Early Diagnosis of Precancerous Cervical lesions
Heru Priyanto Gyne Oncologist Cervical Cancer Symposium Faculty of Medicine - Muhammadiyah University Surakarta Paragon Hotel Solo, February 2012 30/04/2014
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Introduction The most frequent of cancer in Indonesia ~ (34.4% of women cancer) Almost 70% of advanced stage ( > stage IIB) 2, low survival rate 15.000 new cases, 8.000 death 3; 40 – 45 new cases, 20 – 25 dies/day, 1 dies/hour
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Gynecologic Cancer Distribution : Indonesia Trophoblast 5.9% Vagina 0.3% Vulva 0.7% Uterine Corpus 2.7%
Ovary 14.9% Cervical Cancer 75.5%
The most frequent of cancer in gynecologic organ is Cervical Cancer 30/04/2014
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Global mortality per annum •
Worldwide, every 2 minutes a woman dies of cervical cancer
•
The highest burden
•
of disease (up to 80%) occurs in less developed regions where there is a lack of effective screening programmes This demonstrates a
Europe 60,000 new cases 30,000 deaths
North America 14,500 new cases 6,000 deaths
Asia 266,000 new cases 143,000 deaths
Latin America 72,000 new cases 33,000 deaths
Africa 79,000 new cases 62,000 deaths
clear medical need for new cervical cancer interventions
Cervical cancer mortality rates worldwide Cases per 100,000 women per year
< 3.9
< 7.9
< 14.0
< 23.8
< 55.6
30/04/2014 Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. Lyon: IARC CancerBase, 2004.
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Introduction Uterus Ovary Cervik
Anatomy 30/04/2014
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Etiology of Cervical Cancer Virus : HPV : Human Papiloma Virus
High risk (oncogenic)
HPV
Low risk
Tipe 16,18 (>70%)
Human Papiloma Virus (HPV)
(Non – oncogenic)
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Every women at RISK Throughout life, ± 80% of women will be infected with HPV. 50% of women will be infected with cancercausing HPV strains.
(Walboomers: 1999; Burd: 2003). 30/04/2014
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Papillomavirus phylogenetics 39 70 59 68
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Anogenital warts
44 55 PCPV1 13 11
7
32
HPV 18 is most closely related to HPV 45
42
18
45
27 2a 57
61
Warts on hands and feet
6
73 34
RhPV1
HPV 16 is closely related to HPV 31, 33, 35, 52 and 58
3 28 10 29
58 33 52
16
35 31
51 26 30 53 56 66
High-risk (oncogenic) HPV types Low-risk HPV types 30/04/2014 Figure adapted from de Villiers EM, et al. Virology 2004; 324:17–27.
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Most common HPV types associated with cervical cancer worldwide 53.5%
HPV 16 17.2%
HPV 18
HPV 16 + 18 are associated with 70.7% of cervical cancer cases
6.7%
HPV 45
2.9%
HPV 31
19.7%
Others 0
10
20
30
40
50
60
Association of HPV types with cervical cancer, % 30/04/2014 Adapted from Muňoz N, et al. Int J Cancer 2004; 111:278–285.
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Indonesia Age-specific incidence and mortality of cervical cancer
Most common HPV types in cervical cancer 43.0%
HPV 16
38.0%
HPV 18 9.1%
HPV 52
7.4%
HPV 45
2.1%
HPV 82 CC ranking
Incidence
Mortality
All ages
2nd
2nd
15–44 years
2nd
2nd
0
10
20
30
40
50
60
Castellsagué X, et al. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). C105 30/04/2014 10 Available at: www.who.int/hpvcentre (accessed 25 June 2009).
HPV is the necessary cause of cervical cancer1,2 Cancer and causative agent Cervical cancer from HPV
Relative Risk2 300–500
Liver cancer from HBV (Taiwan)
100
Liver cancer from HCV (Italy)
20
Cigarette smoking
10
30/04/2014 1. Wallboomers JH, et al. J Pathol 1999; 189:1219; 2. Bosch FX, et al. J Clin Pathol 2002; 55:244–265.
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100% of cervical cancers are caused by HPV Global total HPV-attributable cancers in 2002 Attributable to HPV
Attributable to HPV 16/18
Total cancers
%
Cases
% all HPV cancer
Cervix
492,800
100
492,800
93.5
>70
344,900
Vulva, vagina
40,000
40*
16,000
3
80
12,800
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
Site
Total
527,100
%
Cases
374,600
30/04/2014 12 Adapted from Parkin DM & Bray F. Vaccine 2006; 24(Suppl 3):S11–S25; Walboomers JMM, et al. J Pathol 1999; 189:12–19.
Natural History of Cervical Cancer
------------------- 3-17 tahun -----------------------
Mild dysplasia
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Moderate dysplasia
Severe dysplasia
Insitu Carcinoma
Invasive Cancer
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How does HPV cause cancer in the cervix?
