Cervical Cancer Symposium - Faculty of Medicine - Muhammadiyah University Surakarta Paragon Hotel Solo, February /04/2014 1

(1)

Early

Early Diagnosis

Diagnosis

of

of P

Precancerous Cervical

recancerous Cervical llesions

esions

Heru

Heru PriyantoPriyanto

Gyne

Gyne OncologistOncologist

Cervical Cancer Symposium

-Faculty of Medicine - Muhammadiyah University Surakarta Paragon Hotel Solo, February 2012

(2)

The most frequent

of cancer in

Indonesia ~ (34.4% of women

Indonesia ~ (34.4% of women cancer)

cancer)

Almost

70% of advanced stage

Introduction

30/04/2014 2

Almost

70% of advanced stage

( > stage IIB)

22

_{, low survival rate}

15.000 new cases, 8.000 death

33

_;

40 40 –

– 45 new cases,

45 new cases,

20

(3)

Vagina 0.3% Vulva 0.7% Trophoblast 5.9%

Gynecologic Cancer Distribution : Indonesia Gynecologic Cancer Distribution : Indonesia

Cervical Cancer 75.5% Uterine Corpus 2.7% Ovary 14.9%

The most frequent

The most frequent of of cancer cancer in gynecologic organ is

(4)

Global mortality per annum

North America 14,500 new cases 6,000 deaths Asia 266,000 new cases 143,000 deaths Europe 60,000 new cases 30,000 deaths • _Worldwide,every 2 minutesa woman dies of cervical cancer

• _{The highest burden}

of disease (up to 80%) occurs in less developed regions where there is a lack

30/04/2014 4

Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. Lyon: IARC CancerBase, 2004.

Cervical cancer mortality rates worldwide

Cases per 100,000 women per year Latin America 72,000 new cases 33,000 deaths Africa 79,000 new cases 62,000 deaths

where there is a lack of effective

screening programmes

• _{This demonstrates}_a

clear medical need

for new cervical cancer interventions

< 7.9 < 14.0 < 23.8 < 55.6 < 3.9

(5)

Uterus Ovary

Cervik

Introduction

(6)

High risk

(oncogenic)

Tipe 16,18

(>70%)

Etiology

Etiology of Cervical Cancer

of Cervical Cancer

Virus : HPV : Human Papiloma Virus

30/04/2014 6

HPV

Low risk

(Non – oncogenic)

(7)

Every women at RISK

Throughout life, ± 80%

of women will be

infected with HPV.

50% of women will be

infected with

cancer-causing HPV strains.

(8)

Papillomavirus phylogenetics

Warts on hands and feet 57 2a 27 61 45 11 18 59 70 39 68 42 32 40 7 55 44 PCPV1 13 Anogenital warts HPV 18 is most closely related to HPV 45 30/04/2014 8 66 5653 30 26 29 10 28 3 6 16 73 34 RhPV1 58 33 52 35 31 warts 51 HPV 16 is closely related to HPV 31, 33, 35, 52 and 58

High-risk (oncogenic) HPV types Low-risk HPV types

(9)

Most common HPV types associated

with cervical cancer worldwide

HPV 16 HPV 18 53.5% 17.2% HPV 16 + 18 are associated with 70.7% of cervical cancer cases 30/04/2014 9

Association of HPV types with cervical cancer, %

HPV 45 HPV 31 Others 6.7% 2.9% 19.7% 0 10 20 30 40 50 60

(10)

Indonesia

Most common HPV types in cervical cancer

Age-specific incidence

and mortality of cervical cancer

HPV 16

HPV 18

43.0%

38.0%

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Castellsagué X, et al. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). C105 Available at: www.who.int/hpvcentre (accessed 25 June 2009).

CC ranking Incidence Mortality All ages 2nd 2nd 15–44 years 2nd 2nd HPV 52 HPV 45 HPV 82 9.1% 7.4% 2.1% 0 10 20 30 40 50 60

(11)

HPV is the necessary cause of cervical

cancer

1,2

Cancer and causative agent

Relative Risk

2

Cervical cancer from HPV 300–500

Liver cancer from HBV (Taiwan) 100

30/04/2014 11

Liver cancer from HBV (Taiwan) 100

Liver cancer from HCV (Italy) 20

(12)

Global total HPV-attributable cancers in 2002 Attributable to HPV % all HPV cancer Attributable to HPV 16/18 Site Total

cancers % Cases % Cases

100% of cervical cancers are caused

by HPV

30/04/2014 12 Cervix 492,800 492,800 344,900 Anus 15,900 90* 14,300 2.7 92 13,100 Oropharynx 9,600 12* 1,100 0.2 91 1,000 Mouth 98,400 3* 2,900 0.5 97 2,800

Adapted from Parkin DM & Bray F. Vaccine 2006; 24(Suppl 3):S11–S25; Walboomers JMM, et al. J Pathol 1999; 189:12–19.

