DALAM MENENTUKAN DERAJAT DIFFERENSIASI DAN PROGNOSA ADENOKARSINOMA

EKSPRESI p53 MUTAN DALAM MENENTUKAN DERAJAT DIFFERENSIASI DAN PROGNOSA ADENOKARSINOMA KOLOREKTAL DI LABORATORIUM PATOLOGI ANATOMI RSUP HAJI ADAM MALIK MEDAN

TESIS YESSI DEVITA AZRAINI DEWI NIM. 107108004

DEPARTEMEN PATOLOGI ANATOMI FAKULTAS KEDOKTERAN UNIVERSITAS SUMATERA UTARA MEDAN 2014

Universitas Sumatera Utara

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EKSPRESI p53 MUTAN DALAM MENENTUKAN DERAJAT DIFFERENSIASI DAN PROGNOSA ADENOKARSINOMA KOLOREKTAL DI LABORATORIUM PATOLOGI ANATOMI RSUP HAJI ADAM MALIK MEDAN

TESIS

UntukMemperolehGelarSpesialisPatologiAnatomi Dalam Program PendidikanDokterSpesialis I PadaFakultasKedokteranUniversitas Sumatera Utara

YESSI DEVITA AZRAINI DEWI NIM. 107 108 004

PROGRAM PENDIDIKAN DOKTER SPESIALIS I DEPARTEMEN PATOLOGI ANATOMI FAKULTAS KEDOKTERAN UNIVERSITAS SUMATERA UTARA MEDAN 2014


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Judul Penelitian

: Ekspresi p53 MutanDalamMenentukanDerajatDiffrensiasi Dan PrognosaAdenocarcinoma colorectal di LaboratoriumPatologiAnatomi RSUP Haji Adam Malik Medan

Nama

: YessiDevitaAzrainiDewi

NIM

: 107 108 004

Program Studi

: Program Pendidikan Dokter Spesialis

Konsentrasi

: Patologi Anatomi

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. T.IbnuAlferraly, M.Ked(PA),Sp.PA, D.Bioet NIP. 196202121989111 001 Ketua Program Studi PatologiAnatomi

KetuaDepartemen

FK USU

PatologiAnatomi FK USU

dr. H. Delyuzar, M.Ked(PA), Sp.PA(K)

dr. T.IbnuAlferraly, M.Ked(PA),Sp.PA, D.Bioet

NIP. 196302191990031 001

NIP. 196202121989111 001


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LEMBAR PANITIA UJIAN

JudulPenelitian

: Ekspresi p53 MutanDalamMenentukanDerajatDiffrensiasi Dan Prognosaadenokarsinomakolorektaldi LaboratoriumPatologiAnatomi RSUP Haji Adam Malik Medan

Nama

: YessiDevitaAzrainiDewi

NIM

: 107 108 004

Program Studi

: ProgramPendidikanDokterSpesialisDepartemenPato logiAnatomiFakultasKedokteranUniversitas Sumatera Utara

Diujipada Hari/Tanggal

: Rabu/21Mei 2014

Pembimbing

: 1. Prof. Dr. HM. Nadjib D. Lubis, Sp.PA(K) 2. Dr.H.T.IbnuAlferrally,M.Ked.(PA),Sp.PA,D.Bioet

Penguji

: 1. dr. H. Delyuzar, M.Ked(PA), Sp.PA(K) 2. dr. H. Joko S. Lukito, Sp.PA(K)


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PERNYATAAN EKSPRESI p53 MUTAN DALAM MENENTUKAN DERAJAT DIFFERENSIASI DAN PROGNOSA ADENOKARSINOMA KOLOREKTALDI LABORATORIUM PATOLOGI ANATOMI RSUP HAJI ADAM MALIK MEDAN

TESIS

Dengan ini saya menyatakan bahwa dalam tesis ini tidak terdapat karya yang Pernah diajukan untuk memperoleh gelar kesarjanaan di suatu perguruan tinggi, Dan sepanjang pengetahuan saya juga tidak terdapat karya atau pendapat yang pernah ditulis atau diterbitkan oleh orang lain, kecuali yang secara tertulis diacu dalam naskah ini dan disebutkan dalam daftar pustaka.

