 0
= PREINVASIVE CARCINOMA
= CARCINOMA IN SITU



 STAGE. I
CONFINED TO UTERUS (EXTENSION TO CORPUS SHOULD
BE DISREGARDED.

STAGE. Ia. – DIAGNOSED ONLY BY MICROSCOPY
STAGE. Ia.1 : - STROMAL INVASION </= 3
mm
- HORIZONTAL SPREAD </= 7 mm
STAGE. Ia.2 : - STROMAL INVASION >3 mm - </= 5 mm
- HORIZONTAL SPREAD </= 7mm



STAGE. Ib.
CLINICALLY VISIBLE LESION CONFINED TO
THE CERVIX OR MICROSCOPIC
LESION GREATER THAN STAGE Ia.1.

STAGE. Ib.1 : - GREATEST DIMENSION </= 4
cm.

STAGE. Ib.2 : - GREATEST DIMENSION > 4
cm.



 STAGE. II
TUMOR INVADES BEYOND THE
UTERUS BUT NOT TO PELVIC WALL
OR TO LOWER THIRD OF THE
VAGINA.

STAGE. IIa.
= WITHOUT PARAMETRIAL
INVASION
STAGE. IIb.
= WITH PARAMETRIAL INVASION



 STAGE. III
TUMOR EXTENDS TO PELVIC WALL AND/OR
INVOLVES LOWER THIRD OF THE VAGINA

STAGE. IIIa.
= INVOLVES LOWER THIRD OF VAGINA NO
EXTENSION TO PELVIC WALL.
STAGE. IIIb.
= TUMOR EXTENDS TO PELVIC WALL
AND/OR
CAUSES HYDRONEPHROSIS OR NON-
FUNCTIONING KIDNEY.



 STAGE. IVa.
. TUMOR INVADES MUCOSA OF BLADDER OR
RECTUM AND/OR EXTENDS BEYOND TRUE
PELVIS.

STAGE. IVb.
= DISTANT METASTASIS



 HPV Infection
 High number of sexual partners
 Low social economic status
 Smoking
 History of STDs
 Any combination of the above



 Pada tahap prakanker sering tidak
menimbulkan gejala sama sekali (92%)
 kecuali ada infeksi: keputihan

 Kalau sudah timbul gejala biasanya kanker
sudah bertumbuh



 Perdarahan pasca senggama
 Keputihan
 Gangguan lain akibat kanker sudah lanjut:
 nyeri pinggul
 gangguan BAB
 gangguan BAK
 BB menurun
 lemah atau kurang darah akibat perdarahan



 Treatment modalities based on stage
 Side effects and toxicities of whole pelvic
radiation and brachytherapy with
chemotherapy
 Sexual side effects of different treatment
 Vaginal shortening
 Vaginal coaptation with radiation therapy
 Radiation necrosis
 Loss of ovarian function
 Decreased lubrication



 Operasi

 Radiasi

 Khemoterapi

 Kombinasi



 Menganut terapi lesi pra kanker
(Konisasi, LEEP, LETZ, Laser)

 Untuk usia tua, jumlah anak cukup dilakukan
sampel histerektomi (tipe I)

 Follow up



 Pada beberapa keadaan dapat dilakukan konisasi
(Coppleson, 1992, Ostor, Roman)

 Ekstra Facial Histerektomi

 Follow up



 Histerektomi Radikal, Diseksi KGB.
(Tipe III)

 Radiasi

 Khemoterapi

 Follow up



Terapi Kanker Serviks
Stadium IB 2 dan IIA,
Tumor lebih 4 cm
 Histerektomi Radikal + Diseksi KGB +
Radioterapi ± Khemoterapi.

 Terapi Radiasi pelvik + Khemoterapi.

 Khemoradiasi sebagai Neo Ajuvan +
Histerektomi Radikal



 Primer radio terapi

 Bisa ditambahkan khemoterapi

 Perawatan Paliatif



 Beberapa kasus kanker serviks stadium II B,
dapat diberikan neo-ajuvan khemoradiasi atau
khemoterapi, kemudian dilakukan histerektomi
radikal.

 Hal ini akan menambah 5 YSR.



