Ekspresi Imunohistokimia Interferon Gamma dan Interleukin-4 pada tumor-tumor jinak dan ganas epitel ovarium tipe Serosum dan Musinosum
INTERLEUKIN-4 PADA TUMOR-TUMOR JINAK DAN GANAS EPITEL OVARIUM TIPE SEROSUM DAN MUSINOSUM TESIS Oleh: AINUN MARDIAH NIM 08718004 PROGRAM DOKTER SPESIALIS DEPARTEMEN PATOLOGI ANATOMI FAKULTAS KEDOKTERAN USU/RSUP H. ADAM MALIK MEDAN 2013
INTERLEUKIN-4 PADA TUMOR-TUMOR JINAK DAN GANAS EPITEL OVARIUM TIPE SEROSUM DAN MUSINOSUM TESIS Untuk Memperoleh Gelar Spesialis Patologi Anatomi Dalam Program Pendidikan Dokter Spesialis Patologi Anatomi Pada Fakultas Kedokteran Universitas Sumatera Utara AINUN MARDIAH 087108004 PROGRAM DOKTER SPESIALIS DEPARTEMEN PATOLOGI ANATOMI FAKULTAS KEDOKTERAN USU/RSUP H. ADAM MALIK MEDAN 2013
Judul Penelitian : Ekspresi Imunohistokimia Interferon Gamma dan Interleukin-4 pada tumor-tumor jinak dan ganas epitel ovarium tipe Serosum dan Musinosum Nama : Ainun Mardiah NIM : 087108004 Program Studi : Program Pendidikan Dokter Spesialis Departemen Patologi Anatomi Fakultas Kedokteran Sumatera Utara
TESIS INI TELAH DIPERIKSA DAN DISETUJUI OLEH :
Pembimbing I
Prof. Dr. HM. Nadjib D. Lubis, Sp.PA(K)NIP. 130 318 033
Pembimbing II
dr. H. Delyuzar, M.Ked(PA), Sp.PA(K) NIP. 19630219 199003 1 001 Ketua Program Studi Ketua Departemen Patologi Anatomi FK USU Patologi Anatomi FK USU
Dr. H. Delyuzar, M.Ked (PA), Sp.PA Dr. T. Ibnu Alferraly, M. Ked (PA), Sp.PA,D. Bioet
NIP. 19630219 199003 1 001 NIP. 19620212 198911 1 001 Tanggal Lulus : 13 November 2013Judul Penelitian : Ekspresi Imunohistokimia IFN- γ dan IL-4 pada tumor-tumor jinak dan ganas epitel ovarium tipe serosum dan musinosum Akan diuji pada Hari/ Tanggal : Jum’at, 15 November 2013 Pembimbing : 1. Prof. dr. H.M.Nadjib Dahlan Lbs, Sp.PA(K) 2. dr. H.Delyuzar, M.Ked.PA, Sp.PA(K) Penguji : 1. dr. H.Soekimin, Sp.PA(K) 2. dr. Jamaluddin Pane, Sp.PA
Halaman
Lembar Persetujuan ...................................................................................................... i Lembar Usulan Penelitian ............................................................................................ ii Daftar Isi...................................................................................................................... iii Daftar Tabel ............................................................................................................... vi Daftar Gambar ............................................................................................................ vii Daftar Singkatan.......................................................................................................... ix Abstrak ........................................................................................................................ x Abstract ....................................................................................................................... xi
Bab 1. Pendahuluan ...................................................................................................... 1
1.1. Latar Belakang .............................................................................................. 1
1.2. Perumusan Masalah ...................................................................................... 2
1.3. Hipotesis ........................................................................................................ 2