Vulva, vagina 40,000 40* 16,000 3 80 12,800

Total 527,100 374,600

(13)

Natural History of Cervical Cancer Natural History of Cervical Cancer

--- 3-17 tahun

---Mild

dysplasia Moderate_dysplasia Severe_dysplasia

Insitu

Carcinoma

Invasive Cancer

(14)

Squamous Mature squamous

layer

Cervical canal

How does HPV cause cancer in the

cervix?

Shedding of virus-laden epithelial cells

Viral assembly (L1, L2, E4)

Viral DNA replication (E6 & E7)

30/04/2014 14 Normal epithelium Basement membrane Basal (stem) cells Parabasal cells Squamous layer Infected epithelium

Frazer IH. Nat Rev Immunol 2004; 4:46–54.

Episomal viral DNA in cell nucleus

(E1 & E2, E6 & E7)

Infection of basal cells (E1 & E2)

(15)

Disease progression

Time Months Years

Low-grade squamous intraepithelial lesions (LSILs) High-grade squamous intraepithelial lesions (HSILs) ICC Screening Treatment Normal epithelium HPV infection; koilocytosis

(16)

Carcinogenesis

(17)

Mode

Mode of transmission

of transmission

Oral Sex - rare

Perinatal - rare

Digital - rare

"Outercourse" - rare

Anal intercourse - often

Vaginal intercourse - often

(18)

Screening and Early Diagnosis

of Cervical Cancer

(19)

Pencegahan

Pencegahan Kanker

Kanker Serviks

Serviks

Pencegahan

Pencegahan Kanker

Kanker Serviks

Serviks

Kanker Serviks merupakan penyakit yang dapat

dicegah

Pencegahan

Pencegahan primerprimer

Pendidikan untuk menurunkan perilaku sek risiko

tinggi.Pemeriksaan untuk menurunkan/mencegah risikorisiko tinggi.Pemeriksaan untuk menurunkan/mencegah risikorisiko terpapar

terpapar virus HPV.virus HPV.

Pencegahan

Pencegahan sekundersekunder

Pengobatan

Pengobatan lesilesi prakankerprakanker sebelumsebelum berkembangberkembang menjadi

menjadi kankerkanker serviksserviks ((melakukanmelakukan testes skriningskrining

Pencegahan

Pencegahan TersierTersier ::

menurunkan

menurunkan morbiditasmorbiditas bilabila telahtelah terdiagnosaterdiagnosa kankerkanker serviks

(20)

Cervical cancer prevention methods

Normal cervix/

CIN 12 _{CIN 2}2 _{CIN 3}3 _ICC3

30/04/2014 20

cervix/ Sub-clinical HPV infection1

CIN 12

1. Image used with permission from Professor Achim Schneider; 2. Image used with permission from Professor Muhieddine Seoud; 3. GSK Image Library

CIN 22 _{CIN 3}3 _ICC3

HPV vaccines:

Primary prevention

Cervical screening

(VIA, Pap smear, HPV testing):

Secondary prevention

Treatment

(21)

Deteksi

Deteksi Dini

Dini Kanker

Kanker Serviks

Serviks

1. Tes skrining

2. Tes pelengkap

(22)

TES

TES Skrining

Skrining

Pap smear

Pemeriksaan sitologi eksfoliatif

dari epitel serviks untuk mendeteksi

30/04/2014 22

lesi prakanker secara dini

(23)

TES

TES P

Pelengkap

elengkap

Tes

Tes HPV DNA

HPV DNA

TES

TES Diagnostik

Diagnostik

TES

TES Diagnostik

Diagnostik

Kolposkopi

Biopsi

(24)

Apakah

Apakah Pemeriksaan

Pemeriksaan

Sitologi

Sitologi/Pap Smear

/Pap Smear itu

itu ??