 Status dari kelenjar getah bening
 Besar ukuran tumor primer
 Kedalaman invasi stroma
 Ada atau tidaknya invasi ke dalam pembuluh
darah atau limfe
 Jenis histopatologi dari sel kanker
 Bebas atau tidaknya tepi vagina



 Primer

 Pre Operasi

 Ajuvan

 Paliatif



 External Beam Radiotherapy (EBRT)
Rotman, 1995, Morris, 1999)

 Brachytherapy (BT)

 Radioterapi Radikal (kombinasi EBRT dan BT)
(Arrai, 1992)



 Neo Ajuvan

 Ajuvan

 Kombinasi Kemoradiasi

 Paliatif



 P. V. B.

 Paclitaxel + Carboplatin

 Cisplatin + Hidroxyurea + 5 FU

 Kombinasi – kombinasi yang lain



 Intra operatif :
 Perdarahan

 Lesi pembuluh darah, ureter, buli – buli, rektum

dan syaraf

 Infeksi



 Post Operatif
Awal : Lanjut :

 ISK  Gangguan Fungsi Buli2
 Trombosis Vena  Lymphedema
 Emboli Paru  Disfungsi seksual
 Fistula
 Demam
 Limposis
 Ileus
 Obstruksi Ureter



 Pada Kulit

 Pada saluran cerna (mual, muntah, diare,
rektal bleeding, proctitis karena radiasi)

 Pada saluran kencing (hematuria)



Komplikasi & Efek samping
Khemoterapi
1. Sistim Hemopoetik :
* Pansitopeni.
2. Sistim Gastrointestinal :
* Mual muntah, diare.
* Stomatitis.
* Perdarahan saluran cerna.
* Enterocolitis.
3. Immunosupressi.
4. Pada kulit :
* Reaksi alergi, iritasi, sampai Steven Johnson
Syndrome.
* Alopecia.
5. Pada Hati :
* Drug induced hepatitis.


6. Pada Paru-paru :
* Interstitial pneumonitis.
7. Pada Jantung :
* Kardiomiopati.
8. Pada Saluran Kencing :
* Chronic azotemia
* Acute renal failure
* Retensi cairan.
9. Pada Sistim Saraf :
* Neuropati.
10. Pada Pembuluh Darah :
* Kerusakan pembuluh darah.



11. Terjadinya keganasan sekunder :
* Leukemia
12. Pada Gonad :
* Amenorrhoe.
* Kegagalan fungsi ovarium.
Infertilitas.
13. Gangguan Metabolik :
* Hiponatremi
* Hiperurisemi
* Hipokalsemi.



Tujuan :
 Untuk mengetahui hasil yang segera dari
pengobatan

 Untuk mengidentifikasi komplikasi dari
pengobatan

 Untuk mendeteksi penyakit yang resisten atau
rekuren



Tahun I - II Setiap 3 bulan

Tahun III – V Setiap 6 bulan

Lebih dari 5 tahun Setiap tahun



FIGO Stage % Cases 5-Year Survival
I 46% 83%
II 28% 64%
III 21% 38%
IV 4% 14%

FIGO Annual Report. J Epi & Biostat 1998;
3(1)



What is
HPV?


Cervical Cancer: History
•1976- Meisels and Fortin noticed cervical neoplasias
were saturated With small “koilocytes”… virus particles.



 Double stranded virus, famili Papopa virus

 Genome sirkuler 7- 8 kilo base-pairs (kbp)
dibungkus kapsid berbentuk icosahedral

 Untaian nukleotidenya :
early region ( E1,2,4,5,6,7)
late region ( L1,2)



 Virion, Genome DNA:
 double-stranded
 circular
 8000 base pair
 Capsid:
 a naked icosahedral
 55 nm in diameter



 Genome virus mempunyai 8 gen (ORFs =
open reading frames):
E (early)1, E2, E4, E5, E6, E7 serta L (late)1 dan
L2
 Absolutely tissue spesific
 Target infeksi: basal keratinocytes
 Ekspresi protein virus pada upper layer



Regulation of Viral
transcription & replication
Growth
E2
Stimulation
E5 E4
Encodes for
E1
minor capsid
protein Regulation of viral
L2
replication
HPV
genome
(-7815 base pairs)
Encodes for
E7
major capsid Transforming genes/
protein growth stimulation
L1
Late gene E6

URR

( Upper regulatory regions )

Gambaran Skematik dari organisasi genome HPV



 HPV DNA :

 > 99 % Ca Cx
 94 % CIN
 46 % normal Cytology



 120 genotypes berbeda
 tergantung sekuens DNA pada gen L1 yang meng-
kode major capsid protein
 30 tipe hidup pada mukosa anogenital
 ada subtype dan varian
 Terbagi menjadi:
 cutaneous types
 mucosotropic types



Group Prototyp Site Acute Chronic
e disease disease
Cutan. 1,2 Skin Warts None
Cutan-HR 5, 8 Skin Flat SCC
lesions
or Warts
Mucos-LR 6, 11 Anogenital Warts None
mucosa

Mucos-HR 16, 18, Anogenital Flat SCC
31, 33, 45 mucosa, lesions
oral
mucosa



Nonenveloped double-
stranded DNA virus1
 >120 types identified2
 ~30–40 anogenital types2,3

~15–20 oncogenic types*,2,3
 HPV 16 and HPV 18 types
account for the majority of
worldwide cervical cancers.4
~15-20 nononcogenic**
types
HPV 6 and 11 types are most
often associated with
external anogenital
warts.3
*High risk; ** Low risk

1. Howley PM, Lowy DR. In: Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 2001:2197–2229.
2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4.
Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111:278–285.



