06 MAR DESE MBER

(1)

06 MARET 2017

Om Swastyastu

(2)

PENCEGAHAN DAN

DETEKSI DINI

KANKER SERVIKS

I N.G. BUDIANA

Divisi Onkologi-Ginekologi,

Departemen Obstetri & Ginekologi,

FK UNUD/RSUP Sanglah Denpasar

(3)

• Lesi Prakanker/Kanker Serviks:



Kausa:

Human Papilloma Virus



Karsinogenesis

• Perjalanan alamiah kanker serviks

• Pencegahan kanker serviks

(4)

• Kanker Ke-2 tersering pada perempuan

Indonesia

1

• _{Hampir 70% sudah pd stadium lanjut}

(> stage IIB)

2

• _{Cakupan Skrining 24,4% (ideal ~ 80%)}

3,4

1).IARC.GLOBOCON 2012

2) INASGO Cancer Registry. 2016

3) HPV Information Centre. Human Papillomavirus and Related Disease Report. 27 July 2017. Available at www.hpvcentre.net

(5)

Sebanyak 58 kasus baru kanker

serviks terjadi setiap harinya.

1 26 wanita Indonesia meninggal

setiap hari karena kanker serviks

1

5

Globocan data 2012

1 BEBAN KANKER SERVIKS DI INDONESIA

Tingkat Kematian, Insidensi, Prevalensi

5 Tahun Tertinggi diantara

Negara-negara di Asia Tenggara

1 _!!!!!

WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human

Papillomavirus and Related Cancers in Indonesia. Summary Report 2014-08-22. Available at www.

Hpvcentre.net

(6)

• Analisis dari 932 spesimen dari wanita di

22 negara menunjukkan prevalensi DNA

HPV pada kanker serviks: 99,7%

HPV adalah penyebab utama

kanker serviks

HPV dan Kanker Serviks

(7)

• HPV ditemukan pada pasien-pasien

kanker serviks: 95,9%

• Sedangkan pada kontrol: 25,4%

Human Papilloma Virus

Di INDONESIA :

De Boer MA, Vet JNI, Azis MF, Cornain S, Purwoto G, van den Akker BEWM, Dijkman A, Peters

AAW, Fleuren GJ. Humanpapilloma virus and other risk factors for cervical cancer in Jakarta,

Indonesia. Int J Gynecol Cancer 2006;16:1809-1814

(8)

• >100 types identified

2 • ~30–40 anogenital

2,3

– Oncogenic*

,2,3

• HPV 16 and HPV 18

types account for the

majority of worldwide

cervical cancers.

4 – Nononcogenic**

• HPV 6 and 11 are most

often associated with

dysplasia and external

anogenital warts.

3

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.

Non enveloped

double-stranded DNA virus

1

(9)

80+%

~40%

~100%

60-90%

~100%

Percentages represent cases attributable to HPV infection 1.Braaten KP et al. Rev Obstet Gynecol. 2008;1:2–10. 2.Hoots BE et al. Int J Cancer. 2009;124:2375–2383.

3.IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Human papillomaviruses. Vol 90. Lyon, France: IARC, 2007.

Kanker

Serviks

1,3

Kanker

Vulva

1

Kanker

Vagina

1

Kanker

Anal

1-3

Kutil

Kelamin

1,3

12-70%

Kanker

Orofaring

3

45%

_Cancer

Penile

3

Tipe kanker High risk

group-16,18,31,33,45,52,58

Tipe non-kanker

grup low risk –

6,11.

(10)

Rute seksual

85 %

Rute Non Seksual

15 %

Kontak Genital :

• Hubungan

senggama

• Genital-genital

• Anal-Genital

• Oral-genital

Extragenital :

• - pakaian

- handuk

- surgical gloves

- biopsi forceps

Vertikal

ibu

Neonatus

Saat lahir

Respiratory

papilomatosis

Horizontal

• Genital-finger

• Ujung jari kuku

1. F.Xavier Bosch et al. International Journal of Gynecology and Obstetrics (2006) 94 (Supplement 1), S8-S21; 2. Sonnex X et al. Sexually Transmitted Infections 1999 Oct;75(5):317-9

(11)

HPV Types

Lead to:

Low-Risk

High-Risk

HPV 6, 11,

40 ,

42, 43, 44,

54, 61,

70, 72, 81

HPV 16, 18,

31, 33, 35, 39, 45,

51, 52, 56, 58, 59,

68 , 73, 82

Benign cervical

changes

Genital warts

Precancer cervical

changes

Cervical cancer

Anal and other cancers

1. Cox. Baillière’s Clin Obstet Gynaecol. 1995;9:1.

2. Munoz et al. N Engl J Med. 2003;348:518.

(12)

Tipe HPV berdasarkan jenis histopatologi

• Adenocarcinoma: dominan HPV tipe 18

(56%)

• Squamous cell carcinoma: dominan HPV tipe

16 (51%)

• Adenosquamous: dominan HPV tipe 18 (46%)

Human Papilloma Virus

Schellekens MC, Dijkman A, Azis MF, Siregar B, Cornain S, Kolkman S, Peters LAW, Fleuren GJ.