1.4. Tujuan Penelitian .......................................................................................... 3
1.4.1. Tujuan Umum ..................................................................................... 3
1.4.2. Tujuan Khusus .................................................................................... 3 1.5.
Manfaat Penelitian ........................................................................................ 3
2.1. Anatomi Dan Histologi Ovarium .................................................................. 4
2.2. Epidemiologi ................................................................................................. 6
2.3. Etiologi dan Faktor Resiko ........................................................................... 7
2.4. Patogenesis .................................................................................................... 7
2.5. Gejala Klinis .................................................................................................. 8
2.6. Deteksi Dini Karsinoma Ovarium ................................................................. 8
2.7. Klasifikasi ..................................................................................................... 9
Bab 2. Tinjauan Pustaka ............................................................................................... 4
2.9. Stadium Klinis ............................................................................................. 11
3.1. Desain Penelitian ......................................................................................... 21
3.6. Variabel Penelitian ....................................................................................... 24
3.5. Kerangka Operasional ................................................................................. 23
3.4.2. Kriteria Eksklusi ................................................................................ 23
3.4.1. Kriteria Inklusi .................................................................................. 23
3.4. Kriteria Inklusi Dan Eksklusi ...................................................................... 23
3.3.2. Besar Sampel ..................................................................................... 22
3.3.1. Populasi ............................................................................................. 21
3.3. Populasi dan Besar Sampel .......................................................................... 21
3.2.2. Waktu Penelitian ............................................................................... 21
3.2.1. Tempat Penelitian .............................................................................. 21
3.2. Tempat dan Waktu Penelitian ...................................................................... 21
Bab 3. Metode Penelitian ........................................................................................... 21
2.10. Grading ...................................................................................................... 12
2.16. Kerangka Konsep ...................................................................................... 20
2.15. Interleukin-4 .............................................................................................. 19
2.14. Inteferon Gamma ....................................................................................... 17
2.13.2.2. Tumor Ganas Musinosum ...................................................... 16
2.13.2.1. Tumor Jinak Musinosum ....................................................... 15
2.13.2. Tumor Musinosum .......................................................................... 15
2.13.1.2. Tumor Ganas Serosum ........................................................... 14
2.13.1.1. Tumor Jinak Serosum ............................................................ 13
2.13.1. Tumor Serosum ............................................................................... 13
2.13. Tumor Epitel Ovarium .............................................................................. 13
2.12. Penatalaksanaan ........................................................................................ 12
2.11. Prognosa .................................................................................................... 12
3.6.1. Variabel Bebas ................................................................................... 24
3.7. Defenisi Operasional .................................................................................... 24
3.8. Cara Kerja .................................................................................................... 25
3.8.1. Pembuatan Sediaan Mikroskopis ....................................................... 26
3.8.2. Prosedur sebelum pulasan antibodi primer ........................................ 26
3.8.3. Protokol Pulasan Imunohistokimia .................................................... 27
3.9. Alat dan Bahan ............................................................................................. 28
3.9.1. Alat-alat Penelitian ............................................................................ 28
3.9.2. Bahan Penelitian ................................................................................ 28
3.10. Instrumen Penelitian .................................................................................. 30
3.11. Analisa Data ............................................................................................... 31
Bab 4. Hasil Penelitian dan Pembahasan .................................................................. 32
4.1. Hasil Penelitaian.......................................................................................... 32
4.1.1. Deskripsi Karakteristik Sampel................................................................ 32
4.1.2. Hasil Pewarnaan Imunohistokimia .......................................................... 33
4.2. Pembahasan ................................................................................................. 38
Bab 5. Kesimpulan dan Saran .................................................................................... 41 Daftar Rujukan ........................................................................................................... 42 Lampiran............ ........................................................................................................ 46
Gambar
Halaman 1.
Anatomi Ovarium……………………………………………………………..4 2. Alat Reproduksi Wanita……………………………………………………... 4 3. Skema…………………………………………………………………………5 4. Folikel Grafian……………………………………………………………… ..6 5. Korpus Luteum…………………………………………………………….. 6 6. Makroskopis Kistadenoma Serosum………………………………………...11 7. Mikroskopis Kistadenoma Serosum…………………………………………15 8. Makroskopis Kistadenokarsinoma Serosum…………………………………15 9. Mikroskopis Kistadenokarsinoma Serosum…………………………………16 10.
Makroskopis Kistadenoma Musinosum……………………………………..16 11. Mikroskopis Kistadenoma Musinosum……………………………………...16 12. Tumor Ganas Musinosum…………………………………………………...16 13. Mikroskopis Gambaran Kelenjar Tumor Ganas Musinosum………………..17 14. Jalur Resmi IFN-γ…………………………………………………………...17 15. Skema IFN-γ………………………………………………………………...18
Tabel Halaman 1.
Klasifikasi Tumor Ovarium Menurut WHO…………………………………10 2. Stadium Klinis Tumor Ovarium Menurut FIGO……………………….........11 3. Grading Tumor Epitel Ovarium……………………………………………...12 4.
Tabel 4.1 Distribusi Frekuensi Karakteristik Penderita tumor jinak dan ganas epitel ovarium tipe serosum dan musinosum berdasarkan usia……………...325. Tabel 4.2 Persentase tampilan imunohistokimia IL-4 pada jenis tumor…….33 6.
Tabel 4.3 Persentase tampilan imunohistokimia IFN-γ pada jenis tumor……………………………………………………………………….. 347. Tabel 4.4 Skor tampilan imunohistokimia IL-4 pada jenis tumor………… 35 8.
Tabel 4.5 Skor tanpilan imunohistokimia IFN-γ pada jenis tumor………….36 9.Tabel 4.6 Hubungan jenis tipe tumor serosum jinak dan ganas dengan ekspresiIL-4 …………………………………………………………………………..38 10.