Shedding of virus-laden epithelial cells
Cervical canal
Viral assembly (L1, L2, E4)
Mature squamous layer
Viral DNA replication (E6 & E7)
Squamous layer
Parabasal cells
Episomal viral DNA in cell nucleus (E1 & E2, E6 & E7)
Basal (stem) cells
Infection of basal cells (E1 & E2)
Basement membrane
Normal epithelium
30/04/2014 Frazer IH. Nat Rev Immunol 2004; 4:46–54.
Infected epithelium 14
Disease progression
Normal epithelium
Years
Months
Time
HPV infection; koilocytosis
CIN I
Low-grade squamous intraepithelial lesions (LSILs)
CIN II
CIN III
ICC
High-grade squamous intraepithelial lesions (HSILs)
Screening Treatment 30/04/2014
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Carcinogenesis
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Mode of transmission Oral Sex - rare Perinatal - rare Digital - rare "Outercourse" - rare Anal intercourse - often Vaginal intercourse - often
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Screening and Early Diagnosis of Cervical Cancer
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Pencegahan Kanker Serviks Kanker Serviks merupakan penyakit yang dapat dicegah Pencegahan primer Pendidikan untuk menurunkan perilaku sek risiko tinggi.Pemeriksaan untuk menurunkan/mencegah risiko terpapar virus HPV. Pencegahan sekunder Pengobatan lesi prakanker sebelum berkembang menjadi kanker serviks (melakukan tes skrining Pencegahan Tersier : menurunkan morbiditas bila telah terdiagnosa kanker serviks dengan pengobatan segera dan komprehensif 30/04/2014
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Cervical cancer prevention methods
Normal cervix/ Sub-clinical HPV infection1
CIN 12
CIN 22
CIN 33
HPV vaccines:
Cervical screening (VIA, Pap smear, HPV testing):
Primary prevention
Secondary prevention
ICC3
Treatment
Treatment 1. Image used with permission from Professor Achim Schneider; 2. Image used with permission from Professor Muhieddine20 30/04/2014 Seoud; 3. GSK Image Library
Deteksi Dini Kanker Serviks
1.Tes skrining 2.Tes pelengkap 3.Tes diagnostik 30/04/2014
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TES Skrining Pap smear
Pemeriksaan sitologi eksfoliatif dari epitel serviks untuk mendeteksi lesi prakanker secara dini IVA (Inspeksi Visual dengan Asam Asetat)
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TES Pelengkap
Tes HPV DNA TES Diagnostik Kolposkopi Biopsi 30/04/2014
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Apakah Pemeriksaan Sitologi/Pap Sitologi /Pap Smear itu ? Pap Smear atau Pap Test adalah pemeriksaan sitologi untuk skrining atau deteksi Kanker Leher Rahim yang dilakukan dengan cara melihat adanya perubahan morfologi sel sel--sel leher rahim dengan teknik pewarnaan Papanicolau kemudian diamati di bawah mikroskop oleh seorang ahli Patologi Anatomi
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PAP Smear
1. Usapan spatula Eyre pada ektoserviks dulu, Pulas di kaca benda 2. Usapan “Cytobrush” pada endoserviks, Pulas di kaca benda 3. Rendam kaca benda dalam alkohol 96%, minimal 30’ 30/04/2014
2).
1).