Gynecologic Oncology 93 (2004):49-53

(13)

• Virus DNA, tdk berkapsul

• Genom: 8000 pasang

basa

• Kapsid:



Kapsid Mayor (L1): 80%

dari total protein



Kapsid Minor (L2)

(14)

Human Papilloma Virus

• Genom virus terbagi :

–

Early region

(E): transkripsi, replikasi dan

transformasi virus

–

Late region

protein (L): mengkode protein

kapsid virus

–

Long control region (LCR)

: mengandung

elemen pengontrol transkripsi dan replikasi

(15)

Fungsi Protein HPV:

Human Papilloma Virus

________________________________________

E1

E2

E4

E5

E6

E7

L1

L2

________________________________________

Replikasi virus

Replikasi dan transkripsi virus

Siklus pertumbuhan dan pematangan virus

Transformasi virus

Onkoprotein, berikatan dengan p53

Onkoprotein, berikatan dengan pRb

Mengkode protein kapsid mayor

Mengkode protein kapsid minor

(16)

(17)

(18)

1.Stanley M. Vaccine 2006; 24: S106-13, 2.Tindle, Nat Rev Cancer 2002; 2, 59, 3.Stanley M. Vaccine 2006; 24: S16-22, 4. Stanley M. HPV Today 2007; 11: 1-16

Local infection

1-4

Infect the epithelium through micro abration

No viremia

1-4

Enters basal epithelial cells, integrates DNA in host cell

1-4

Replication in the cells and remains entirely intraepithelial

Local immunosupression

1-4

1-4

Uses the natural life cycle of epithelial cells to release new viruses

1-4

Doesn’t cause cell deaths

No inflammation,

1-4

No attraction of immune cells

Poor exposure to Antigen Presenting Cells

(19)

Perjalanan infeksi HPV ?

Jika terinfeksi HPV

80% akan dibersihkan

dengan sistem immun

(kekebalan)

10- 20% berkemungkinan menjadi

infeksi persisten (menetap)

Risiko menjadi kanker serviks

Kebanyakan pria dan wanita yang telah berhubungan seksual, berisiko

terinfeksi HPV

Lebih dari 75% wanita yg berhubungan intim, pernah

terinfeksi HPV, puncak di antara umur 18-22 tahun

(20)

Biopsy

Regress

Persist

Progress Progress

Result

to CIS to Invasion

CIN1

57%

32%

11%

1%

CIN2

43%

35%

22%

5%

CIN3

32%

56%

--

>12%

CIN = Cervical Intraepithelial Neoplasia

Source: Öst

Ö

r AG. Int J Gynecol Pathol. 1993;12(2):186-192.

(21)

(22)

Lesi Prakanker Serviks

• Infeksi HPV, CIN-1/displasia ringan

CIN derajat rendah (LSIL)

• CIN-2/displasia sedang, CIN-3/displasia berat,

karsinoma insitu

(23)

(24)

PENCEGAHAN

DETEKSI

DINI

PENGOBATAN

EDUKASI

KONDOM

VAKSINASI

PAP SMEAR

Inspeksi Visual

dg Asam Asetat

(IVA)

Kemoterapi

Radioterapi

Pembedahan

(25)

Pencegahan Primer

Strategi Pencegahan Kanker Serviks

• Menghilangkan/mengurangi risiko kanker

serviks pd individu normal:



Edukasi/Promosi



Vaksinasi

(26)

Vaksinasi HPV diprioritaskan untuk individu yang naïve

terhadap HPV yaitu target usia 9-13 tahun.

(WHO position paper 2014)

Masih bisa

menerima

manfaat dari

vaksinasi HPV

World Health Organization, United Nations Population Fund. Preparing for the Introduction of HPV Vaccines: Policy and Programme Guidance for Countries. World Health Organization; 2006. World Health Organization. Weekly Epidemiological Record. 2009;15(84):117–132.