Medan, 6 Mei 2014 Peneliti

Yessi Devita Azraini Dewi NIM : 107 108 004


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DAFTAR ISI Halaman LEMBAR PERSETUJUAN ................................................................................. ii LEMBAR PANITIA UJIAN ............................................................................... iii SURAT PERNYATAAN BEBAS PLAGIARISME ......................................... iv DAFTAR ISI ...........................................................................................................v DAFTAR GAMBAR .......................................................................................... viii DAFTAR TABEL ................................................................................................ ix DAFTAR SINGKATAN ........................................................................................x ABSTRAK ........................................................................................................... xii BAB I. PENDAHULUAN ......................................................................................1 1.1. Latar Belakang ...........................................................................................1 1.2. Perumusan Masalah ...................................................................................3 1.3. Hipotesis ....................................................................................................3 1.4. Tujuan Penelitian .......................................................................................3 1.4.1. Tujuan Umum ...................................................................................3 1.4.2. Tujuan Khusus ..................................................................................4 1.5. Manfaat Penelitian .....................................................................................4 BAB II. TINJAUAN PUSTAKA ...........................................................................5 2.1. Kolon (UsusBesar) .....................................................................................5 2.1.1. Anatomi dan Histologi .....................................................................5 2.1.2. FungsiKolon .....................................................................................7 2.2. Karsinoma Kolon .......................................................................................7 2.2.1. Epidemiologi ....................................................................................7 2.2.2. Etiologi .............................................................................................8 2.2.3. GejalaKlinis ....................................................................................10 2.2.4. DeteksiDini .....................................................................................11 2.2.5. Patogenesa ......................................................................................12 2.2.6. Gambaran Mikroskopis Karsinoma Kolorektal..............................15 2.2.6.1.Adenocarcinoma ......................................................................15 2.2.6.2.Mucinous adenocarcinoma ......................................................16


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2.2.6.3.Signet ring cell rcinoma ...........................................................17 2.2.6.4.Adenosquamous carcinoma .....................................................18 2.2.6.5.Medullary carcinoma ...............................................................19 2.2.6.6.Undifferentiated carcinoma .....................................................19 2.2.6.7.Squamous cell carcinoma ........................................................20 2.2.6.8.Small cell carcinoma ................................................................21 2.3. Gen p53 ....................................................................................................22 2.4. Immunohistokimia p53 ............................................................................29 2.5. KerangkaTeori .........................................................................................32 2.6. KerangkaKonsep ......................................................................................33

BAB III. METODE PENELITIAN ....................................................................34 3.1. Metode Rancangan Penelitian..................................................................34 3.2. Tempat dan WaktuPenelitian ...................................................................34 3.2.1. Tempat Penelitian...........................................................................34 3.2.2. Waktu Penelitian ............................................................................34 3.3. Subjek Penelitian .....................................................................................35 3.3.1. Populasi ..........................................................................................35 3.3.2. Sampel ............................................................................................35 3.4. Jumlah Sampel .........................................................................................35 3.5. Kriteria Penelitian ....................................................................................36 3.5.1. Kriteria Inklusi ...............................................................................36 3.5.2. Kriteria Eksklusi.............................................................................37 3.6. Variabel Penelitian ...................................................................................37 3.6.1. Variabel Bebas / Independent ........................................................37 3.6.2. Variabel Tergantung / Dependent ..................................................37 3.7. Kerangka Operasional ..............................................................................38 3.8. Definisi Operasional ................................................................................39 3.9. Cara Kerja ................................................................................................41 3.9.1. Pembuatan Sediaan Mikroskopis ...................................................41 3.9.2. Tatacara Pulasan Antibody Primer .................................................42 3.9.3. Tatacara Perwarnaan Immunohistokimia p53................................43


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3.10. Alat dan Bahan .........................................................................................44 3.10.1. Alat Penelitian ................................................................................44 3.10.2. Bahan Penelitian.............................................................................44 3.11. Instrumen Penelitian ................................................................................46 3.12. Analisa Data .............................................................................................46 BAB IV HASIL DAN PEMBAHASAN PENELITIAN .......................................47 4.1.HasilPenelitian ...........................................................................................47 4.1.1. Distribusi Penderita Adenokarsinoma Kolorektal Berdasarkan Usia ...........................................................................47 4.1.2. Distribusi Penderita Adenokarsinoma Kolorektal Berdasarkan Jenis Kelamin ............................................................48 4.1.3. Distribusi Penderita Adenokarsinoma Kolorektal Berdasarkan Lokasi Jaringan .........................................................49 4.1.4. Distribusi Penderita Adenokarsinoma Kolorektal Berdasarkan Grading Histopatologi ..............................................49 4.1.5. Distribusi Penderita Adenokarsinoma Kolorektal Berdasarkan Tampilan p53 Mutan .................................................50 4.2.Uji Statistik ................................................................................................51 4.3.Pembahasan ................................................................................................54 BAB V KESIMPULAN .........................................................................................56 5.1.Kesimpulan ................................................................................................56 5.2.Saran ...........................................................................................................57 DAFTAR PUSTAKA ...........................................................................................58


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DAFTAR GAMBAR Gambar Halaman 2.1.