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PAP Smear Persentase transfer sel epitel pada kaca benda berdasarkan variasi alat
6,5 % dengan kapas lidi / spatula 8,4 % dengan cytobrush 18,1 % gabungan cytobrush dengan spatula
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PAP Smear
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PAP Smear
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PAP Smear Kelebihan Thin Prep / LBC / SSBC • Menurunkan angka negati palsu dan positif palsu • Menurunkan angka Kesalahan interpretasi • Meningkatkan akurasi Tes Pap • Mengurangi kelelahan skriner
Kekurangan Thin Prep • Harga mahal
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Padanan dari Klasifikasi Papanicolao Smear Class I
Class II
Normal
Inflam
Normal
WNL
Mild
NEGATIF
Mod
Dysplasia CIN I
Atypia Benign Cellular Changes
Class III
CIN II
Koilocytosis
Class IV Sev CIS
Class V Cancer
CIN III
Cancer
AS CUS
LGSIL
HGSIL
HGSIL
Carcinoma
AS CUS
LGSIL
HGSIL
HGSIL
Carcinoma
IVA Test
INSPEKSI VISUAL dengan ASAM ASETAT (IVA ) Alternatif skrining Non –invasif Mudah-murah Di Puskesmas Hasil LANGSUNG Sensitivitas,spesifisitas memadai
MEMADAI UNTUK NEGARA ERKEMBANG 30/04/2014
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IVA Test ALAT / BAHAN IVA • Meja pemeriksaan • Sumber cahaya yang cukup • Asam asetat 3 - 5 % • Kapas lidi • Sarung tangan bersih ( lebih baik steril) • Spekulum vagina
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Seminar IBI -322011
IVA Test
Epitel Normal
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CIN / Lesi Pra Pra--Kanker
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IVA Test • CUKA DAPUR (mengandung asam asetat 20%) • ASAM ASETAT UNTUK IVA (3-5%) • Untuk membuat asam 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
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IVA Test posisi litotomi, tampilkan serviks, nilai mencurigakan kanker, tidak perlu IVA apakah SSK tampak seluruhnya? Jika tidak tampak IVA, beri catatan, sebaiknya tes Pap SSK terlihat semua, IVA, tunggu 1 menit, apk timbul epitel putih lakukan penillaian Video 30/04/2014
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Pemulasan Asam Asetat NIS I, LSIL Sebelum
Setelah
Nabothian cyst
Epitel merah keabuan sampai kuning kemerahan
Cuffed gland opening
IVA Test
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PEMERIKSAAN HPV DNA
Pemeriksaan molekuler dengan metode “hybrid capture” / PCR untuk mendeteksi adanya DNA Human Papiloma Virus tipe “high risk” pada sampel yang diambil dari serviks 30/04/2014
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TES DIAGNOSTIK
Kolposkopi
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Clinical appearance of precancerous lesions ( CIN )
LGSIL 30/04/2014
HGSIL
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Options / suggestions therapies for CIN CIN I : Follow Up CIN I and HPV + : ??? CIN I and II : Cryosurgery E. Cautery LEEP / LLETZ
CIN III
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: LLETZ
PIT POGI XIX Jakarta 41 2011
BIOPSI
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Krioterapi IVA + Lesi derajat rendah (NIS 1 - 2 ) Lesi Derajat tinggi (NIS 3 ?)
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Elektrokauter
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2 months postpost-cauterization44
Konisasi - LEEP / LLETZ
Video 30/04/2014
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Take Home Message HPV Infection Cervical Carcinogenesis Pre-Cancer Stage gives us the opportunity to do screening and therapy, so it does not develop into invasive cancer. 30/04/2014
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Thank You 30/04/2014
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Pengobatan Kanker Serviks
• Operasi • Kemoterapi • Radioterapi
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Radikal Histerektomi
Video 30/04/2014
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Pengobatan Kanker Serviks
Robotic Surgery – Utrecth Medical Center - Netherlands 30/04/2014
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Video Robotic Surgery – Utrecth Medical Center – Netherlands, 2011 30/04/2014
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HPV Vaccination against Cervical Cancer
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Lindungi Kesehatan Wanita LINDUNGI KEHIDUPAN
Siapa yang berisiko Kanker Serviks ? 30/04/2014
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WHO statement on safety of HPV vaccines
Recipients of both the quadrivalent and bivalent HPV vaccines have reported more injection adverse events (pain, swelling, erythema) than recipients of placebo or HAV control, regardless of age Incidence of local adverse event does not vary by preprevaccination HPV infection status
30/04/2014 WHO Position Paper (April 2009); Available at: www.who.int/immunization/documents/positionpapers/en/index.html (Accessed 25 June 2009).
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Vaccine : prevention at the site of infection HPV
Neutralizing antibody
• Vaccination induces serum Cervical canal antibodies • High serum antibody levels correlate with high antibody levels Cervical epithelium at the site of infection1 Blood vessel • Antibodies neutralize the virus Epithelial tear and prevent viral entry into cells2,3 Basement membrane
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. 30/04/2014 J Infect Dis 2009; 200:166–171.
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Sexual exposure Yes
No
Screening based on local guidelines Vaccination • HPV vaccination is best administered prior to sexual debut • Vaccination can also be recommended to healthy older women who are already sexually active
(not mandatory prior to vaccination)
Negative
Vaccination
• Vaccination is also recommended for women who have cleared a prior HPV infection 30/04/2014
Positive
Manage according to local guidelines
Vaccination as appropriate 57
Basu P, et al. J Obstet Gynaecol Res 2009; in press.
Recommendations on HPV vaccination from the Asian Cervical Cancer Prevention Advisory Board (ACCPAB)
WHO HPV vaccination recommendations
"WHO recognizes the importance of cervical cancer and other HPV--related disease as global health problems and HPV recommends that routine HPV vaccination should be included in national immunization program.
WHO 30/04/2014 Position Paper (April 2009); Available at: www.who.int/immunization/documents/positionpapers/en/index.html (Accessed 25 June 2009).
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Take Home Message
SPSS 30/04/2014
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www.indocancer.com www.doctorhandsbook.com
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