US FDA. FDA Licenses New Vaccine for Prevention of Cervical Cancer and Other Diseases in Females Caused by Human Papillomavirus. Available at

http://www.fda.gov/bbs/topics/NEWS/2006/NEW01385.html.2006. Accessed October, 2007.

The American College of Obstetricians and Gynecologists. Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. ObstetGynecol. 2006; 108 : 699 – 705

(27)

REKOMENDASI WHO

World Health Organization, United Nations Population Fund. Preparing for the Introduction of HPV Vaccines: Policy and Programme Guidance for Countries. World Health Organization; 2006. World Health Organization. Weekly Epidemiological Record. 2009;15(84):117–132.

US FDA. FDA Licenses New Vaccine for Prevention of Cervical Cancer and Other Diseases in Females Caused by Human Papillomavirus. Available at

http://www.fda.gov/bbs/topics/NEWS/2006/NEW01385.html.2006. Accessed October, 2007.

The American College of Obstetricians and Gynecologists. Human Papillomavirus Vaccination. ACOG Committee Opinion No. 704 Juni 2017

Vaksinasi membantu memberikan perlindungan

3 Vaksinasi direkomendasikan tanpa melihat aktivitas seksual

seseorang atau paparan sebelumnya terhadap HPV.

Vaksinasi direkomendasikan bahkan bila pasien tersebut

positif pada tes HPV DNA

4 Primary prevention:

(28)

• Vaksin HPV



Vaksin Kanker Serviks

• Proteksi tehadap HPV

risiko tinggi yang paling

banyak menyebabkan

kanker (70%)  yaitu

HPV 16 dan 18

(29)

Vaksin

Quadrivalen

(30)

Keuntungan Vaksin HPV

• Vaksinasi merangsang pembentukan

antibodi serum

•Data menunjukkan bahwa antibodi

serum yang diinduksi vaksin,

bertransudasi ke lokasi infeksi

1-4

•Makin tinggi kadar antibodi serum,

artinya kadar antibodi di lokasi infeksi

juga semakin tinggi

5,6

•Antibodi menetralisir virus dan

mencegah virus masuk kedalam sel

7,8

1. Parr EL et al. J Virol 1997;71(11):8109-15, 2. Nardelli-Haefliger D et al. J Natl Cancer Inst 2003;95(15):1128-37, 3. Schiller JT et al. Nat Rev Microbiol 2004;2(4):343-7, 4. Kemp TJ et al. Clin Vaccine Immunol 2008;15(1):60-4, 5. Stanley et al. Vaccine 2006; 24 Suppl 3, S106, 6. Poncelet et al. ESPID, Porto, Portugal 2007; Abstract 37, session ES2, 7. Stanley M. HPV Today 2007; 11: 1-16, 8. Einstein M, Cancer Immunol Immunother 2007; 57(4):443-51.

(31)

Tes HPV

• Tes HPV yang ada hanya dapat mendeteksi apakah

seorang wanita telah terinfeksi HPV risiko tinggi

(16, 18, 31, 35, 45, 52, 58, dll)

• Tidak dapat menentukan jenis HPV yang

menginfeksi

Bukan merupakan keharusan sebelum

pemberian vaksin !!

(32)

Pedoman HOGI – wanita berusia 10-55 thn

(Andrijono. Kanker Serviks. Edisi 3. Divisi Onkologi.

Dept. Obstetri-Ginekologi FKUI, Jakarta. Balai Penerbit FKUI; 2010: 111)

Pedoman IDAI – remaja putri



10 tahun

(Ikatan Dokter Anak Indonesia (IDAI) 2010

Pedoman PAPDI – remaja putri & wanita berusia 12-55 tahun

(PAPDI- Buku Konsensus Imunisasi Dewasa 2008)

(33)

Bila Hasil Tes Skrining Abnormal

• Bila hasil tes skrining abnormal, misal

terdapat lesi pra kanker



obati dulu lesi pra kanker tersebut

• Vaksin bukan merupakan pengobatan

untuk lesi pra kanker!!