Tabel 4.7 Hubungan jenis tipe tumor musinosum jinak dan ganas dengan ekspresi IL-4…………………………………………………………………3911. Tabel 4.8 Hubungan jenis tipe tumor serosum jinak dan ganas dengan ekspresi
IFN- γ…………………………………………………………………………40
12. Tabel 4.9 Hubungan jenis tipe musinosum jinak dan ganas dengan ekspresi
IFN- γ…………………………………………………………………………41 BRCA-1 : Breast Cancer Antigen-1 BRCA-2 : Breast Cancer Antigen-2 DAB : Diamino Benzydine DNA : Deoxyribonucleic Acid FIGO : Federation International Obstetry and Gynocology FSH : Follicle Stimulating Hormon HE : Haematoxylin Eosin IgE : Imunoglobulin-E Ig-G : Imunoglobulin-G
IL-4 ; Interleukin-4
IFN- γ
: Interferon Gamma LH : Luteinizing Hormon MET : Mixed Epithelial Tumor MHC : Major Histo Compability NK : Natural Killer PBS : Phospat Buffer Saline SMA : Smooth Muscle Actin USG : UltrasonografiWHO : World Health Organization
Ekspresi IFN- γ dan IL-4 Pada Tumor-tumor Jinak dan Ganas Epitel Ovarium
tipe Serosum dan Musinosum
Ainun Mardiah, Nadjib Dahlan Lubis, Delyuzar Departemen Patologi Anatomi Fakultas Kedokteran Sumatera Utara
ABSTRAK
Latar Belakang: Tumor serosum dan musinosum merupakan varian dari tumor
epitel ovarium. IFN-
γ hubungannya dengan tumor mempunyai aktifitas anti
proliferasi tetapi pada keadaan tertentu IFN-
γ mempunyai efek anti apoptosis
terhadap sel tumor ovarium manusia. Sebenarnya terapi IFN-
γ seperti pedang bermata
dua yang mempunyai aktifitas anti dan protumorigenic, tergantung pada keadaan selular, lingkungan mikro, dan / atau konteks molekul. Sitokin IL-4 berperan sebagai anti apoptosis. Tujuan penelitian ini adalah melihat perbedaan ekspresi IFN-
γ dan IL- 4 pada tumor jinak dan ganas epitel ovarium tipe serosum dan musinosum.
Metode: Penelitian ini merupakan penelitian deskriptif analitik dengan pendekatan
cross sectional pada 40 sampel jaringan tumor jinak dan ganas serosum dan
musinosum, kemudian dilakukan pemeriksaan imunohistokimia dengan antibodi IFN- γ dan IL-4 pada masing-masing tumor (n=10).
Hasil: Pada penelitian ini IL-4 menunjukkan ekspresi positif sebanyak 60% (n=6)
dan negatif 40% (n=4) pada tumor jinak serosum, sedangkan pada tumor ganas serosum menunjukkan ekspresi positif 90% (n=9) dan negatif 10% (n=1). Pada tumor jinak musinosum IL-4 menunjukkan ekspresi positif 40% (n=4) dan negatif 60% (n=6), sedangkan pada tumor ganas musinosum seluruhnya menunjukkan ekspresi positif (100%). IFN-
γ menunjukkan ekspresi positif sebanyak 50% (n=5) dan negatif
50% (n=5) pada tumor jinak serosum, sedangkan tumor ganas serosum menunjukkan ekspresi positif 40% (n=4) dan negatif 60% (n=6). Pada tumor jinak musinosum IFN-
γ menunjukkan ekspresi positif 60% (n=6) dan negatif 40% (n=4), sedangkan pada
tumor ganas musinosum menunjukkan ekspresi positif 80% (n=80) dan negatif 20% (n=2).
Kesimpulan: Terdapat perbedaan ekspresi IFN- γ dan IL-4 pada tumor jinak dan ganas epitel ovarium serosum dan musinosum.
Kata Kunci: imunohistokimia, IFN- γ, IL-4, tumor epitel ovarium, tumor serosum, tumor musinosum.
Background: Serous and mucinous tumors are variant of epithelial ovarian tumors. IFN - γ associated with anti-proliferative activity of the tumor, but in the spesific situation IFN-
γ has anti apoptosis effect against the ovarian tumor cells. Actually IFN- γ treatment is a double-
edged sword whose anti- and protumorigenic activities are dependent on the cellular,
microenvironment, and/or molecular context. The cytokines IL-4 acts as an anti-apoptotic.The purpose of this study is to view the difference expression of IFN- γ and IL-4 in benign
and malignant serous and mucinous epithelial ovarian tumors.
Methods: This study is a descriptive analytic assesment with cross-sectional approach in 40
samples of benign and malignant serous and mucinous tumors. Immunohistochemistry with
IFN - γ and IL - 4 were performed in each tumors (n=10).
Results: In this study the expression of IL-4 was positive in 60% ( n=6) and negative in 40%
(n=4) in the benign serous tumors, whereas in the malignant serous tumors was positive in 90% (n=9) and negative in 10% (n=1). In the benign mucinous tumors the expression of IL-4was positive in 40%(n=4) and negative in 60% (n= 6), whereas in the malignant mucinous
tumors was entirely positive (100%). Expression of IFN- γ was positive in 50% (n=5) and
negative in 50% (n=5) in the benign serous tumors, whereas in the malignant serous tumors was positive in 40%(n=4) and negative in 60%(n=6). In the benign mucinous tumors theexpression of IFN- γ was positive in 60%(n=6) and negative in 40%(n=4), whereas the
malignant mucinous tumors was positive in 80%(n=80) and negative in 20%(n=2).Conclusion: There is a difference expression of IFN- γ and IL-4 in benign and malignant serous and mucinous epithelial ovarian tumors.
Keywords: immunohistochemistry, IFN-
γ, IL-4, epithelial ovarian tumor, serous tumor, and mucinous tumor.