Anatomi Usus Besar .....................................................................................5

2.2.

Lapisan Pada Usus Besar .............................................................................6

2.3.

Classic Adenocarcinoma Sequence ............................................................13

2.4.

Microsatelite Instability Pathway ..............................................................14

2.5.

Well differentiated adenocarcinoma colon ................................................15

2.6.

Moderate differentiated adenocarcinoma colon ........................................15

2.7.

Poorly differentiated adenocarcinoma colon .............................................16

2.8.

Undifferentiated carcinoma colon .............................................................16

2.9.

Mucinous Adenocarcinoma ........................................................................17

2.10. Signet Ring Cell Carcinoma .......................................................................17 2.11. Adenosquamous Carcinoma .......................................................................18 2.12. Medullary Carcinoma ................................................................................19 2.13. Undifferentiated Carcinoma ......................................................................20 2.14. Squamous Cell Carcinoma .........................................................................21 2.15. Small Cell Carcinoma ................................................................................22 2.16. Peran Gen p53 Pada Proses SiklusSel ........................................................26 2.17. Nuclear Staining Protein p53 .....................................................................30 2.18. p53 Staining Score (0) ................................................................................30 2.19. p53 Staining Score (1+)..............................................................................31 2.20. p53 Staining Score (2+)..............................................................................31 2.21. p53 Staining Score (3+)..............................................................................31


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DAFTAR TABEL TabelHalaman 4.1.

DistribusiPenderitaAdenokarsinomaKolorektalBerdasarkanUsia .............47

4.2.

DistribusiPenderitaAdenokarsinomaKolorektalBerdasarkan JenisKelamin ..............................................................................................48

4.3.

DistribusiPenderitaAdenokarsinomaKolorektalBerdasarkan LokasiJaringan ...........................................................................................49

4.4.

DistribusiPenderitaAdenokarsinomaKolorektalBerdasarkan GradingHistopatologi.................................................................................50

4.5.

DistribusiPenderitaAdenokarsinomaKolorektalBerdasarkan Tampilan p53 Mutan ..................................................................................50

4.6.

Crosstab 4x3 Tampilan p53 MutandenganGrading

HistopatologiAdenokarsinomaKolorektal……………………………....51 4.7.


HistopatologiAdenokarsinomaKolorektal..............................................................52 4.8.


HistopatologiAdenokarsinomaKolorektal..............................................................53