(34)

• Efek samping minimal

• Antara lain :

– Kemerahan pada tempat suntikan

– Pusing

– Demam

(35)

Vaksin Jangan Diberikan Pada :

– Sakit Berat

– Hamil

– Dalam waktu dekat

berencana hamil

(36)

• Skrining rutin tetap

harus dilakukan

• Bukan berarti sudah

divaksinasi berarti

bebas skrining rutin

• Mengurangi risiko

70-80% terjadinya kanker

serviks

(37)

Vaksin HPV Yang Tersedia

• Gardasil

®



Proteksi terhadap HPV 6, 11, 16 dan 18



Pemberian 0 – 2 – 6

• Cervarix

®



Proteksi terhadap HPV 16 dan 18



Pemberian 0 – 1 – 6

(38)

Hari ini

Vaksinasi 1

1/2 Bulan Kemudian

Vaksinasi 2

6 Bulan Kemudian

Vaksinasi 3

Vaksinasi Selesai

Skrining rutin

Pemberian Vaksinasi

(39)

Pencegahan Sekunder

Strategi Pencegahan Kanker Serviks

• Deteksi dini fase lesi prakanker dan

melakukan terapi secara adekuat sebelum

berkembang menjadi kanker serviks

(40)

SCREENING METHOD OF CERVICAL PRECANCER LESION

Cytology

Pap

LBC

Conventional

DNA HPV

Amplification

Non

amplification

In situ

hibridisation

Blot Southern

Target

_(tracer)

Probe

Signal

PCR

LCR

HC

- Denny, L. 2012. Cytological screening for cervical cancer prevention. Best Practice & Research Clinical Obstetrics and Gynaecology. Cape Town, 26:189-96.

- Brown, A., Trimble, C. 2012. New technologies for cervical cancer screening. Best Practice & Research Clinical Obstetrics and Gynaecology. Baltimore, 26:232-42.

Visual

inspection

Direct

Colposcopy

VIA

VILI

DNA

HPV

COLPOSCO

PY

INSPECTION

METHOD

(VIA/VILI)

CYTOLOG

Y

Conventional

LBC

(41)

dr.Hans Hinselmann

dr.Helmut Wirths

(1925)

+

Low grade lesion with

acetowhite epitel, good

vascular pattern

High grade lesion with

dense acetowhite

epitel, coarse and

abnormal vascular

pattern

Fusco, E., Padula, F., Mancini, E., Cavallere, A., Grubisic, G. 2008. History of colposcopy: a brief biography of Hinselmann. Journal of Prenatal Medicinel. Rome, 2(2): 19-23.

VISUAL

INSPECTI

ON

METHOD

VIA

_VILI

+

indirect

(42)

VIA

Speculum

inspection

Acetic acid

3% - 5%

Light

source

+

Aceto acetic white (+)

Cervical

neoplasia

Sensitivity

85.50%

(compare with

conventional

cytology)

Sensitivity

80.75%

(compare with

histopathology

biopsy)

Specificity

82.35%

(compare with

conventional

cytology)

Specificity

73.78%

(compare with

histopathology

biopsy)

More coarse and

clearly

W H O , 1985

(43)

+

-- Menopause & elderly

women accuracy

- False positive

- Widely available

- Simple, feasible, cheap

- Low resources area

VIA

Sankaranarayanan, R., Nessa, A., Esmy, P., Dangou, J. 2012. Visual inspection methods for cervical cancer prevention. Best Practice & Research Clinical Obstetrics and Gynaecology, 26:221-32.

(44)

INTERPRETASI IVA

1. NEGATIF

licin, merah muda, bentuk porsio

normal

2. POSITIF

plak putih, epitel acetowhite (bercak

putih)

(indikasi lesi prakanker serviks)

Makin putih & jelas, makin tajam batasnya

(45)

(46)

MESRA

☺ MURAH

☺ EFEKTIF

☺ SEDERHANA

☺ RASIONAL

☺ AMAN

“TIDAK PERLU TENAGA

KHUSUS”

(47)

SEE

IVA

TREAT

??

SEE AND TREAT

(SINGLE VISIT APPROACH)

(48)

(49)

KRIOTERAPI

☻ PROSEDUR RELATIF MUDAH

☻ MENGHANCURKAN SEL PRAKANKER

☻ PENDINGINAN DENGAN GAS CO2, N2O

☻ MENCIPTAKAN BOLA ES 4-5 MM LATERAL

CRYOPROBE

☻ WAKTU 15 MENIT

☻ TANPA ANESTESI

☻ RAWAT JALAN

(50)

Cryotherapy. Probe krio menutupi lesi (a,b). Pembentukan bola es (c,d

(51)

(a) Bola es pada serviks segera setelah krioterapi, (b) Penampakan 2

minggu setelah krioterapi. (c) 3 bulan setelah krioterapi. (d) 1 tahun

(52)

IVA

KRIOTERAPI

M E S R A

METODE SINGLE VISIT APPROACH/

SEE & TREAT

(53)

(54)

Speculum

inspection

Lugol’s

Iodine

Light

source

+

V I L I

dr. Walter Schiller, 1930

Non absorption area,

yellow mustard (+)

Not

recommended as

single screening

Sensitivity

44% - 92%

Specificity

75%-85%

Additional

screening, if the

results doubted

Sankaranarayanan, R., Nessa, A., Esmy, P., Dangou, J. 2012. Visual inspection methods for cervical cancer prevention. Best Practice & Research Clinical Obstetrics and Gynaecology, 26:221-32.