Pap Smear atau Pap Test adalah

pemeriksaan

sitologi

untuk skrining atau

deteksi

Kanker

Leher

Rahim

yang

dilakukan dengan cara melihat adanya

30/04/2014 24

dilakukan dengan cara melihat adanya

perubahan

perubahan morfologi

morfologi sel

sel--sel

sel leher

leher rahim

rahim

dengan teknik pewarnaan Papanicolau

kemudian diamati di bawah mikroskop

oleh seorang ahli Patologi Anatomi

(25)

1. Usapan spatula Eyre pada ektoserviks dulu,

Pulas di kaca benda

2. Usapan “Cytobrush” pada 2).

PAP Smear

2. Usapan “Cytobrush” pada endoserviks,

Pulas di kaca benda 3. Rendam kaca benda

dalam alkohol 96%, minimal 30’

1). 2).

(26)

Persentase transfer sel epitel pada kaca benda

berdasarkan variasi alat

Persentase transfer sel epitel pada kaca benda

berdasarkan variasi alat

6,5 %

6,5 % dengan

dengan kapas

kapas lidi

lidi / spatula

/ spatula

PAP Smear

30/04/2014 26

6,5 %

6,5 % dengan

dengan kapas

kapas lidi

lidi / spatula

/ spatula

8,4 %

8,4 % dengan

dengan cytobrush

cytobrush

18,1 %

(27)

(28)

PAP Smear

(29)

Kelebihan Thin Prep / LBC / SSBC

•

Menurunkan angka negati palsu dan positif palsu • Menurunkan angka Kesalahan interpretasi

• Meningkatkan akurasi Tes Pap • Mengurangi kelelahan skriner

PAP Smear

• Mengurangi kelelahan skriner

Kekurangan Thin Prep

(30)

Padanan dari Klasifikasi Papanicolao Smear

Class I Class II Class III Class IV Class V Normal Inflam Mild Mod Sev

CIS Cancer D y s p l a s i a

Normal Atypia CIN I CIN II CIN III Cancer

K o i l o c y t o s i s WNL Benign Cellular Changes AS

CUS LGSIL HGSIL HGSIL Carcinoma

NEGATIF AS

(31)

IVA Test

Alternatif skrining

Non –invasif

INSPEKSI VISUAL

INSPEKSI VISUAL dengan

dengan

ASAM ASETAT (IVA )

Non –invasif

Mudah-murah Di Puskesmas

Hasil LANGSUNG

Sensitivitas,spesifisitas memadai

(32)

IVA Test

ALAT / BAHAN IVA

• Meja pemeriksaan • Sumber cahaya yang

cukup

30/04/2014 32

cukup

• Asam asetat 3 - 5 % • Kapas lidi

• Sarung tangan bersih ( lebih baik steril)

• Spekulum vagina

Seminar

(33)

IVA Test

Epitel

(34)

• CUKA DAPUR (mengandung asam asetat 20%)

• ASAM ASETAT UNTUK IVA (3-5%)

• Untuk membuat asam asetat 5% dengan cara

IVA Test

30/04/2014 34

asetat 5% dengan cara mengambil 1 bagian cuka dapur + 4 bagian air

• Untuk membuat asam asetat 3% dengan cara mengambil 2 bagian cuka dapur + 11 bagian air

(35)

IVA Test

posisi litotomi,

tampilkan serviks, nilai mencurigakan kanker, tidak perlu IVA

apakah SSK tampak seluruhnya?

Jika tidak tampak 

Video Video

Jika tidak tampak  IVA, beri catatan, sebaiknya  tes Pap SSK terlihat semua, IVA, tunggu 1 menit, apk timbul epitel putih lakukan penillaian

(36)

Sebelum

_Setelah

Pemulasan Asam Asetat

Nabothian cyst

NIS I, LSIL

Epitel merah keabuan sampai kuning

(37)

IVA Test

(38)

PEMERIKSAAN

HPV

HPV DNA

DNA

30/04/2014 38

Pemeriksaan molekuler dengan metode “hybrid capture” / PCR untuk mendeteksi adanya DNA Human Papiloma Virus tipe “high risk” pada sampel yang diambil dari serviks

(39)

TES DIAGNOSTIK TES DIAGNOSTIK

(40)

Clinical appearance of precancerous

Clinical appearance of precancerous lesions

lesions

( CIN )

30/04/2014 40

LGSIL

(41)

Options / suggestions therapies for CIN

CIN I : Follow Up CIN I : Follow Up CIN I and HPV + :

CIN I and HPV + : ??????