14.6
HPV Type
16
18
69.7
45
25.7
31
North America/
Europe 17 33
52.5
52
67.6 58
South Asia
12.6 Others
Northern Africa
57

Central/South Indonesia: 16 = 43,7 %
America 18 = 39,4 %
*A pooled analysis and multicenter case control study (N = 3607)
1. Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111:278–285.


Natural HPV Disease Progression

Definitive
Efficacy

0 to 1 Year 0 to 5 Years Up to 20 Years

Persistent CIN Cervical
Infection 2/3 Cancer
Initial or
HPV AIS
Infx
CIN 1

Cleared HPV Infection



 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)



Routes of HPV Transmission



Normal HPV Infection / CIN 2 / CIN 3 /
Cervix CIN* 1 Cervical Cancer

1. 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.



 Abstinence and lifetime mutual monogamy
 risk avoidance Vs. risk reduction
 Condoms offer little protection from infection
but may reduce the likelihood of developing
warts or cancer
 Prophylactic vaccines offer strong promise for
prevention in the future



 Mucosotropic HPV virions tetap tinggal pd
lokasi infeksi awal dan tidak memicu lisis sel

 Dg terjadinya replikasi normal sel, antigenic
capsid protein tdk diekspresikan sampai sel
berdifferensiasi menjadi lapisan superfisial

 Sel yg terinfeksi HPV resisten thd NK cells
tapi dpt dilisis oleh cytokine-activated NK
cells dan macrophage  perlu waktu untuk
membersihkan infeksi dg sistem immune



 Innate response terjadi segera, seroconversi menjadi
antibodi thd HR-HPV bisa perlu waktu 6 bln sampai
1 tahun. Seroconversi untuk tipe LR hampir
bersamaan dg saat infeksi

 Antibodi thd protein capsid bisa bertahan sampai 10
– 15 tahun

 Ab penting untuk mencegah infeksi dan re-infeksi

 Strong cell-mediated response penting untuk viral
clearance ( mell APC, T helper cells, cytolitic T cells
dan costimulatory cytokines)



 HPV sangat resistent terhadap panas dan
proses pengeringan (desiccation).1
 Transmisi non seksual melalui penggunaan
alat-lat pribadi dapat juga terjadi, seperti
penggunaan bersama handuk, pakaian yang
telah terkontaminasi. 1
 Kebanyakan infeksi HPV bisa bertahan
selama 8 bulan dan kemudian menghilang.
Namun sesudah 2 tahun, ditemukan sekitar
10% wanita masih membawa virus yang aktif
dalam vagina dan serviks2

1.Roden RJ Infect Dis 1997;176:1076-9;2.McIntosh N JHPIEGO Str Papers 2000;8:1-14;



HPV sulit dikultur
Tes deteksi dan tipe HPV 3 tes :
Hybrid Capture 2 ( HC2)
Polymerase Chain Reaction
(PCR)
In Situ Hybridization (ISH)



PENCEGAHAN DETEKSI DINI PENGOBATAN

EDUKASI PAP SMEAR Kemoterapi
Radioterapi
KONDOM VIA Pembedahan

VAKSINASI atau

Konsultasi
kepada dokter
anda



SANGAT
PERLU


 PREVENTIF

ATAU

 TERAPETIK



Prophylactic vaccine
Induction of effective humoral
immune responses to protect from
infection/antigen

Therapeutic vaccine
Stimulating cellular immune
responses to eliminate the virally
infected cell/antigen
Bell MC, Alvarez RD.Int J Gynec Cancer, 2005,15: 4-12



 Cervarix® / GSK:
- Vaksin Bivalen
- Untuk HPV 16 dan 18
- Jadwal : 0 – 1 – 6

 Gardasil® / MSD:
- Vaksin Quadrivalen
- Untuk HPV 16, 18 dan 6, 11
- Jadwal : 0 – 2 – 6

 Suntik : im, deltoid



Cancer cx is still a disease with high
insidence mortality and costly

Primary and secondary prevention can
reduce incidence and cancer death

Vaccine is an alternative in developing
country that can not run and organized
screening properly



Hindari penyebab Hindari faktor
resiko

Deteksi dini
VAKSINASI dg test Pap

Jangan takut dengan perkataan KANKER
Timbulkan keyakinan, bila ditemukan lebih dini,
penyakit dapat disembuhkan


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