(55)

Speculum

inspection

Normal saline, acetic acid

3%-5%, lugol’s iodine

lluminated stereoscopic

and magnified

+

Reid Index

False

Negative

21.65%

(compare with

LBC)

Sensitivity

87.23%

(compare with

LBC)

Specificity

75.68%

(compare with

LBC)

Hinselman, 1925

- Suwiyoga, K., Mas, G. 2008. Akurasi Kolposkopi pada Lesi Serviks. Majalah Kedokteran Udayana. 24:12-5.

- Marel, J., Baars, R., Rodriguez, A., Quint, W., Sandt, M., Berkhof, J. 2014. The increased detection of cervical intraepithelial neoplasia when using a second biopsy at colposcopy. Gynecology Oncology. Netherland, 135: 201-7.

COLPOSCOPY

False

Positive

15.25%

(compare with

LBC)

(56)

- Leeson, S. 2012. Advances in colposcopy: new technologies to challenge current practice. European Journal of Obstetrics & Gynecology and Reproductive Biology. United Kingdom, 182: 140-45.

- Safaeian, M., Solomon, D., Castle, P. 2007. Cervical Cancer Prevention-Cervical Screening: Science in Evolution. Obstet Gynecol Clin N Am, 34: 739-60

COLPOSCOPY INDICATION

• Screening test result positive

• Suspicious cervical appearance

• External genital wart  any screening result

• Clinically found leucoplacia

• High risk cervical neoplasia:

-

Abnormal cytology, include ASCUS, with oncogenic

HPV test (+)

(57)

dr. Papanicolaou (1920)

The cytological hallmark

of LSIL is the koilocyte.

The

nuclei are large and

coarsely dark.

HSIL. The nuclei in the

cell group at the center

of the field are

hyperchromatic

but only mildly enlarged.

CYTOLO

GY

Conventional

Cytology

(Pap)

Liquid Base

Cytology

(58)

(59)

CONVENTIONAL CYTOLOGY (PAP SMEAR)

LIMITATION

Smear

factor

Resources

factor

Remaining cell

at cytobrush ≥

80%

Artefact/poor

staining

Pap

Operator

Lab

technicians

Inadequacy smear

± 13.8%

False negative

± 30%

Denny, L. 2012. Cytological screening for cervical cancer prevention. Best Practice & Research Clinical Obstetrics and Gynaecology. Cape Town, 26: 189-96.

(60)

Cervical

cell smear

Liquid

medium

+

Suspension

Thin, homogenous, debris free

Cervical smear coverage

(90-100% vs 10-20%)

ASCUS identification

(18% vs 2.1%)

LBC vs conventional PAP

Smear inadequacy

(5.7% vs 13.8%)

(FDA, 1995)

L B C

(FDA, 1999)

Sankaranarayanan, R., Gaffikin, L., Jacob, M., Sellors, J., Robles, S. 2005. A critical assessment of screening methods for cervical neplasia. International Journal of Gynecology and Obstetrics, 89: S4-S12.

(61)

CONVENTIONAL CYTOLOGY vs LBC

Conventional Cytology

L B C

> 80% collected sample spilled

Virtually, 100% sample rinse in LBC vial

Blood, vaginal discharge, debris contained in

smear

Blood, vaginal discharge, debris non diagnostic

separated from the cell  excluded from smear

Poor cell distribution

Filtration  good cell distribution dan

randomisation

Many cell missed&artefact  limited accuracy

Thin cell layer free artefact  representative

Not representative sample  not reflect patient

actual condition

Abnormality detection

Beerman, H., Dorst, E., Boumeester, V., Hogendoorn, P. 2009. Superior performance of liquid-based versus conventional cytology in a population-based cervical cancer screening program. Gynecology Oncology, 112: 572-76.

(62)

Anttilla, A., Aoki, D., Arbyn, M, Austoker, J., Bosch, X., Chirenje, Z. 2005. IARC Handbooks of Cancer Prevention: Cervic Cancer Screening. First Edition. IARC press: South Africa Selatan. p. 1-242