CIN I and II : Cryosurgery CIN I and II : Cryosurgery

E. Cautery E. Cautery LEEP / LLETZ LEEP / LLETZ

30/04/2014 _{PIT POGI XIX Jakarta 2011}41

CIN III : LLETZ CIN III : LLETZ

LEEP / LLETZ LEEP / LLETZ

(42)

BIOPSI

(43)

IVA +

Lesi derajat rendah (NIS 1 - 2 ) Lesi Derajat tinggi (NIS 3 ?)

Krioterapi

(44)

Elektrokauter

30/04/2014 44

2 months post

(45)

Konisasi

Konisasi -- LEEP / LLETZ

LEEP / LLETZ

Video Video

(46)

Take Home Message

Cervical Carcinogenesis

HPV Infection

30/04/2014 46

Pre-Cancer Stage

gives us the opportunity to do screening and therapy, so it does not develop into invasive cancer.

(47)

Thank You

(48)

(49)

Pengobatan

Pengobatan Kanker

Kanker Serviks

Serviks

••

Operasi

••

Kemoterapi

••

Radioterapi

(50)

Radikal Histerektomi

30/04/2014 50

Video Video

(51)

Pengobatan

Pengobatan Kanker

Kanker Serviks

Serviks

Robotic Surgery

(52)

30/04/2014 52

Robotic Surgery

Robotic Surgery –– UtrecthUtrecth Medical Center Medical Center –– Netherlands, 2011Netherlands, 2011 Video Video

(53)

HPV Vaccination

(54)

Lindungi Kesehatan Wanita

LINDUNGI KEHIDUPAN

30/04/2014 54

Siapa

Siapa yang

yang berisiko

berisiko

Kanker

(55)

WHO statement on safety of

HPV vaccines

Recipients of both the

Recipients of both the quadrivalentquadrivalent and bivalent HPV vaccines and bivalent HPV vaccines

30/04/2014 55

Recipients of both the

Recipients of both the quadrivalentquadrivalent and bivalent HPV vaccines and bivalent HPV vaccines have reported more injection adverse events (pain, swelling, have reported more injection adverse events (pain, swelling, erythema) than recipients of placebo or HAV control, regardless erythema) than recipients of placebo or HAV control, regardless of age

of age

Incidence of local adverse event does not vary by pre Incidence of local adverse event does not vary by pre--vaccination HPV infection status

vaccination HPV infection status

(56)

Vaccine : prevention at the site of

infection

• Vaccination induces serum antibodies

• High serum antibody levels

correlate with high antibody levels

HPV Cervical canal Neutralizing antibody Cervical 30/04/2014 56

correlate with high antibody levels

at the site of infection1

• Antibodies neutralize the virus and prevent viral entry into cells2,3 Blood vessel Epithelial tear Basement membrane Cervical epithelium

1. Schwarz TF, Vaccine 2009; 27:581–587; 2. Stanley M. HPV Today 2007; 11:1–16; 3. Einstein M. Cancer Immunol

Immunother 2007; 57:443–451; 4. Einstein MH, et al. Lancet Infect Dis 2009; 9:347–356; 5. Schiller JT and Lowy DR. J Infect Dis 2009; 200:166–171.

(57)

Recommendations on HPV vaccination from the Asian

Cervical Cancer Prevention Advisory Board (ACCPAB)

Sexual exposure

No

Vaccination

Yes

Screening based on local guidelines

(not mandatory prior to vaccination)

J Obst et Gynae col Res 200 9; in press. 30/04/2014 57 Vaccination Negative Vaccination Positive Manage according to local guidelines Vaccination as appropriate • HPV vaccination is best

administered prior to sexual debut • Vaccination can also be

recommended to healthy older women who are already sexually active

• Vaccination is also recommended for women who have cleared a prior HPV infection

Basu P , et a l. J Obst et Gynae col Res

(58)

WHO HPV vaccination recommendations

30/04/2014 58

"WHO recognizes the importance of cervical cancer and other "WHO recognizes the importance of cervical cancer and other HPV

HPV--related disease as global health problems and related disease as global health problems and recommends that routine HPV vaccination

recommends that routine HPV vaccination should be included should be included in national immunization program.

in national immunization program.

WHO Position Paper (April 2009); Available at: www.who.int/immunization/documents/positionpapers/en/index.html (Accessed 25 June 2009).

(59)

Take Home Message

(60)

www.indocancer.com

www.doctorhandsbook.com

30/04/2014 60