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DAFTAR SINGKATAN ACS

: American Cancer Society

APC

: Antigen Presenting Cell

CA

: Carbohydrate Antigen

CEA

: Carcino Embryonic Antigen

CT-Scan

: Computed Tomography-Scan

DNA

: Deoxyribo Nucleic Acid

FAP

: Familial Adenomatous Polyposis

HNPCC

: Hereditary Non Polyposis Colon Cancer

IBD

: Inflammatory Bowel Disease

MRI

: Magnetic Resonance Imaging

USG

: Ultrasonography

LOH

: Lost Of Heterozigocity

LOE

: Lost Of expresion

WHO

: World Health Organization

SMAD 2

: Smooth muscle actin +Mothers Against

Decapentaplegic homolog 2 MLH 1

: MutL Homolog 1

MSH

: MutS Homolog

PMS

: Post Meotic Segregation increased

TCF-4

: Transcription factor 4

IGF2R

: Insulin-like growth factor 2 Receptor

PBS

: Phosphate Buffer Saline

DAB

: 4-dimethylaminoazobenzene


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PAb

: p53 Antibody

IHK

: Immunohistokimia

SPSS

: Statistical Package for the Social Science

SEER

: Surveillance Epidemiology and Results


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ABSTRAK

Latar Belakang. Kanker merupakan problem penting bagi kesehatan masyarakat diseluruh dunia terutama pada negara-negara berkembang. Sekitar sepuluh juta kasus baru didiagnosa setiap tahunnya. Angka kejadian adenokarsinoma kolon ditemukan lebih banyak pada laki-laki daripada perempuan. Berdasarkan World Health Organization 90% kasuskarsinoma kolorektal tipe adenokarsinoma. Penyebabnya hilang fungsi dari tumor supresor gen p53. Mutasi, delesi kecil dan insersi dapat menyebabkan kerusakan fungsi protein secara total maupun parsial. Over ekspresi p53 mutan berhubungan dengan grading histologi dari karsinoma kolorektal dan cenderung lebih sering pada karsinoma kolorektal yang aktivitas proliferasinya tinggi. Tujuan. Untuk mengetahui ekspresi p53 mutan dalam menentukan derajat differensiasi dan prognosa adenokarsinoma kolorektal di Laboratorium Patologi Anatomi RSUP Haji Adam Malik Medan Metode. Penelitian ini menggunakan rancangan observasional dengan melakukan pendekatan cross sectional. Sampel penelitan ini adalah sediaan blok parafin dari 59 jaringan karsinoma korektal yang didiagnosa sesuai dengan kriteria inklusi. Semua variabel diwarnai dengan immunohistokimia p53 mutan. Hasil. Distribusi terbanyak penderita karsinoma kolorektal berdasarkan; kelompok usia 60 tahun sebanyak 24 kasus (40.68%), jeniskelamin; laki-laki sebanyak 36 kasus (61.02%), lokasi jaringan; colon sebanyak 36 kasus (61.02%), grading adenokarsinoma ; well differentiated adenocarcinoma sebanyak 27 kasus (45.76%) dan berdasarkan tampilan p53 mutan yang terbanyak adalah skor +1 (lemah): 35 kasus (59,32%). Perhitungan fisher exact dengan tabel crosstab 2x2 bahwa p value= 0,427 (p value> 0,05). Kesimpulan. Tidak ada perbedaan ekspresi p53 mutan dengan grading histopatologi pada adenokarsinoma kolorektal. Kata kunci: adenokarsinoma, karsinoma kolorektal, immunohistokimia p53mutan Kata kunci: adenokarsinoma, karsinomakolorektal, immunohistokimia p53


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ABSTRACT Background : Cancer is important problem in public health worldwide especially in developed countries. About 10 millions new cases was diagnosed every year. Colorectal carcinoma is more common in man than woman. Despite significant advances in both surgical methodology and adjuvant therapy regimes, long-term survival for CRC patients remains in the range of 50-60%. Based on WHO, 90 % colorectal carcinoma was adenocarcinoma. Colorectal carcinoma is caused by a collection of various genetic changes and the most common cause is a loss of function of the p53 tumor suppressor gene. P53 tumor suppressor gene plays an important role in cell cycle and apoptosis. This gene encodes for a 53 Daphosphoprotein and is frequently targeted for inactivation in a wide range of tumours. It is the target of point mutations and small deletions and insertions that lead to total or partial abolition of protein function. Inactivation is believed to abolish the ability of p53 to maintain genomic integrity through regulation of various activities, including the control of cell cycle arrest, DNA repair and apoptosis.. Accumulation of p53 in tumor cells can be detected with a specific p53 antibody. Mutation on p53 gen and over ekspression of p53 is common incolorectal carcinoma tissue then p53 mutant and p53 wild type can be targeted by p53 specific antibody. P53 overexpression associated with colorectal carcinoma histologycal grade and tend more common in colorectal carcinoma with high proliferation activity. Objective : To assess p53 mutan expression in determining differentiation grade and prognose adenocarcinoma colorectal and the prognose of adenocarcinoma colorectal at Anatomic Pathology laboratory of RSUP Haji Adam Malik Medan. Methods :The study designwasobservationaldesignwithcross sectionalapproach. All variables were immunohistochemically stained with p53 mutant. The variables were measured only oncean datone moment. The samples usedin this study were the sample preparation of paraffin blocks from 59 colorectal carcinoma tissues which diagnosed patologically according inclusion criteria. All variables were immunohistochemically stained with p53 mutant. Results :Distribution ofpatientsby age group mostly aged over 60 years which is 24 cases (40.68%). Distribution ofpatients by sex mostly male which is 36 cases (61.02%). 36 cases (61,02%) were located on colon. The majority, 27 cases (45,76%) were diagnosed aswell differentiated adenocarcinoma. Colorectal carcinoma samples based on p53 mutant expression were score+1(weak) were 35 cases (59,32%). Calculation ofchi-square with 2x2 crosstabtable, p value=0.427(p value>0.05). Conclusion. No difference between p53 mutant expression with histopathological grade incolorectal adenocarcinoma. Key world: adenocarcinoma, carcinoma colorectal, p53 immunohistochemistry.


DALAM MENENTUKAN DERAJAT DIFFERENSIASI DAN PROGNOSA ADENOKARSINOMA

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